Review ArticleRadix Bupleuri A Review of Traditional Uses BotanyPhytochemistry Pharmacology and Toxicology
Fude Yang1 Xiaoxv Dong2 Xingbin Yin2 WenpingWang2 Longtai You2 and Jian Ni12
1Gansu University of Chinese Medicine Lanzhou 730000 China2School of Chinese Materia Medica Beijing University of Chinese Medicine Beijing 100102 China
Correspondence should be addressed to Jian Ni njtcm263net
Received 14 February 2017 Accepted 20 April 2017 Published 16 May 2017
Academic Editor Gail B Mahady
Copyright copy 2017 Fude Yang et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Radix Bupleuri (Chaihu) has been used as a traditional medicine for more than 2000 years in China Japan Korea and otherAsian countries Phytochemical studies demonstrated that this plant contains essential oils triterpenoid saponins polyacetylenesflavonoids lignans fatty acids and sterols Crude extracts and pure compounds isolated from Radix Bupleuri exhibited variousbiological activities such as anti-inflammatory anticancer antipyretic antimicrobial antiviral hepatoprotective neuroprotectiveand immunomodulatory effects However Radix Bupleuri could also lead to hepatotoxicity particularly in high doses and withlong-termuse Pharmacokinetic studies have demonstrated that themajor bioactive compounds (saikosaponins a b2 c and d) wereabsorbed rapidly in rats after oral administration of the extract of Radix Bupleuri This review aims to comprehensively summarizethe traditional uses botany phytochemistry pharmacology toxicology and pharmacokinetics of Radix Bupleuri reported to datewith an emphasis on its biological properties and mechanisms of action
1 Introduction
Radix Bupleuri also called ldquoChaihurdquo in Chinese is derivedfrom the dried roots of Bupleurum chinenseDC and Bupleu-rum scorzonerifolium Willd [1] As a traditional herbalmedicine Radix Bupleuri has been used widely for thetreatments of influenza fever inflammation malaria men-strual disorders and hepatitis in China Japan Korea andother Asian countries [2 3] According to ancient Chinesemedical literatures Radix Bupleuri is capable of regulatingthe exterior and interior metabolisms dispersing evil heatfrom the superficies soothing the liver and promotingyang and qi (representing ldquolife energyrdquo or ldquolife forcerdquo inTCM theories) In recent decades investigations of RadixBupleuri have focused on its biological activities includingits anti-inflammatory [4 5] anticancer [6 7] antipyretic [8]antimicrobial [9] antiviral [10] hepatoprotective [11] andimmunomodulatory effects [12] In addition Radix Bupleurialso exhibited significant effects on membrane fluidity [13]These studies have resulted in the isolation of essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols from this plant [14] Among them
triterpenoid saponins are known to be the major bioactivecompounds [15 16] Saikosaponins a and d are commonlyused as chemical standards for quality evaluation of RadixBupleuri in the current Chinese Pharmacopoeia and recentpublications However an increasing number of recentlypublished studies have reported adverse effects of RadixBupleuri The purpose of this review is to provide updatedcomprehensive information on the traditional uses botanyphytochemistry pharmacology toxicology and pharmacoki-netics of Radix Bupleuri based on scientific literatures inthe past few decades This study will facilitate exploringthe therapeutic potential of this plant and evaluate futureresearch opportunities
2 Traditional Uses
Radix Bupleuri which is characterized by a wide spectrumof biological and pharmacological effects has been used asa famous traditional Chinese medicinal herb with a historyof medical use in China According to TCM theory RadixBupleuri is thought to regulate the exterior and interior
HindawiBioMed Research InternationalVolume 2017 Article ID 7597596 22 pageshttpsdoiorg10115520177597596
2 BioMed Research International
metabolisms disperse evil heat from superficies sooth theliver and promote yang and qi [1]Radix Bupleuriwas initiallyrecorded in Shennong Bencao Jing a famous monograph oftraditional Chinese medicine written in China in 200 AD[17] According to a record of traditional Chinese medicinedated 2000 years ago Radix Bupleuri had mainly been usedfor the treatment of mouth-bitterness throat-drying andeyes-dazzling In other monographs of Materia Medica suchas Jin Kui Yao Lue Kaibao Bencao Bencao Gangmu andXinbian Bencao this plant was described to be used for thetreatment of common cold with fever influenza hepatitismalaria menoxenia and hyperlipidemia [18] CurrentlyRadix Bupleuri exerts other pharmacological effects suchas balancing different organs and energies within the bodystrengthening the action of the digestive tract improving liverand circulatory system function and relieving liver tension[19] Therefore it is also used as a popular tonic herb inChina In Korea and Japan this plant is commonly used forthe treatment of fever pain and inflammation associatedwith influenza and the common cold [20] In addition thisplant is also used as analgesics in the treatment of distendingpain in the hypochondriac region of the chest and againstamenorrhoea
Radix Bupleuri is combined with other herbs in manyclassical formulas to improve clinical effect Xiaoyaosan(XYS) a well-known formula for relieving depression isoriginated from the book of ldquoTaiping Huimin Heji Jufangrdquo inSong Dynasty (960ndash1279 AD) consisting of Radix BupleuriRadix Angelicae Sinensis Radix Paeoniae Alba RhizomaAtractylodis Macrocephalae Poria Radix GlycyrrhizaeHerbaMenthae and Rhizoma Zingiberis Recens XYS exerts var-ious pharmacological effects including soothing the liverand improving the circulation of qi to relieve depressionFurthermore it has been commonly recognized as a safe andeffective prescription in the treatment of depressive disorder[21ndash23] The 2015 edition of the Chinese Pharmacopoeialists 97 Chinese patent medicines containing Radix Bupleuriand the compatible herbs that are more frequently describedincludeRadixGlycyrrhizaeRhizomaZingiberis RecensRadixScutellariae and Panax ginseng Table 1 lists subsets of theChinese patent drugs containing Radix Bupleuri in differentformulations Although Radix Bupleuri has been used to treatcertain diseases in ethnomedicines for thousands of yearsthis herbal medicine should be comprehensively understoodand recent information should be obtained for its clinical use
3 Botanical Characterization and Distribution
According to the Chinese pharmacopoeia Radix Bupleuri isderived from the dried roots of Bupleurum chinense DC andBupleurum scorzonerifolium Willd (Figure 1) The former isknown as ldquoBeichaihurdquo (Northern Chinese Thorowax Root)and the latter is known as ldquoNanchaihurdquo (Southern ChineseThorowax Root) due to the difference of the origin anddescription The drug is collected in spring or autumnremoved from the aerial part and soil and dried
Beichaihu As a herbaceous perennial plant Bupleurum chi-nenseDC grows to the height of 50ndash85 cm Its root is conical
taupe and approximately 6ndash20 cm in length Its stems areerect tufted and apex branched The leaves are alternate theleaf blades are broadly linear-lanceolate 4ndash7 times 06ndash08 cm insize the apex is acuminate Compound umbels are axillaryand terminal approximately 1ndash4 cm in length the bracts are0 or 2-3 linear the petals are 5 and bright yellow The fruitsare oblong brown and approximately 3mm in length Theyblossom from July to September and fruit from August toOctober This plant is widely cultivated in China Japan andKorea Moreover it grows in grasslands stream banks sunnyslopes and roadsides and other locations with altitudes of100ndash2700m [24]
Nanchaihu Bupleurum scorzonerifolium Willd is a herba-ceous perennial plant and approximately 30ndash60 cm high Itsroot is flexuose reddish brown and approximately 4ndash10 cmin length Its stems are 1ndash3 usually glabrous and apexbranchedThe leaf blades are linear or linear-lanceolate 6ndash16times 02ndash07 cm in size the apex is acuminate Compoundumbels are axillary and terminal the bracts are 1ndash3 thepetals are 5 and yellow The fruits are ellipsoid dark brownapproximately 2-3mm in length They blossom from Julyto August and fruit from August to October This plant isalso widely cultivated in East Asian countries such as ChinaJapan and Korea It grows in shrub forest margins sunnymountain slopes dry grasslands and other locations withaltitudes of 200ndash3000m [24]
There were approximately 36 Bupleurum species andvarieties in different districts and markets due to the slightlydifferent morphologic appearance of Bupleurum plantsincluding B longiradiatum Turcz with toxic ingredients andB hamiltonii Balak with very little active constituents [2526] Inevitably this situation will compromise the values ofRadix Bupleuri and even imperil the safety of the consumersUntil now several techniques have been developed to identifyand distinguish them including TLC [27] HPLC [28ndash30]HPLC-ELSD [31 32] HPLC-MS [33 34] UPLC-MS [35] andcapillary electrochromatography [36] Among thesemethodsmentioned above HPLC-ELSD is the most commonly usedanalytical method for evaluating the quality and authenticityof Radix Bupleuri The total amounts of saikosaponins a andd are used as the indicator compounds to characterize thequality of this plant with minimum contents of 03 in thePharmacopoeia of Peoplersquos Republic of China
4 Chemical Constituents
In the past few decades approximately 74 compounds havebeen isolated from Radix Bupleuri including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols Triterpenoid saponins flavonoidsand essential oil which possess multiple pharmacologicalactivities are considered as the main active ingredients ofRadix Bupleuri Their structures are shown in (Table 2)(Figures 2ndash6)
41 Volatile Compounds (Essential Oils) The essential oils ofRadix Bupleuri are regarded as one of the most important
BioMed Research International 3
Table 1 The traditional and clinical uses of Radix Bupleuri in China
Preparation name Compositions Traditional uses
Xiao Chai Hudecoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Radix Glycyrrhizae RhizomaZingiberis Recens Fructus jujubae
Curing thoracic and hypochondrium fullnessmouth-bitterness throat-drying and eyes-dazzling
Da Chai Hudecoction
Radix Bupleuri Radix Scutellariae Pinellia ternataRhizoma Zingiberis Recens Fructus jujubae FructusAurantii immaturus Radix Paeoniae Alba Rheumpalmatum
Treating diarrhea or constipation
Chaihu Guizhidecoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Radix Glycyrrhizae RhizomaZingiberis Recens Fructus jujubae Radix PaeoniaeAlba Ramulus cinnamomi
Curing fever with cold aversion restless arthralgia oflimbs and epigastric induration
Chaihu GuizhiGanjiang decoction
Radix Bupleuri Ramulus cinnamomi RhizomaZingiberis Radix Scutellariae Radix GlycyrrhizaeTrichosanthes kirilowii Ostreae Concha
Curing palpitation fullness of the upper abdomen anda bitter taste in the mouth
Chaihu plusMangxiao decoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Radix Glycyrrhizae RhizomaZingiberis Recens Fructus jujubae Natrii Sulfas
Curing thoracic and hypochondrium fullness retchingcounterflow hot flashes mouth-bitternessthroat-drying eyes-dazzling and constipation
Chaihu plus LongguMuli decoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Rhizoma Zingiberis Recens Fructusjujubae Rheum palmatum Ramulus cinnamomiOstreae Concha Os Draconis Poria cocos Minium
Curing thoracic and hypochondrium fullness difficultyin micturition and delirium
Buzhong Yiqidecoction
Radix Astragali Radix Bupleuri Panax ginseng RadixGlycyrrhizae Rhizoma Cimicifugae Radix Angelicaesinensis Atractylodis Macrocephalae Rhizoma CitriReticulatae Pericarpium
Curing prolapse of uterus prolapse of rectum uterinebleeding shortness of breath and tiredness and paletongue
Chaige Jieji decoction
Radix Bupleuri Radix Puerariae lobatae RadixGlycyrrhizae Radix Scutellariae Rhizoma et RadixNotopterygii Radix Angelicae dahuricae RadixPaeoniae Alba Radix Platycodonis Gypsum fibrosumRhizoma Zingiberis Recens Fructus jujubae
Curing mind-cold due to exogenous evils headacheand vexation and sleeplessness
Zheng Chaihu YinRadix Bupleuri Pericarpium Citri Reticulatae RadixSaposhnikovia Radix Paeoniae Rubra RadixGlycyrrhizae Rhizoma Zingiberis Recens
Curing mind-cold due to exogenous evils fever withchilliness headache and body pain
Xuefu Zhuyudecoction
Radix Angelicae sinensis Radix Rehmanniae SemenPersicae Flos Carthami Fructus Aurantii RadixBupleuri Radix Glycyrrhizae Radix PlatycodonisRhizoma Chuanxiong Radix Achyranthis BidentataeRadix Paeoniae Rubra
Treating blood pressure related symptoms caused by qistagnation and blood stasis syndrome
Shengxian DecoctionRadix Astragali Radix Bupleuri RhizomaAnemarrhenae Radix Platycodonis RhizomaCimicifugae
Curing coronary heart disease chronic congestive heartfailure vital myocarditis and myocardial ischemia
Xiaoyao san
Radix Bupleuri Radix Angelicae Sinensis RadixPaeoniae Alba Rhizoma Atractylodis MacrocephalaePoria Radix Glycyrrhizae Herba Menthae andRhizoma Zingiberis Recens
Soothing the liver and improving the circulation of qi torelieve depression
Chaihu Shugan SanRadix Bupleuri Fructus Aurantii RhizomaChuanxiong Rhizoma Cyperi Pericarpium CitriReticulatae Radix Paeoniae Rubra Radix Glycyrrhizae
Curing neurologic impairment and depression
Sini San Radix Bupleuri Fructus Aurantii Radix PaeoniaeRubra Radix Glycyrrhizae
Curing insomnia liver injury hepatitis chronic stressmodel and palmoplantar hidrosis
Tongqi San Radix Bupleuri Rhizoma Cyperi RhizomaChuanxiong Curing deafness tinnitus and stagnation of liver qi
Danzhi Xiaoyao SanRadix Bupleuri Radix Angelicae Sinensis RadixPaeoniae Alba Rhizoma Atractylodis MacrocephalaePoria Cortex Moutan Fructus Gardeniae
Curing headache menoxenia distending pain in thelower abdomen and depression
4 BioMed Research International
Table 1 Continued
Preparation name Compositions Traditional uses
Yigan Yiqi Jieyu Keli
Radix Bupleuri Fructus Aurantii Radix Paeoniae AlbaRadix et Rhizoma Salviae miltiorrhizae RadixAstragali Radix Codonopsis Ramulus cinnamomiPoria Acanthopanax senticosus (Rupr et Maxim)Harms Fructus trichosanthis Rhizoma PinelliaePreparatum and others
Curing chronic hepatitis hypochondriac pain bloatingand lassitude
Xiaorsquo er Tuire Keli
Radix Bupleuri Folium isatidis Radix Isatidis FlosLonicerae Japonicae Cortex Moutan Cape JasmineFruit Radix Scutellariae Herba Lophatheri PheretimaRhizoma paridis Radix et Rhizoma Cynanchi Atrati
Curing cold due to exogenous wind-heat in children
Dalitong Keli
Radix Bupleuri Fructus Aurantii Radix AucklandiaePericarpium Citri Reticulatae Pinelliae RhizomaPraeparatum Cum Alumine Herba Taraxaci Crataegifructus Semen Arecae Paederia scandens RadixCodonopsis Rhizoma Corydalis Massa MedicataFermentata
Curing epigastric fullness belching dry mouth andmouth pain
Bubai Keli
Fructus Psoraleae Dolichos lablab L Folium EpimediiRadix Bupleuri Radix et Rhizoma Salviaemiltiorrhizae Vigna umbellata Ohwi et Ohashi RadixSophorae Flavescentis Glycine max (L) Merr
Nourishing the spleen and warming the kidneys
Ganmao Qingre Keli
Schizonepetae Spica Radix Bupleuri Herba menthaehaplocalycis Radix Saposhnikovia Perillae FoliumRadix Puerariae lobatae Radix Platycodonis SemenArmeniacae amarum Radix Angelicae dahuricaeCorydalis bungeana Herba
Curing cold cough fever headache rhinorrhea andpharyngoxerosis
Qizhi Weitong tabletRadix Bupleuri Rhizoma Corydalis Rhizoma CyperiFructus Aurantii Radix Paeoniae Alba RadixGlycyrrhizae
Curing stagnation of liver qi abdominal distention andepigastric pain
Lidan tablet
Rheum palmatum Flos Lonicerae Japonicae HerbaLysimachiae Radix Aucklandiae RhizomaAnemarrhenae Folium isatidis Radix Bupleuri RadixPaeoniae Alba Radix Scutellariae Natrii Sulfas HerbaArtemisiae Scopariae
Curing hypochondriac pain constipation oliguria withreddish urine headache and vomiting
Ruhe Sanjie tablet
Radix Bupleuri Radix Angelicae sinensis RadixAstragali Radix Curcumae Tulipa edulis RadixRhapontici Ecklonia kurome Okam SargassumFolium Epimedii Herba Pyrolae
Curing lump in breast and mammary glandhyperplasia
Jianwei Yuyang tablet
Radix Bupleuri Radix Paeoniae Alba RadixCodonopsis Rhizoma Corydalis Bletilla striata(Thunb) Reiehb f Indigo Naturalis ConchaMargaritifera Usta
Curing dysphoria distention and loose stools andpeptic ulcer
Longdan Xiegan pill
Radix et Rhizoma Gentianae Radix Bupleuri RadixScutellariae Fructus Gardeniae Rhizoma alismatisCaulis Akebiae Semen Plantaginis Radix Angelicaesinensis Radix Rehmanniae Radix Glycyrrhizae
Curing hepatochlic hygropyrexia dizziness deafnesstinnitus and mouth-bitterness
Qingwen Jiedu pill
Radix Bupleuri Folium isatidis Fructus ForsythiaeRadix Scrophulariae Radix Trichosanthis RadixPlatycodonis Fructus Arctii Radix SaposhnikoviaRadix Puerariae lobatae Radix Scutellariae RadixAngelicae dahuricae Rhizoma Chuanxiong and others
Curing headache throat-drying and mumps
Shugan Hewei pill
Rhizoma Cyperi Radix Paeoniae Alba Fructus citriSarcodactylis Radix Aucklandiae Radix CurcumaeRhizoma Atractylodis Macrocephalae PericarpiumCitri Reticulatae Radix Bupleuri Herba PogostemonisRadix Glycyrrhizae Semen Raphani and others
Curing disharmony between liver and stomachepigastric pain inappetence and vomiting
Huayu Quban capsuleRadix Bupleuri Radix Scutellariae Radix Angelicaesinensis Herba menthae haplocalycis Flos CarthamiRadix Paeoniae Rubra
Curing chloasma and acne
BioMed Research International 5
Table 1 Continued
Preparation name Compositions Traditional uses
Ruzengning capsuleRadix Bupleuri Folium Artemisiae Argyi FoliumEpimedii Fructus Toosendan Radix AsparagiRhizoma bolbostemmatis
Curing lump in breast and mammary gland hyperplasia
Mangan Jieyu capsule
Radix Bupleuri Radix Angelicae sinensis RadixPaeoniae Alba Atractylodis Macrocephalae RhizomaPoria Radix Glycyrrhizae Herba menthae haplocalycisRadix et Rhizoma Salviae miltiorrhizae FructusToosendan Fructus citri Rhizoma Corydalis andothers
Curing chest congestion inappetence abdominaldistention and chronic hepatitis
Biyuanshu capsule
Radix Bupleuri Radix Scutellariae Herba menthaehaplocalycis Radix Angelicae dahuricae FlosMagnoliae Fructus Xanthii Fructus Gardeniae Radixet Rhizoma Asari Rhizoma Chuanxiong RadixAstragali Radix Platycodonis Poria Caulis Akebiae
Curing rhinitis and nasosinusitis
Figure 1The whole plant of Bupleurum chinenseDC (A) the whole plant of Bupleurum scorzonerifoliumWilld (B) the roots of Bupleurumchinense DC (C) the roots of Bupleurum scorzonerifoliumWilld (D)
bioactive compounds owing to their antifungal and anti-inflammatory activities [37 38] In one study the essentialoils in Radix Bupleuri were extracted by steam distillationand solvent extraction and then analyzed by GCMS 78peaks were identified Among these peaks the major volatilecompounds were 3-methylbutanal (724) pentanal (574)hexanal (2011) furan-2-carbaldehyde (2523) and hep-tanal (1207) [39] However in another study the resultsshowed that E-2-heptanal furan 2-pentyl and E-2-nonenalwere some of the main compounds of the oil [40]
42 Triterpenoid Saponins Triterpenoid saponins are themain active components of Radix Bupleuri which exhibit abroad spectrum of biological and pharmacological effectsincluding analgesic immunomodulatory hepatoprotectiveimmunomodulatory anti-inflammatory antitumor andantiviral activities [3 41ndash43] Currently approximately 35saponins have been isolated from Radix Bupleuri (Figure 2)[44ndash54] Among them saikosaponins a c and d are themajor bioactive constituents found in Radix Bupleurihowever a variety of minor saikosaponins have also been
isolated [16] The cytotoxic and antiproliferative effects ofsaikosaponins a and d have been attracting much interest inrecent years [55] Additionally more information about theintimate relationship between the structural characterizationof saikosaponins and their cytotoxic evaluations is verynecessary
43 Polyacetylenes Four polyacetylene compounds fromRadix Bupleuri have been identified including (2Z8Z10E)-pentadecatriene-46-diyne-1-ol (36) (2Z8E10E)-pentadec-atriene-46-diyne-1-ol (37) (2Z8Z10E)-heptadecatriene-46-diyne-1-ol (38) and bupleurynol (39) (Figure 3) [56 57]
44 Flavonoids So far twelve flavonoids have been isolatedand identified from Radix Bupleuri including quercetin(40) isorhamnetin (41) isorhamnetin-3-O-glucoside (42)puerarin (43) rutin (44) narcissin (45) eugenin (46)saikochromeA (47) saikochromic acid (48) 741015840-dihydroxy-isoflavone-7-O-120573-D-glucoside (49) saikochromosideA (50)and saikoisoflavonoside A (51) (Figure 4) [58ndash63]
6 BioMed Research International
Table 2 Chemical compounds isolated from Radix Bupleuri
Classification Number Chemical component Reference
Saponins
1 Saikosaponin a [44]2 Saikosaponin c [44]3 Saikosaponin d [44]4 Saikosaponin e [45]5 Prosaikogenin G [46]6 Prosaikogenin F [46]7 210158401015840-O-Acetylsaikosaponin a [47]8 310158401015840-O-Acetylsaikosaponin a [48]9 610158401015840-O-Acetylsaikosaponin a [49]10 23-O-Acetylsaikosaponin a [50]11 610158401015840-O-Acetylsaikosaponin d [51]
12 23-Hydroxy-13120573 28120573-epoxy-olean-11-ene-16-one3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside [52]
13 312057316120573-Dihydroxy-23-O-acetyl-13120573 28120573-epoxy-olean-11-ene3-O-120573-D-fucopyranoside [47]
14 Bupleuroside I [45]15 Saikosaponin b1 [45 49]16 Saikosaponin b2 [45 49]17 610158401015840-O-Acetyl-saikosaponin b2 [51]18 Saikosaponin h [47 53]19 Prosaikogenin D [54]20 Prosaikogenin A [47]
2131205732328-Trihydroxy-11 13(18)-diene-16-one
3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside
[47]
22 Bupleuroside V [45]23 Bupleuroside X [45]24 Bupleuroside XII [45]25 Saikosaponin v-1 [51]26 Saikosaponin b3 [44 53]27 Saikosaponin b4 [44 53]28 Saikosaponin f [45]
29 3120573161205732328-Tetrahydroxy-11120572-methoxy-olean-12-ene3-O-120573-D-fucopyranoside [47]
30 31205731612057328-Trihydroxyl-11120572-methoxy-olean-12-ene-O-120573-D-fucopyranoside [47]
31 Bupleuroside VII [45]32 Saikosaponin g [53]33 Saikosaponin i [53]34 Bupleuroside VIII [45]35 Bupleuroside XI [45]
Polyacetylenes
36 (2Z8Z10E)-pentadecatriene-46-diyne-1-ol [56]37 (2Z8E10E)-pentadecatriene-46-diyne-1-ol [56 57]38 (2Z8Z10E)-heptadecatriene-46-diyne-1-ol [56]39 Bupleurynol [56 57]
BioMed Research International 7
Table 2 Continued
Classification Number Chemical component Reference
Flavonoids
40 Quercetin [60]41 Isorhamnetin [60]42 Isorhamnetin-3-O-glucoside [60]43 Puerarin [60]44 Rutin [60]45 Narcissin [59]46 Eugenin [62]47 Saikochrome A [62 63]48 Saikochromic acid [60]49 741015840-Dihydroxy-isoflavone-7-O-120573-D-glucoside [60]50 Saikochromoside A [59]51 Saikoisoflavonoside A [61]
Lignans
52 Nortrachelogenin [63]53 Nemerosin [62]54 Kaerophyllin [62]55 Isochaihulactone [62]56 Isokaerophyllin [62]57 (minus)-yatein [62]58 Chinensinaphthol [62]59 Chaihunaphthone [62]
Fatty acids
60 Fumaric acid [64]61 Butanedioic acid [64]62 Pentadecanoic acid [65]63 Palmitoleic acid [65]64 Palmitic acid [65]65 Oleic acid [65]66 Stearic acid [65]67 11-Hexadecenoic acid [65]68 13-Octadecenoic acid [65]69 Linoleic acid [65]70 Tetracosanoic acid [64]71 9S12S13S-Trihydroxy-10E-octadecenoic acid [63]
Sterols72 120572-Spinasterol [64]73 24120585-Methylcholesta-7 22E-diene-312057351205726120573-triol [63]74 24120585-Ethylcholest-22E-end-312057351205726120573-Triol [63]
45 Ligans Lignans existing in numerous plants weredetected in the roots of Bupleurum scorzonerifolium WilldThese lignans included nortrachelogenin (52) nemerosin(53) kaerophyllin (54) isochaihulactone (55) isokaero-phyllin (56) (minus)-yatein (57) chinensinaphthol (58) andchaihunaphthone (59) (Figure 5) [62 63]
46 Other Compounds There are also other components inRadix Bupleuri including 12 fatty acids fumaric acid (60)butanedioic acid (61) pentadecanoic acid (62) palmitoleicacid (63) palmitic acid (64) oleic acid (65) stearic acid(66) 11-hexadecenoic acid (67) 13-octadecenoic acid (68)
linoleic acid (69) tetracosanoic acid (70) and 9S12S13S-trihydroxy-10E-octadecenoic acid (71) Three sterols com-pounds namely 120572-spinasterol (72) 24120585-methylcholesta-7 22E-diene-312057351205726120573-triol (73) and 24120585-ethylcholest-22E-end-312057351205726120573-triol (74) were also isolated and identified fromthis plant (Figure 6) [63ndash65]
5 Pharmacological Effects
Radix Bupleuri exerts a great variety of pharmacologi-cal activities due to its complexbioactive compounds Anoverview of the pharmacological studies on Radix Bupleuriispresented in detail in the following sections
8 BioMed Research International
O
R1
R1 R2 R3 R4
R2R1
R1 R2
R1 R2
R3
R3 R4
R1
R1
R2
R2
R3
R1
R1
R1
R2
R3
CH2R2
CH2R3
CH2R2
CH2OH
CH2OH
CH2OH
CH2OH
R3O
R4O
R4O
R3O
R2O
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH훽-OH훽-OH훽-OH훽-OH
훽-OH
훽-OH훽-OH
훽-OH훽-OH훽-OH훽-OH
훽-OH훽-OH
훼-OH
훼-OH
훼-OH
훼-OH훼-OH훼-OH
훼-OH
훼-OH
훼-OH
훼-OH
OH
OH
OHOHOHOHOH
OHOH
OH
1234567891011121314
1516171819202122232425
262728293031
3233
3435
H
H
OAc
OAc=O
=O
=O
COOH
COOH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Fuc-훽-D-Fuc-
2㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-3㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-2)-훽-D-Glc-(1-3)-훽-D-Fuc-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
COOCH2-(CHOH)3-CH2OHCH2OH
CH2OH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
6㰀㰀-acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-
OCH3
OCH3
OCH3
OHOH
OH
OH
OCH3
H
HH
H
H
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-2)-훽-D-Ara-(1-3)-훽-D-GlcA-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
Figure 2 Chemical structures of triterpenoid saponins
BioMed Research International 9
OH
OH
3736
3938
OH
OH
Figure 3 Chemical structures of polyacetylenes
51 Anti-inflammatory Effects Radix Bupleuri has beenwidely used for the treatment of several types of chronicinflammatory diseases The crude polysaccharides(80mgkg) isolated from the roots of Bupleurum chinenseDC significantly attenuated lung injury by inhibiting thelevel of myeloperoxidase (MPO) tumor necrosis factor-120572(TNF-120572) and serum nitric oxide (NO) [66] Chun et alreported that saikosaponins from Radix Bupleuri exhibitedanti-inflammatory activity on inflammatory processesincluding inhibition of inflammatory exudation capillarypermeability inflammatory mediators release migrationof white cells connective tissue hyperplasia and a varietyof allergic inflammation [67] Ma et al was the first toshow that saikosaponins exerted anti-inflammatory activityon paw edema mainly via regulating the nicotinate andnicotinamide metabolism and arachidonic acid metabolism[5] Zhu et al found that saikosaponin a (SSa) exhibitedan inhibitory effect on proinflammatory cytokines inLPS-stimulated macrophages The mechanism of theseactions involved the regulation of MAPK and NF-120581B signalspathways [68] In another study SSa dose-dependentlyinhibited the production of ROS TNF-120572 IL-8 COX-2 andiNOS in LPS-stimulated human umbilical endothelial cells(HUVECs) by upregulating of the LXR120572-ABCA1 signalingpathway [69] Moreover Lee et al showed that saikosaponinc (SSc) was also shown to inhibited LPS-induced apoptosis inHUVECs via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation [70] Zhao et al showed thatSSa also suppressed TNF-120572 and IL-6 concentrations inthe intestines of septic rats through the inhibition of thenucleotide-binding oligomerization domain 2 (NOD2)NF-120581B signaling pathway [71] Saikosaponin d (SSd) has beenreported to inhibit PGE2 production and intracellular freeCa2+ concentration ([Ca2+]i) in a concentration-dependentmanner with an IC50 value of 3 120583m in C6 rat glioma cells[72]
In addition several studies showed that a widerange of Radix Bupleuri preparations also exhibited anti-inflammatory effects in in vitro and in vivo model Li et alshowed that Saireito and its active components (SSd) couldsuppress the proliferation of mesangial cells and expansionof the mesangial matrix in the rat glomerulonephritismodel [73] In experimental chronic pancreatitis rats modelldquoChai-hu-shu-gan powderrdquo exerted anti-inflammatory andantifibrotic effects by inhibiting the expression of nuclearfactor-120581B (NF-120581B) and TNF-120572 mRNA in the pancreas [74]Furthermore it also reduced the abnormally high plasmalevel of cholecystokinin improved the gastricmovement andavoided nausea and flatulence [75] In another experimenta Chinese herbal formula called ldquoRCM-101rdquo (containingFlos magnoliae Radix Bupleuri Radix Glycyrrhizae RadixAngelicae Sinensis etc) inhibited the NO production andiNOS protein expression in LPS-stimulated rat aorta andRaw 2647 macrophages [76]
52 Anticancer Effects The extracts and compounds ofRadix Bupleuri also possessed anticancerantitumor effectThe acetone extract of Bupleurum scorzonerifolium couldinhibit the proliferation of A549 human lung cancer cellsin a dose-dependent manner via causing cell cycle arrestin the G2M phase increasing microtubule stabilizationsuppressing telomerase activity activating ERK 12 andcaspase-39 in A549 cells [77ndash79] Saponins isolated fromRadix Bupleuri also exhibited significantly anti-proliferativeactivity in human non-small cell lung cancer A549 cellsthrough Fas-dependent apoptotic pathway [80] Su et alfound that thewater extracts ofRadix Bupleuri could enhance5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cellsthrough cell arrest at the late G1early S phase while pro-tecting normal blood lymphocytes [6] SSd showed verypotent activity against the HepG2 cell line with an IC50value of 125mgml The mechanism of cytotoxicity was
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
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[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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MEDIATORSINFLAMMATION
of
2 BioMed Research International
metabolisms disperse evil heat from superficies sooth theliver and promote yang and qi [1]Radix Bupleuriwas initiallyrecorded in Shennong Bencao Jing a famous monograph oftraditional Chinese medicine written in China in 200 AD[17] According to a record of traditional Chinese medicinedated 2000 years ago Radix Bupleuri had mainly been usedfor the treatment of mouth-bitterness throat-drying andeyes-dazzling In other monographs of Materia Medica suchas Jin Kui Yao Lue Kaibao Bencao Bencao Gangmu andXinbian Bencao this plant was described to be used for thetreatment of common cold with fever influenza hepatitismalaria menoxenia and hyperlipidemia [18] CurrentlyRadix Bupleuri exerts other pharmacological effects suchas balancing different organs and energies within the bodystrengthening the action of the digestive tract improving liverand circulatory system function and relieving liver tension[19] Therefore it is also used as a popular tonic herb inChina In Korea and Japan this plant is commonly used forthe treatment of fever pain and inflammation associatedwith influenza and the common cold [20] In addition thisplant is also used as analgesics in the treatment of distendingpain in the hypochondriac region of the chest and againstamenorrhoea
Radix Bupleuri is combined with other herbs in manyclassical formulas to improve clinical effect Xiaoyaosan(XYS) a well-known formula for relieving depression isoriginated from the book of ldquoTaiping Huimin Heji Jufangrdquo inSong Dynasty (960ndash1279 AD) consisting of Radix BupleuriRadix Angelicae Sinensis Radix Paeoniae Alba RhizomaAtractylodis Macrocephalae Poria Radix GlycyrrhizaeHerbaMenthae and Rhizoma Zingiberis Recens XYS exerts var-ious pharmacological effects including soothing the liverand improving the circulation of qi to relieve depressionFurthermore it has been commonly recognized as a safe andeffective prescription in the treatment of depressive disorder[21ndash23] The 2015 edition of the Chinese Pharmacopoeialists 97 Chinese patent medicines containing Radix Bupleuriand the compatible herbs that are more frequently describedincludeRadixGlycyrrhizaeRhizomaZingiberis RecensRadixScutellariae and Panax ginseng Table 1 lists subsets of theChinese patent drugs containing Radix Bupleuri in differentformulations Although Radix Bupleuri has been used to treatcertain diseases in ethnomedicines for thousands of yearsthis herbal medicine should be comprehensively understoodand recent information should be obtained for its clinical use
3 Botanical Characterization and Distribution
According to the Chinese pharmacopoeia Radix Bupleuri isderived from the dried roots of Bupleurum chinense DC andBupleurum scorzonerifolium Willd (Figure 1) The former isknown as ldquoBeichaihurdquo (Northern Chinese Thorowax Root)and the latter is known as ldquoNanchaihurdquo (Southern ChineseThorowax Root) due to the difference of the origin anddescription The drug is collected in spring or autumnremoved from the aerial part and soil and dried
Beichaihu As a herbaceous perennial plant Bupleurum chi-nenseDC grows to the height of 50ndash85 cm Its root is conical
taupe and approximately 6ndash20 cm in length Its stems areerect tufted and apex branched The leaves are alternate theleaf blades are broadly linear-lanceolate 4ndash7 times 06ndash08 cm insize the apex is acuminate Compound umbels are axillaryand terminal approximately 1ndash4 cm in length the bracts are0 or 2-3 linear the petals are 5 and bright yellow The fruitsare oblong brown and approximately 3mm in length Theyblossom from July to September and fruit from August toOctober This plant is widely cultivated in China Japan andKorea Moreover it grows in grasslands stream banks sunnyslopes and roadsides and other locations with altitudes of100ndash2700m [24]
Nanchaihu Bupleurum scorzonerifolium Willd is a herba-ceous perennial plant and approximately 30ndash60 cm high Itsroot is flexuose reddish brown and approximately 4ndash10 cmin length Its stems are 1ndash3 usually glabrous and apexbranchedThe leaf blades are linear or linear-lanceolate 6ndash16times 02ndash07 cm in size the apex is acuminate Compoundumbels are axillary and terminal the bracts are 1ndash3 thepetals are 5 and yellow The fruits are ellipsoid dark brownapproximately 2-3mm in length They blossom from Julyto August and fruit from August to October This plant isalso widely cultivated in East Asian countries such as ChinaJapan and Korea It grows in shrub forest margins sunnymountain slopes dry grasslands and other locations withaltitudes of 200ndash3000m [24]
There were approximately 36 Bupleurum species andvarieties in different districts and markets due to the slightlydifferent morphologic appearance of Bupleurum plantsincluding B longiradiatum Turcz with toxic ingredients andB hamiltonii Balak with very little active constituents [2526] Inevitably this situation will compromise the values ofRadix Bupleuri and even imperil the safety of the consumersUntil now several techniques have been developed to identifyand distinguish them including TLC [27] HPLC [28ndash30]HPLC-ELSD [31 32] HPLC-MS [33 34] UPLC-MS [35] andcapillary electrochromatography [36] Among thesemethodsmentioned above HPLC-ELSD is the most commonly usedanalytical method for evaluating the quality and authenticityof Radix Bupleuri The total amounts of saikosaponins a andd are used as the indicator compounds to characterize thequality of this plant with minimum contents of 03 in thePharmacopoeia of Peoplersquos Republic of China
4 Chemical Constituents
In the past few decades approximately 74 compounds havebeen isolated from Radix Bupleuri including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols Triterpenoid saponins flavonoidsand essential oil which possess multiple pharmacologicalactivities are considered as the main active ingredients ofRadix Bupleuri Their structures are shown in (Table 2)(Figures 2ndash6)
41 Volatile Compounds (Essential Oils) The essential oils ofRadix Bupleuri are regarded as one of the most important
BioMed Research International 3
Table 1 The traditional and clinical uses of Radix Bupleuri in China
Preparation name Compositions Traditional uses
Xiao Chai Hudecoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Radix Glycyrrhizae RhizomaZingiberis Recens Fructus jujubae
Curing thoracic and hypochondrium fullnessmouth-bitterness throat-drying and eyes-dazzling
Da Chai Hudecoction
Radix Bupleuri Radix Scutellariae Pinellia ternataRhizoma Zingiberis Recens Fructus jujubae FructusAurantii immaturus Radix Paeoniae Alba Rheumpalmatum
Treating diarrhea or constipation
Chaihu Guizhidecoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Radix Glycyrrhizae RhizomaZingiberis Recens Fructus jujubae Radix PaeoniaeAlba Ramulus cinnamomi
Curing fever with cold aversion restless arthralgia oflimbs and epigastric induration
Chaihu GuizhiGanjiang decoction
Radix Bupleuri Ramulus cinnamomi RhizomaZingiberis Radix Scutellariae Radix GlycyrrhizaeTrichosanthes kirilowii Ostreae Concha
Curing palpitation fullness of the upper abdomen anda bitter taste in the mouth
Chaihu plusMangxiao decoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Radix Glycyrrhizae RhizomaZingiberis Recens Fructus jujubae Natrii Sulfas
Curing thoracic and hypochondrium fullness retchingcounterflow hot flashes mouth-bitternessthroat-drying eyes-dazzling and constipation
Chaihu plus LongguMuli decoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Rhizoma Zingiberis Recens Fructusjujubae Rheum palmatum Ramulus cinnamomiOstreae Concha Os Draconis Poria cocos Minium
Curing thoracic and hypochondrium fullness difficultyin micturition and delirium
Buzhong Yiqidecoction
Radix Astragali Radix Bupleuri Panax ginseng RadixGlycyrrhizae Rhizoma Cimicifugae Radix Angelicaesinensis Atractylodis Macrocephalae Rhizoma CitriReticulatae Pericarpium
Curing prolapse of uterus prolapse of rectum uterinebleeding shortness of breath and tiredness and paletongue
Chaige Jieji decoction
Radix Bupleuri Radix Puerariae lobatae RadixGlycyrrhizae Radix Scutellariae Rhizoma et RadixNotopterygii Radix Angelicae dahuricae RadixPaeoniae Alba Radix Platycodonis Gypsum fibrosumRhizoma Zingiberis Recens Fructus jujubae
Curing mind-cold due to exogenous evils headacheand vexation and sleeplessness
Zheng Chaihu YinRadix Bupleuri Pericarpium Citri Reticulatae RadixSaposhnikovia Radix Paeoniae Rubra RadixGlycyrrhizae Rhizoma Zingiberis Recens
Curing mind-cold due to exogenous evils fever withchilliness headache and body pain
Xuefu Zhuyudecoction
Radix Angelicae sinensis Radix Rehmanniae SemenPersicae Flos Carthami Fructus Aurantii RadixBupleuri Radix Glycyrrhizae Radix PlatycodonisRhizoma Chuanxiong Radix Achyranthis BidentataeRadix Paeoniae Rubra
Treating blood pressure related symptoms caused by qistagnation and blood stasis syndrome
Shengxian DecoctionRadix Astragali Radix Bupleuri RhizomaAnemarrhenae Radix Platycodonis RhizomaCimicifugae
Curing coronary heart disease chronic congestive heartfailure vital myocarditis and myocardial ischemia
Xiaoyao san
Radix Bupleuri Radix Angelicae Sinensis RadixPaeoniae Alba Rhizoma Atractylodis MacrocephalaePoria Radix Glycyrrhizae Herba Menthae andRhizoma Zingiberis Recens
Soothing the liver and improving the circulation of qi torelieve depression
Chaihu Shugan SanRadix Bupleuri Fructus Aurantii RhizomaChuanxiong Rhizoma Cyperi Pericarpium CitriReticulatae Radix Paeoniae Rubra Radix Glycyrrhizae
Curing neurologic impairment and depression
Sini San Radix Bupleuri Fructus Aurantii Radix PaeoniaeRubra Radix Glycyrrhizae
Curing insomnia liver injury hepatitis chronic stressmodel and palmoplantar hidrosis
Tongqi San Radix Bupleuri Rhizoma Cyperi RhizomaChuanxiong Curing deafness tinnitus and stagnation of liver qi
Danzhi Xiaoyao SanRadix Bupleuri Radix Angelicae Sinensis RadixPaeoniae Alba Rhizoma Atractylodis MacrocephalaePoria Cortex Moutan Fructus Gardeniae
Curing headache menoxenia distending pain in thelower abdomen and depression
4 BioMed Research International
Table 1 Continued
Preparation name Compositions Traditional uses
Yigan Yiqi Jieyu Keli
Radix Bupleuri Fructus Aurantii Radix Paeoniae AlbaRadix et Rhizoma Salviae miltiorrhizae RadixAstragali Radix Codonopsis Ramulus cinnamomiPoria Acanthopanax senticosus (Rupr et Maxim)Harms Fructus trichosanthis Rhizoma PinelliaePreparatum and others
Curing chronic hepatitis hypochondriac pain bloatingand lassitude
Xiaorsquo er Tuire Keli
Radix Bupleuri Folium isatidis Radix Isatidis FlosLonicerae Japonicae Cortex Moutan Cape JasmineFruit Radix Scutellariae Herba Lophatheri PheretimaRhizoma paridis Radix et Rhizoma Cynanchi Atrati
Curing cold due to exogenous wind-heat in children
Dalitong Keli
Radix Bupleuri Fructus Aurantii Radix AucklandiaePericarpium Citri Reticulatae Pinelliae RhizomaPraeparatum Cum Alumine Herba Taraxaci Crataegifructus Semen Arecae Paederia scandens RadixCodonopsis Rhizoma Corydalis Massa MedicataFermentata
Curing epigastric fullness belching dry mouth andmouth pain
Bubai Keli
Fructus Psoraleae Dolichos lablab L Folium EpimediiRadix Bupleuri Radix et Rhizoma Salviaemiltiorrhizae Vigna umbellata Ohwi et Ohashi RadixSophorae Flavescentis Glycine max (L) Merr
Nourishing the spleen and warming the kidneys
Ganmao Qingre Keli
Schizonepetae Spica Radix Bupleuri Herba menthaehaplocalycis Radix Saposhnikovia Perillae FoliumRadix Puerariae lobatae Radix Platycodonis SemenArmeniacae amarum Radix Angelicae dahuricaeCorydalis bungeana Herba
Curing cold cough fever headache rhinorrhea andpharyngoxerosis
Qizhi Weitong tabletRadix Bupleuri Rhizoma Corydalis Rhizoma CyperiFructus Aurantii Radix Paeoniae Alba RadixGlycyrrhizae
Curing stagnation of liver qi abdominal distention andepigastric pain
Lidan tablet
Rheum palmatum Flos Lonicerae Japonicae HerbaLysimachiae Radix Aucklandiae RhizomaAnemarrhenae Folium isatidis Radix Bupleuri RadixPaeoniae Alba Radix Scutellariae Natrii Sulfas HerbaArtemisiae Scopariae
Curing hypochondriac pain constipation oliguria withreddish urine headache and vomiting
Ruhe Sanjie tablet
Radix Bupleuri Radix Angelicae sinensis RadixAstragali Radix Curcumae Tulipa edulis RadixRhapontici Ecklonia kurome Okam SargassumFolium Epimedii Herba Pyrolae
Curing lump in breast and mammary glandhyperplasia
Jianwei Yuyang tablet
Radix Bupleuri Radix Paeoniae Alba RadixCodonopsis Rhizoma Corydalis Bletilla striata(Thunb) Reiehb f Indigo Naturalis ConchaMargaritifera Usta
Curing dysphoria distention and loose stools andpeptic ulcer
Longdan Xiegan pill
Radix et Rhizoma Gentianae Radix Bupleuri RadixScutellariae Fructus Gardeniae Rhizoma alismatisCaulis Akebiae Semen Plantaginis Radix Angelicaesinensis Radix Rehmanniae Radix Glycyrrhizae
Curing hepatochlic hygropyrexia dizziness deafnesstinnitus and mouth-bitterness
Qingwen Jiedu pill
Radix Bupleuri Folium isatidis Fructus ForsythiaeRadix Scrophulariae Radix Trichosanthis RadixPlatycodonis Fructus Arctii Radix SaposhnikoviaRadix Puerariae lobatae Radix Scutellariae RadixAngelicae dahuricae Rhizoma Chuanxiong and others
Curing headache throat-drying and mumps
Shugan Hewei pill
Rhizoma Cyperi Radix Paeoniae Alba Fructus citriSarcodactylis Radix Aucklandiae Radix CurcumaeRhizoma Atractylodis Macrocephalae PericarpiumCitri Reticulatae Radix Bupleuri Herba PogostemonisRadix Glycyrrhizae Semen Raphani and others
Curing disharmony between liver and stomachepigastric pain inappetence and vomiting
Huayu Quban capsuleRadix Bupleuri Radix Scutellariae Radix Angelicaesinensis Herba menthae haplocalycis Flos CarthamiRadix Paeoniae Rubra
Curing chloasma and acne
BioMed Research International 5
Table 1 Continued
Preparation name Compositions Traditional uses
Ruzengning capsuleRadix Bupleuri Folium Artemisiae Argyi FoliumEpimedii Fructus Toosendan Radix AsparagiRhizoma bolbostemmatis
Curing lump in breast and mammary gland hyperplasia
Mangan Jieyu capsule
Radix Bupleuri Radix Angelicae sinensis RadixPaeoniae Alba Atractylodis Macrocephalae RhizomaPoria Radix Glycyrrhizae Herba menthae haplocalycisRadix et Rhizoma Salviae miltiorrhizae FructusToosendan Fructus citri Rhizoma Corydalis andothers
Curing chest congestion inappetence abdominaldistention and chronic hepatitis
Biyuanshu capsule
Radix Bupleuri Radix Scutellariae Herba menthaehaplocalycis Radix Angelicae dahuricae FlosMagnoliae Fructus Xanthii Fructus Gardeniae Radixet Rhizoma Asari Rhizoma Chuanxiong RadixAstragali Radix Platycodonis Poria Caulis Akebiae
Curing rhinitis and nasosinusitis
Figure 1The whole plant of Bupleurum chinenseDC (A) the whole plant of Bupleurum scorzonerifoliumWilld (B) the roots of Bupleurumchinense DC (C) the roots of Bupleurum scorzonerifoliumWilld (D)
bioactive compounds owing to their antifungal and anti-inflammatory activities [37 38] In one study the essentialoils in Radix Bupleuri were extracted by steam distillationand solvent extraction and then analyzed by GCMS 78peaks were identified Among these peaks the major volatilecompounds were 3-methylbutanal (724) pentanal (574)hexanal (2011) furan-2-carbaldehyde (2523) and hep-tanal (1207) [39] However in another study the resultsshowed that E-2-heptanal furan 2-pentyl and E-2-nonenalwere some of the main compounds of the oil [40]
42 Triterpenoid Saponins Triterpenoid saponins are themain active components of Radix Bupleuri which exhibit abroad spectrum of biological and pharmacological effectsincluding analgesic immunomodulatory hepatoprotectiveimmunomodulatory anti-inflammatory antitumor andantiviral activities [3 41ndash43] Currently approximately 35saponins have been isolated from Radix Bupleuri (Figure 2)[44ndash54] Among them saikosaponins a c and d are themajor bioactive constituents found in Radix Bupleurihowever a variety of minor saikosaponins have also been
isolated [16] The cytotoxic and antiproliferative effects ofsaikosaponins a and d have been attracting much interest inrecent years [55] Additionally more information about theintimate relationship between the structural characterizationof saikosaponins and their cytotoxic evaluations is verynecessary
43 Polyacetylenes Four polyacetylene compounds fromRadix Bupleuri have been identified including (2Z8Z10E)-pentadecatriene-46-diyne-1-ol (36) (2Z8E10E)-pentadec-atriene-46-diyne-1-ol (37) (2Z8Z10E)-heptadecatriene-46-diyne-1-ol (38) and bupleurynol (39) (Figure 3) [56 57]
44 Flavonoids So far twelve flavonoids have been isolatedand identified from Radix Bupleuri including quercetin(40) isorhamnetin (41) isorhamnetin-3-O-glucoside (42)puerarin (43) rutin (44) narcissin (45) eugenin (46)saikochromeA (47) saikochromic acid (48) 741015840-dihydroxy-isoflavone-7-O-120573-D-glucoside (49) saikochromosideA (50)and saikoisoflavonoside A (51) (Figure 4) [58ndash63]
6 BioMed Research International
Table 2 Chemical compounds isolated from Radix Bupleuri
Classification Number Chemical component Reference
Saponins
1 Saikosaponin a [44]2 Saikosaponin c [44]3 Saikosaponin d [44]4 Saikosaponin e [45]5 Prosaikogenin G [46]6 Prosaikogenin F [46]7 210158401015840-O-Acetylsaikosaponin a [47]8 310158401015840-O-Acetylsaikosaponin a [48]9 610158401015840-O-Acetylsaikosaponin a [49]10 23-O-Acetylsaikosaponin a [50]11 610158401015840-O-Acetylsaikosaponin d [51]
12 23-Hydroxy-13120573 28120573-epoxy-olean-11-ene-16-one3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside [52]
13 312057316120573-Dihydroxy-23-O-acetyl-13120573 28120573-epoxy-olean-11-ene3-O-120573-D-fucopyranoside [47]
14 Bupleuroside I [45]15 Saikosaponin b1 [45 49]16 Saikosaponin b2 [45 49]17 610158401015840-O-Acetyl-saikosaponin b2 [51]18 Saikosaponin h [47 53]19 Prosaikogenin D [54]20 Prosaikogenin A [47]
2131205732328-Trihydroxy-11 13(18)-diene-16-one
3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside
[47]
22 Bupleuroside V [45]23 Bupleuroside X [45]24 Bupleuroside XII [45]25 Saikosaponin v-1 [51]26 Saikosaponin b3 [44 53]27 Saikosaponin b4 [44 53]28 Saikosaponin f [45]
29 3120573161205732328-Tetrahydroxy-11120572-methoxy-olean-12-ene3-O-120573-D-fucopyranoside [47]
30 31205731612057328-Trihydroxyl-11120572-methoxy-olean-12-ene-O-120573-D-fucopyranoside [47]
31 Bupleuroside VII [45]32 Saikosaponin g [53]33 Saikosaponin i [53]34 Bupleuroside VIII [45]35 Bupleuroside XI [45]
Polyacetylenes
36 (2Z8Z10E)-pentadecatriene-46-diyne-1-ol [56]37 (2Z8E10E)-pentadecatriene-46-diyne-1-ol [56 57]38 (2Z8Z10E)-heptadecatriene-46-diyne-1-ol [56]39 Bupleurynol [56 57]
BioMed Research International 7
Table 2 Continued
Classification Number Chemical component Reference
Flavonoids
40 Quercetin [60]41 Isorhamnetin [60]42 Isorhamnetin-3-O-glucoside [60]43 Puerarin [60]44 Rutin [60]45 Narcissin [59]46 Eugenin [62]47 Saikochrome A [62 63]48 Saikochromic acid [60]49 741015840-Dihydroxy-isoflavone-7-O-120573-D-glucoside [60]50 Saikochromoside A [59]51 Saikoisoflavonoside A [61]
Lignans
52 Nortrachelogenin [63]53 Nemerosin [62]54 Kaerophyllin [62]55 Isochaihulactone [62]56 Isokaerophyllin [62]57 (minus)-yatein [62]58 Chinensinaphthol [62]59 Chaihunaphthone [62]
Fatty acids
60 Fumaric acid [64]61 Butanedioic acid [64]62 Pentadecanoic acid [65]63 Palmitoleic acid [65]64 Palmitic acid [65]65 Oleic acid [65]66 Stearic acid [65]67 11-Hexadecenoic acid [65]68 13-Octadecenoic acid [65]69 Linoleic acid [65]70 Tetracosanoic acid [64]71 9S12S13S-Trihydroxy-10E-octadecenoic acid [63]
Sterols72 120572-Spinasterol [64]73 24120585-Methylcholesta-7 22E-diene-312057351205726120573-triol [63]74 24120585-Ethylcholest-22E-end-312057351205726120573-Triol [63]
45 Ligans Lignans existing in numerous plants weredetected in the roots of Bupleurum scorzonerifolium WilldThese lignans included nortrachelogenin (52) nemerosin(53) kaerophyllin (54) isochaihulactone (55) isokaero-phyllin (56) (minus)-yatein (57) chinensinaphthol (58) andchaihunaphthone (59) (Figure 5) [62 63]
46 Other Compounds There are also other components inRadix Bupleuri including 12 fatty acids fumaric acid (60)butanedioic acid (61) pentadecanoic acid (62) palmitoleicacid (63) palmitic acid (64) oleic acid (65) stearic acid(66) 11-hexadecenoic acid (67) 13-octadecenoic acid (68)
linoleic acid (69) tetracosanoic acid (70) and 9S12S13S-trihydroxy-10E-octadecenoic acid (71) Three sterols com-pounds namely 120572-spinasterol (72) 24120585-methylcholesta-7 22E-diene-312057351205726120573-triol (73) and 24120585-ethylcholest-22E-end-312057351205726120573-triol (74) were also isolated and identified fromthis plant (Figure 6) [63ndash65]
5 Pharmacological Effects
Radix Bupleuri exerts a great variety of pharmacologi-cal activities due to its complexbioactive compounds Anoverview of the pharmacological studies on Radix Bupleuriispresented in detail in the following sections
8 BioMed Research International
O
R1
R1 R2 R3 R4
R2R1
R1 R2
R1 R2
R3
R3 R4
R1
R1
R2
R2
R3
R1
R1
R1
R2
R3
CH2R2
CH2R3
CH2R2
CH2OH
CH2OH
CH2OH
CH2OH
R3O
R4O
R4O
R3O
R2O
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH훽-OH훽-OH훽-OH훽-OH
훽-OH
훽-OH훽-OH
훽-OH훽-OH훽-OH훽-OH
훽-OH훽-OH
훼-OH
훼-OH
훼-OH
훼-OH훼-OH훼-OH
훼-OH
훼-OH
훼-OH
훼-OH
OH
OH
OHOHOHOHOH
OHOH
OH
1234567891011121314
1516171819202122232425
262728293031
3233
3435
H
H
OAc
OAc=O
=O
=O
COOH
COOH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Fuc-훽-D-Fuc-
2㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-3㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-2)-훽-D-Glc-(1-3)-훽-D-Fuc-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
COOCH2-(CHOH)3-CH2OHCH2OH
CH2OH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
6㰀㰀-acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-
OCH3
OCH3
OCH3
OHOH
OH
OH
OCH3
H
HH
H
H
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-2)-훽-D-Ara-(1-3)-훽-D-GlcA-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
Figure 2 Chemical structures of triterpenoid saponins
BioMed Research International 9
OH
OH
3736
3938
OH
OH
Figure 3 Chemical structures of polyacetylenes
51 Anti-inflammatory Effects Radix Bupleuri has beenwidely used for the treatment of several types of chronicinflammatory diseases The crude polysaccharides(80mgkg) isolated from the roots of Bupleurum chinenseDC significantly attenuated lung injury by inhibiting thelevel of myeloperoxidase (MPO) tumor necrosis factor-120572(TNF-120572) and serum nitric oxide (NO) [66] Chun et alreported that saikosaponins from Radix Bupleuri exhibitedanti-inflammatory activity on inflammatory processesincluding inhibition of inflammatory exudation capillarypermeability inflammatory mediators release migrationof white cells connective tissue hyperplasia and a varietyof allergic inflammation [67] Ma et al was the first toshow that saikosaponins exerted anti-inflammatory activityon paw edema mainly via regulating the nicotinate andnicotinamide metabolism and arachidonic acid metabolism[5] Zhu et al found that saikosaponin a (SSa) exhibitedan inhibitory effect on proinflammatory cytokines inLPS-stimulated macrophages The mechanism of theseactions involved the regulation of MAPK and NF-120581B signalspathways [68] In another study SSa dose-dependentlyinhibited the production of ROS TNF-120572 IL-8 COX-2 andiNOS in LPS-stimulated human umbilical endothelial cells(HUVECs) by upregulating of the LXR120572-ABCA1 signalingpathway [69] Moreover Lee et al showed that saikosaponinc (SSc) was also shown to inhibited LPS-induced apoptosis inHUVECs via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation [70] Zhao et al showed thatSSa also suppressed TNF-120572 and IL-6 concentrations inthe intestines of septic rats through the inhibition of thenucleotide-binding oligomerization domain 2 (NOD2)NF-120581B signaling pathway [71] Saikosaponin d (SSd) has beenreported to inhibit PGE2 production and intracellular freeCa2+ concentration ([Ca2+]i) in a concentration-dependentmanner with an IC50 value of 3 120583m in C6 rat glioma cells[72]
In addition several studies showed that a widerange of Radix Bupleuri preparations also exhibited anti-inflammatory effects in in vitro and in vivo model Li et alshowed that Saireito and its active components (SSd) couldsuppress the proliferation of mesangial cells and expansionof the mesangial matrix in the rat glomerulonephritismodel [73] In experimental chronic pancreatitis rats modelldquoChai-hu-shu-gan powderrdquo exerted anti-inflammatory andantifibrotic effects by inhibiting the expression of nuclearfactor-120581B (NF-120581B) and TNF-120572 mRNA in the pancreas [74]Furthermore it also reduced the abnormally high plasmalevel of cholecystokinin improved the gastricmovement andavoided nausea and flatulence [75] In another experimenta Chinese herbal formula called ldquoRCM-101rdquo (containingFlos magnoliae Radix Bupleuri Radix Glycyrrhizae RadixAngelicae Sinensis etc) inhibited the NO production andiNOS protein expression in LPS-stimulated rat aorta andRaw 2647 macrophages [76]
52 Anticancer Effects The extracts and compounds ofRadix Bupleuri also possessed anticancerantitumor effectThe acetone extract of Bupleurum scorzonerifolium couldinhibit the proliferation of A549 human lung cancer cellsin a dose-dependent manner via causing cell cycle arrestin the G2M phase increasing microtubule stabilizationsuppressing telomerase activity activating ERK 12 andcaspase-39 in A549 cells [77ndash79] Saponins isolated fromRadix Bupleuri also exhibited significantly anti-proliferativeactivity in human non-small cell lung cancer A549 cellsthrough Fas-dependent apoptotic pathway [80] Su et alfound that thewater extracts ofRadix Bupleuri could enhance5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cellsthrough cell arrest at the late G1early S phase while pro-tecting normal blood lymphocytes [6] SSd showed verypotent activity against the HepG2 cell line with an IC50value of 125mgml The mechanism of cytotoxicity was
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
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[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
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[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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MEDIATORSINFLAMMATION
of
BioMed Research International 3
Table 1 The traditional and clinical uses of Radix Bupleuri in China
Preparation name Compositions Traditional uses
Xiao Chai Hudecoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Radix Glycyrrhizae RhizomaZingiberis Recens Fructus jujubae
Curing thoracic and hypochondrium fullnessmouth-bitterness throat-drying and eyes-dazzling
Da Chai Hudecoction
Radix Bupleuri Radix Scutellariae Pinellia ternataRhizoma Zingiberis Recens Fructus jujubae FructusAurantii immaturus Radix Paeoniae Alba Rheumpalmatum
Treating diarrhea or constipation
Chaihu Guizhidecoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Radix Glycyrrhizae RhizomaZingiberis Recens Fructus jujubae Radix PaeoniaeAlba Ramulus cinnamomi
Curing fever with cold aversion restless arthralgia oflimbs and epigastric induration
Chaihu GuizhiGanjiang decoction
Radix Bupleuri Ramulus cinnamomi RhizomaZingiberis Radix Scutellariae Radix GlycyrrhizaeTrichosanthes kirilowii Ostreae Concha
Curing palpitation fullness of the upper abdomen anda bitter taste in the mouth
Chaihu plusMangxiao decoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Radix Glycyrrhizae RhizomaZingiberis Recens Fructus jujubae Natrii Sulfas
Curing thoracic and hypochondrium fullness retchingcounterflow hot flashes mouth-bitternessthroat-drying eyes-dazzling and constipation
Chaihu plus LongguMuli decoction
Radix Bupleuri Radix Scutellariae Panax ginsengPinellia ternata Rhizoma Zingiberis Recens Fructusjujubae Rheum palmatum Ramulus cinnamomiOstreae Concha Os Draconis Poria cocos Minium
Curing thoracic and hypochondrium fullness difficultyin micturition and delirium
Buzhong Yiqidecoction
Radix Astragali Radix Bupleuri Panax ginseng RadixGlycyrrhizae Rhizoma Cimicifugae Radix Angelicaesinensis Atractylodis Macrocephalae Rhizoma CitriReticulatae Pericarpium
Curing prolapse of uterus prolapse of rectum uterinebleeding shortness of breath and tiredness and paletongue
Chaige Jieji decoction
Radix Bupleuri Radix Puerariae lobatae RadixGlycyrrhizae Radix Scutellariae Rhizoma et RadixNotopterygii Radix Angelicae dahuricae RadixPaeoniae Alba Radix Platycodonis Gypsum fibrosumRhizoma Zingiberis Recens Fructus jujubae
Curing mind-cold due to exogenous evils headacheand vexation and sleeplessness
Zheng Chaihu YinRadix Bupleuri Pericarpium Citri Reticulatae RadixSaposhnikovia Radix Paeoniae Rubra RadixGlycyrrhizae Rhizoma Zingiberis Recens
Curing mind-cold due to exogenous evils fever withchilliness headache and body pain
Xuefu Zhuyudecoction
Radix Angelicae sinensis Radix Rehmanniae SemenPersicae Flos Carthami Fructus Aurantii RadixBupleuri Radix Glycyrrhizae Radix PlatycodonisRhizoma Chuanxiong Radix Achyranthis BidentataeRadix Paeoniae Rubra
Treating blood pressure related symptoms caused by qistagnation and blood stasis syndrome
Shengxian DecoctionRadix Astragali Radix Bupleuri RhizomaAnemarrhenae Radix Platycodonis RhizomaCimicifugae
Curing coronary heart disease chronic congestive heartfailure vital myocarditis and myocardial ischemia
Xiaoyao san
Radix Bupleuri Radix Angelicae Sinensis RadixPaeoniae Alba Rhizoma Atractylodis MacrocephalaePoria Radix Glycyrrhizae Herba Menthae andRhizoma Zingiberis Recens
Soothing the liver and improving the circulation of qi torelieve depression
Chaihu Shugan SanRadix Bupleuri Fructus Aurantii RhizomaChuanxiong Rhizoma Cyperi Pericarpium CitriReticulatae Radix Paeoniae Rubra Radix Glycyrrhizae
Curing neurologic impairment and depression
Sini San Radix Bupleuri Fructus Aurantii Radix PaeoniaeRubra Radix Glycyrrhizae
Curing insomnia liver injury hepatitis chronic stressmodel and palmoplantar hidrosis
Tongqi San Radix Bupleuri Rhizoma Cyperi RhizomaChuanxiong Curing deafness tinnitus and stagnation of liver qi
Danzhi Xiaoyao SanRadix Bupleuri Radix Angelicae Sinensis RadixPaeoniae Alba Rhizoma Atractylodis MacrocephalaePoria Cortex Moutan Fructus Gardeniae
Curing headache menoxenia distending pain in thelower abdomen and depression
4 BioMed Research International
Table 1 Continued
Preparation name Compositions Traditional uses
Yigan Yiqi Jieyu Keli
Radix Bupleuri Fructus Aurantii Radix Paeoniae AlbaRadix et Rhizoma Salviae miltiorrhizae RadixAstragali Radix Codonopsis Ramulus cinnamomiPoria Acanthopanax senticosus (Rupr et Maxim)Harms Fructus trichosanthis Rhizoma PinelliaePreparatum and others
Curing chronic hepatitis hypochondriac pain bloatingand lassitude
Xiaorsquo er Tuire Keli
Radix Bupleuri Folium isatidis Radix Isatidis FlosLonicerae Japonicae Cortex Moutan Cape JasmineFruit Radix Scutellariae Herba Lophatheri PheretimaRhizoma paridis Radix et Rhizoma Cynanchi Atrati
Curing cold due to exogenous wind-heat in children
Dalitong Keli
Radix Bupleuri Fructus Aurantii Radix AucklandiaePericarpium Citri Reticulatae Pinelliae RhizomaPraeparatum Cum Alumine Herba Taraxaci Crataegifructus Semen Arecae Paederia scandens RadixCodonopsis Rhizoma Corydalis Massa MedicataFermentata
Curing epigastric fullness belching dry mouth andmouth pain
Bubai Keli
Fructus Psoraleae Dolichos lablab L Folium EpimediiRadix Bupleuri Radix et Rhizoma Salviaemiltiorrhizae Vigna umbellata Ohwi et Ohashi RadixSophorae Flavescentis Glycine max (L) Merr
Nourishing the spleen and warming the kidneys
Ganmao Qingre Keli
Schizonepetae Spica Radix Bupleuri Herba menthaehaplocalycis Radix Saposhnikovia Perillae FoliumRadix Puerariae lobatae Radix Platycodonis SemenArmeniacae amarum Radix Angelicae dahuricaeCorydalis bungeana Herba
Curing cold cough fever headache rhinorrhea andpharyngoxerosis
Qizhi Weitong tabletRadix Bupleuri Rhizoma Corydalis Rhizoma CyperiFructus Aurantii Radix Paeoniae Alba RadixGlycyrrhizae
Curing stagnation of liver qi abdominal distention andepigastric pain
Lidan tablet
Rheum palmatum Flos Lonicerae Japonicae HerbaLysimachiae Radix Aucklandiae RhizomaAnemarrhenae Folium isatidis Radix Bupleuri RadixPaeoniae Alba Radix Scutellariae Natrii Sulfas HerbaArtemisiae Scopariae
Curing hypochondriac pain constipation oliguria withreddish urine headache and vomiting
Ruhe Sanjie tablet
Radix Bupleuri Radix Angelicae sinensis RadixAstragali Radix Curcumae Tulipa edulis RadixRhapontici Ecklonia kurome Okam SargassumFolium Epimedii Herba Pyrolae
Curing lump in breast and mammary glandhyperplasia
Jianwei Yuyang tablet
Radix Bupleuri Radix Paeoniae Alba RadixCodonopsis Rhizoma Corydalis Bletilla striata(Thunb) Reiehb f Indigo Naturalis ConchaMargaritifera Usta
Curing dysphoria distention and loose stools andpeptic ulcer
Longdan Xiegan pill
Radix et Rhizoma Gentianae Radix Bupleuri RadixScutellariae Fructus Gardeniae Rhizoma alismatisCaulis Akebiae Semen Plantaginis Radix Angelicaesinensis Radix Rehmanniae Radix Glycyrrhizae
Curing hepatochlic hygropyrexia dizziness deafnesstinnitus and mouth-bitterness
Qingwen Jiedu pill
Radix Bupleuri Folium isatidis Fructus ForsythiaeRadix Scrophulariae Radix Trichosanthis RadixPlatycodonis Fructus Arctii Radix SaposhnikoviaRadix Puerariae lobatae Radix Scutellariae RadixAngelicae dahuricae Rhizoma Chuanxiong and others
Curing headache throat-drying and mumps
Shugan Hewei pill
Rhizoma Cyperi Radix Paeoniae Alba Fructus citriSarcodactylis Radix Aucklandiae Radix CurcumaeRhizoma Atractylodis Macrocephalae PericarpiumCitri Reticulatae Radix Bupleuri Herba PogostemonisRadix Glycyrrhizae Semen Raphani and others
Curing disharmony between liver and stomachepigastric pain inappetence and vomiting
Huayu Quban capsuleRadix Bupleuri Radix Scutellariae Radix Angelicaesinensis Herba menthae haplocalycis Flos CarthamiRadix Paeoniae Rubra
Curing chloasma and acne
BioMed Research International 5
Table 1 Continued
Preparation name Compositions Traditional uses
Ruzengning capsuleRadix Bupleuri Folium Artemisiae Argyi FoliumEpimedii Fructus Toosendan Radix AsparagiRhizoma bolbostemmatis
Curing lump in breast and mammary gland hyperplasia
Mangan Jieyu capsule
Radix Bupleuri Radix Angelicae sinensis RadixPaeoniae Alba Atractylodis Macrocephalae RhizomaPoria Radix Glycyrrhizae Herba menthae haplocalycisRadix et Rhizoma Salviae miltiorrhizae FructusToosendan Fructus citri Rhizoma Corydalis andothers
Curing chest congestion inappetence abdominaldistention and chronic hepatitis
Biyuanshu capsule
Radix Bupleuri Radix Scutellariae Herba menthaehaplocalycis Radix Angelicae dahuricae FlosMagnoliae Fructus Xanthii Fructus Gardeniae Radixet Rhizoma Asari Rhizoma Chuanxiong RadixAstragali Radix Platycodonis Poria Caulis Akebiae
Curing rhinitis and nasosinusitis
Figure 1The whole plant of Bupleurum chinenseDC (A) the whole plant of Bupleurum scorzonerifoliumWilld (B) the roots of Bupleurumchinense DC (C) the roots of Bupleurum scorzonerifoliumWilld (D)
bioactive compounds owing to their antifungal and anti-inflammatory activities [37 38] In one study the essentialoils in Radix Bupleuri were extracted by steam distillationand solvent extraction and then analyzed by GCMS 78peaks were identified Among these peaks the major volatilecompounds were 3-methylbutanal (724) pentanal (574)hexanal (2011) furan-2-carbaldehyde (2523) and hep-tanal (1207) [39] However in another study the resultsshowed that E-2-heptanal furan 2-pentyl and E-2-nonenalwere some of the main compounds of the oil [40]
42 Triterpenoid Saponins Triterpenoid saponins are themain active components of Radix Bupleuri which exhibit abroad spectrum of biological and pharmacological effectsincluding analgesic immunomodulatory hepatoprotectiveimmunomodulatory anti-inflammatory antitumor andantiviral activities [3 41ndash43] Currently approximately 35saponins have been isolated from Radix Bupleuri (Figure 2)[44ndash54] Among them saikosaponins a c and d are themajor bioactive constituents found in Radix Bupleurihowever a variety of minor saikosaponins have also been
isolated [16] The cytotoxic and antiproliferative effects ofsaikosaponins a and d have been attracting much interest inrecent years [55] Additionally more information about theintimate relationship between the structural characterizationof saikosaponins and their cytotoxic evaluations is verynecessary
43 Polyacetylenes Four polyacetylene compounds fromRadix Bupleuri have been identified including (2Z8Z10E)-pentadecatriene-46-diyne-1-ol (36) (2Z8E10E)-pentadec-atriene-46-diyne-1-ol (37) (2Z8Z10E)-heptadecatriene-46-diyne-1-ol (38) and bupleurynol (39) (Figure 3) [56 57]
44 Flavonoids So far twelve flavonoids have been isolatedand identified from Radix Bupleuri including quercetin(40) isorhamnetin (41) isorhamnetin-3-O-glucoside (42)puerarin (43) rutin (44) narcissin (45) eugenin (46)saikochromeA (47) saikochromic acid (48) 741015840-dihydroxy-isoflavone-7-O-120573-D-glucoside (49) saikochromosideA (50)and saikoisoflavonoside A (51) (Figure 4) [58ndash63]
6 BioMed Research International
Table 2 Chemical compounds isolated from Radix Bupleuri
Classification Number Chemical component Reference
Saponins
1 Saikosaponin a [44]2 Saikosaponin c [44]3 Saikosaponin d [44]4 Saikosaponin e [45]5 Prosaikogenin G [46]6 Prosaikogenin F [46]7 210158401015840-O-Acetylsaikosaponin a [47]8 310158401015840-O-Acetylsaikosaponin a [48]9 610158401015840-O-Acetylsaikosaponin a [49]10 23-O-Acetylsaikosaponin a [50]11 610158401015840-O-Acetylsaikosaponin d [51]
12 23-Hydroxy-13120573 28120573-epoxy-olean-11-ene-16-one3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside [52]
13 312057316120573-Dihydroxy-23-O-acetyl-13120573 28120573-epoxy-olean-11-ene3-O-120573-D-fucopyranoside [47]
14 Bupleuroside I [45]15 Saikosaponin b1 [45 49]16 Saikosaponin b2 [45 49]17 610158401015840-O-Acetyl-saikosaponin b2 [51]18 Saikosaponin h [47 53]19 Prosaikogenin D [54]20 Prosaikogenin A [47]
2131205732328-Trihydroxy-11 13(18)-diene-16-one
3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside
[47]
22 Bupleuroside V [45]23 Bupleuroside X [45]24 Bupleuroside XII [45]25 Saikosaponin v-1 [51]26 Saikosaponin b3 [44 53]27 Saikosaponin b4 [44 53]28 Saikosaponin f [45]
29 3120573161205732328-Tetrahydroxy-11120572-methoxy-olean-12-ene3-O-120573-D-fucopyranoside [47]
30 31205731612057328-Trihydroxyl-11120572-methoxy-olean-12-ene-O-120573-D-fucopyranoside [47]
31 Bupleuroside VII [45]32 Saikosaponin g [53]33 Saikosaponin i [53]34 Bupleuroside VIII [45]35 Bupleuroside XI [45]
Polyacetylenes
36 (2Z8Z10E)-pentadecatriene-46-diyne-1-ol [56]37 (2Z8E10E)-pentadecatriene-46-diyne-1-ol [56 57]38 (2Z8Z10E)-heptadecatriene-46-diyne-1-ol [56]39 Bupleurynol [56 57]
BioMed Research International 7
Table 2 Continued
Classification Number Chemical component Reference
Flavonoids
40 Quercetin [60]41 Isorhamnetin [60]42 Isorhamnetin-3-O-glucoside [60]43 Puerarin [60]44 Rutin [60]45 Narcissin [59]46 Eugenin [62]47 Saikochrome A [62 63]48 Saikochromic acid [60]49 741015840-Dihydroxy-isoflavone-7-O-120573-D-glucoside [60]50 Saikochromoside A [59]51 Saikoisoflavonoside A [61]
Lignans
52 Nortrachelogenin [63]53 Nemerosin [62]54 Kaerophyllin [62]55 Isochaihulactone [62]56 Isokaerophyllin [62]57 (minus)-yatein [62]58 Chinensinaphthol [62]59 Chaihunaphthone [62]
Fatty acids
60 Fumaric acid [64]61 Butanedioic acid [64]62 Pentadecanoic acid [65]63 Palmitoleic acid [65]64 Palmitic acid [65]65 Oleic acid [65]66 Stearic acid [65]67 11-Hexadecenoic acid [65]68 13-Octadecenoic acid [65]69 Linoleic acid [65]70 Tetracosanoic acid [64]71 9S12S13S-Trihydroxy-10E-octadecenoic acid [63]
Sterols72 120572-Spinasterol [64]73 24120585-Methylcholesta-7 22E-diene-312057351205726120573-triol [63]74 24120585-Ethylcholest-22E-end-312057351205726120573-Triol [63]
45 Ligans Lignans existing in numerous plants weredetected in the roots of Bupleurum scorzonerifolium WilldThese lignans included nortrachelogenin (52) nemerosin(53) kaerophyllin (54) isochaihulactone (55) isokaero-phyllin (56) (minus)-yatein (57) chinensinaphthol (58) andchaihunaphthone (59) (Figure 5) [62 63]
46 Other Compounds There are also other components inRadix Bupleuri including 12 fatty acids fumaric acid (60)butanedioic acid (61) pentadecanoic acid (62) palmitoleicacid (63) palmitic acid (64) oleic acid (65) stearic acid(66) 11-hexadecenoic acid (67) 13-octadecenoic acid (68)
linoleic acid (69) tetracosanoic acid (70) and 9S12S13S-trihydroxy-10E-octadecenoic acid (71) Three sterols com-pounds namely 120572-spinasterol (72) 24120585-methylcholesta-7 22E-diene-312057351205726120573-triol (73) and 24120585-ethylcholest-22E-end-312057351205726120573-triol (74) were also isolated and identified fromthis plant (Figure 6) [63ndash65]
5 Pharmacological Effects
Radix Bupleuri exerts a great variety of pharmacologi-cal activities due to its complexbioactive compounds Anoverview of the pharmacological studies on Radix Bupleuriispresented in detail in the following sections
8 BioMed Research International
O
R1
R1 R2 R3 R4
R2R1
R1 R2
R1 R2
R3
R3 R4
R1
R1
R2
R2
R3
R1
R1
R1
R2
R3
CH2R2
CH2R3
CH2R2
CH2OH
CH2OH
CH2OH
CH2OH
R3O
R4O
R4O
R3O
R2O
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH훽-OH훽-OH훽-OH훽-OH
훽-OH
훽-OH훽-OH
훽-OH훽-OH훽-OH훽-OH
훽-OH훽-OH
훼-OH
훼-OH
훼-OH
훼-OH훼-OH훼-OH
훼-OH
훼-OH
훼-OH
훼-OH
OH
OH
OHOHOHOHOH
OHOH
OH
1234567891011121314
1516171819202122232425
262728293031
3233
3435
H
H
OAc
OAc=O
=O
=O
COOH
COOH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Fuc-훽-D-Fuc-
2㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-3㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-2)-훽-D-Glc-(1-3)-훽-D-Fuc-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
COOCH2-(CHOH)3-CH2OHCH2OH
CH2OH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
6㰀㰀-acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-
OCH3
OCH3
OCH3
OHOH
OH
OH
OCH3
H
HH
H
H
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-2)-훽-D-Ara-(1-3)-훽-D-GlcA-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
Figure 2 Chemical structures of triterpenoid saponins
BioMed Research International 9
OH
OH
3736
3938
OH
OH
Figure 3 Chemical structures of polyacetylenes
51 Anti-inflammatory Effects Radix Bupleuri has beenwidely used for the treatment of several types of chronicinflammatory diseases The crude polysaccharides(80mgkg) isolated from the roots of Bupleurum chinenseDC significantly attenuated lung injury by inhibiting thelevel of myeloperoxidase (MPO) tumor necrosis factor-120572(TNF-120572) and serum nitric oxide (NO) [66] Chun et alreported that saikosaponins from Radix Bupleuri exhibitedanti-inflammatory activity on inflammatory processesincluding inhibition of inflammatory exudation capillarypermeability inflammatory mediators release migrationof white cells connective tissue hyperplasia and a varietyof allergic inflammation [67] Ma et al was the first toshow that saikosaponins exerted anti-inflammatory activityon paw edema mainly via regulating the nicotinate andnicotinamide metabolism and arachidonic acid metabolism[5] Zhu et al found that saikosaponin a (SSa) exhibitedan inhibitory effect on proinflammatory cytokines inLPS-stimulated macrophages The mechanism of theseactions involved the regulation of MAPK and NF-120581B signalspathways [68] In another study SSa dose-dependentlyinhibited the production of ROS TNF-120572 IL-8 COX-2 andiNOS in LPS-stimulated human umbilical endothelial cells(HUVECs) by upregulating of the LXR120572-ABCA1 signalingpathway [69] Moreover Lee et al showed that saikosaponinc (SSc) was also shown to inhibited LPS-induced apoptosis inHUVECs via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation [70] Zhao et al showed thatSSa also suppressed TNF-120572 and IL-6 concentrations inthe intestines of septic rats through the inhibition of thenucleotide-binding oligomerization domain 2 (NOD2)NF-120581B signaling pathway [71] Saikosaponin d (SSd) has beenreported to inhibit PGE2 production and intracellular freeCa2+ concentration ([Ca2+]i) in a concentration-dependentmanner with an IC50 value of 3 120583m in C6 rat glioma cells[72]
In addition several studies showed that a widerange of Radix Bupleuri preparations also exhibited anti-inflammatory effects in in vitro and in vivo model Li et alshowed that Saireito and its active components (SSd) couldsuppress the proliferation of mesangial cells and expansionof the mesangial matrix in the rat glomerulonephritismodel [73] In experimental chronic pancreatitis rats modelldquoChai-hu-shu-gan powderrdquo exerted anti-inflammatory andantifibrotic effects by inhibiting the expression of nuclearfactor-120581B (NF-120581B) and TNF-120572 mRNA in the pancreas [74]Furthermore it also reduced the abnormally high plasmalevel of cholecystokinin improved the gastricmovement andavoided nausea and flatulence [75] In another experimenta Chinese herbal formula called ldquoRCM-101rdquo (containingFlos magnoliae Radix Bupleuri Radix Glycyrrhizae RadixAngelicae Sinensis etc) inhibited the NO production andiNOS protein expression in LPS-stimulated rat aorta andRaw 2647 macrophages [76]
52 Anticancer Effects The extracts and compounds ofRadix Bupleuri also possessed anticancerantitumor effectThe acetone extract of Bupleurum scorzonerifolium couldinhibit the proliferation of A549 human lung cancer cellsin a dose-dependent manner via causing cell cycle arrestin the G2M phase increasing microtubule stabilizationsuppressing telomerase activity activating ERK 12 andcaspase-39 in A549 cells [77ndash79] Saponins isolated fromRadix Bupleuri also exhibited significantly anti-proliferativeactivity in human non-small cell lung cancer A549 cellsthrough Fas-dependent apoptotic pathway [80] Su et alfound that thewater extracts ofRadix Bupleuri could enhance5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cellsthrough cell arrest at the late G1early S phase while pro-tecting normal blood lymphocytes [6] SSd showed verypotent activity against the HepG2 cell line with an IC50value of 125mgml The mechanism of cytotoxicity was
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Medicinal ChemistryInternational Journal of
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AddictionJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
4 BioMed Research International
Table 1 Continued
Preparation name Compositions Traditional uses
Yigan Yiqi Jieyu Keli
Radix Bupleuri Fructus Aurantii Radix Paeoniae AlbaRadix et Rhizoma Salviae miltiorrhizae RadixAstragali Radix Codonopsis Ramulus cinnamomiPoria Acanthopanax senticosus (Rupr et Maxim)Harms Fructus trichosanthis Rhizoma PinelliaePreparatum and others
Curing chronic hepatitis hypochondriac pain bloatingand lassitude
Xiaorsquo er Tuire Keli
Radix Bupleuri Folium isatidis Radix Isatidis FlosLonicerae Japonicae Cortex Moutan Cape JasmineFruit Radix Scutellariae Herba Lophatheri PheretimaRhizoma paridis Radix et Rhizoma Cynanchi Atrati
Curing cold due to exogenous wind-heat in children
Dalitong Keli
Radix Bupleuri Fructus Aurantii Radix AucklandiaePericarpium Citri Reticulatae Pinelliae RhizomaPraeparatum Cum Alumine Herba Taraxaci Crataegifructus Semen Arecae Paederia scandens RadixCodonopsis Rhizoma Corydalis Massa MedicataFermentata
Curing epigastric fullness belching dry mouth andmouth pain
Bubai Keli
Fructus Psoraleae Dolichos lablab L Folium EpimediiRadix Bupleuri Radix et Rhizoma Salviaemiltiorrhizae Vigna umbellata Ohwi et Ohashi RadixSophorae Flavescentis Glycine max (L) Merr
Nourishing the spleen and warming the kidneys
Ganmao Qingre Keli
Schizonepetae Spica Radix Bupleuri Herba menthaehaplocalycis Radix Saposhnikovia Perillae FoliumRadix Puerariae lobatae Radix Platycodonis SemenArmeniacae amarum Radix Angelicae dahuricaeCorydalis bungeana Herba
Curing cold cough fever headache rhinorrhea andpharyngoxerosis
Qizhi Weitong tabletRadix Bupleuri Rhizoma Corydalis Rhizoma CyperiFructus Aurantii Radix Paeoniae Alba RadixGlycyrrhizae
Curing stagnation of liver qi abdominal distention andepigastric pain
Lidan tablet
Rheum palmatum Flos Lonicerae Japonicae HerbaLysimachiae Radix Aucklandiae RhizomaAnemarrhenae Folium isatidis Radix Bupleuri RadixPaeoniae Alba Radix Scutellariae Natrii Sulfas HerbaArtemisiae Scopariae
Curing hypochondriac pain constipation oliguria withreddish urine headache and vomiting
Ruhe Sanjie tablet
Radix Bupleuri Radix Angelicae sinensis RadixAstragali Radix Curcumae Tulipa edulis RadixRhapontici Ecklonia kurome Okam SargassumFolium Epimedii Herba Pyrolae
Curing lump in breast and mammary glandhyperplasia
Jianwei Yuyang tablet
Radix Bupleuri Radix Paeoniae Alba RadixCodonopsis Rhizoma Corydalis Bletilla striata(Thunb) Reiehb f Indigo Naturalis ConchaMargaritifera Usta
Curing dysphoria distention and loose stools andpeptic ulcer
Longdan Xiegan pill
Radix et Rhizoma Gentianae Radix Bupleuri RadixScutellariae Fructus Gardeniae Rhizoma alismatisCaulis Akebiae Semen Plantaginis Radix Angelicaesinensis Radix Rehmanniae Radix Glycyrrhizae
Curing hepatochlic hygropyrexia dizziness deafnesstinnitus and mouth-bitterness
Qingwen Jiedu pill
Radix Bupleuri Folium isatidis Fructus ForsythiaeRadix Scrophulariae Radix Trichosanthis RadixPlatycodonis Fructus Arctii Radix SaposhnikoviaRadix Puerariae lobatae Radix Scutellariae RadixAngelicae dahuricae Rhizoma Chuanxiong and others
Curing headache throat-drying and mumps
Shugan Hewei pill
Rhizoma Cyperi Radix Paeoniae Alba Fructus citriSarcodactylis Radix Aucklandiae Radix CurcumaeRhizoma Atractylodis Macrocephalae PericarpiumCitri Reticulatae Radix Bupleuri Herba PogostemonisRadix Glycyrrhizae Semen Raphani and others
Curing disharmony between liver and stomachepigastric pain inappetence and vomiting
Huayu Quban capsuleRadix Bupleuri Radix Scutellariae Radix Angelicaesinensis Herba menthae haplocalycis Flos CarthamiRadix Paeoniae Rubra
Curing chloasma and acne
BioMed Research International 5
Table 1 Continued
Preparation name Compositions Traditional uses
Ruzengning capsuleRadix Bupleuri Folium Artemisiae Argyi FoliumEpimedii Fructus Toosendan Radix AsparagiRhizoma bolbostemmatis
Curing lump in breast and mammary gland hyperplasia
Mangan Jieyu capsule
Radix Bupleuri Radix Angelicae sinensis RadixPaeoniae Alba Atractylodis Macrocephalae RhizomaPoria Radix Glycyrrhizae Herba menthae haplocalycisRadix et Rhizoma Salviae miltiorrhizae FructusToosendan Fructus citri Rhizoma Corydalis andothers
Curing chest congestion inappetence abdominaldistention and chronic hepatitis
Biyuanshu capsule
Radix Bupleuri Radix Scutellariae Herba menthaehaplocalycis Radix Angelicae dahuricae FlosMagnoliae Fructus Xanthii Fructus Gardeniae Radixet Rhizoma Asari Rhizoma Chuanxiong RadixAstragali Radix Platycodonis Poria Caulis Akebiae
Curing rhinitis and nasosinusitis
Figure 1The whole plant of Bupleurum chinenseDC (A) the whole plant of Bupleurum scorzonerifoliumWilld (B) the roots of Bupleurumchinense DC (C) the roots of Bupleurum scorzonerifoliumWilld (D)
bioactive compounds owing to their antifungal and anti-inflammatory activities [37 38] In one study the essentialoils in Radix Bupleuri were extracted by steam distillationand solvent extraction and then analyzed by GCMS 78peaks were identified Among these peaks the major volatilecompounds were 3-methylbutanal (724) pentanal (574)hexanal (2011) furan-2-carbaldehyde (2523) and hep-tanal (1207) [39] However in another study the resultsshowed that E-2-heptanal furan 2-pentyl and E-2-nonenalwere some of the main compounds of the oil [40]
42 Triterpenoid Saponins Triterpenoid saponins are themain active components of Radix Bupleuri which exhibit abroad spectrum of biological and pharmacological effectsincluding analgesic immunomodulatory hepatoprotectiveimmunomodulatory anti-inflammatory antitumor andantiviral activities [3 41ndash43] Currently approximately 35saponins have been isolated from Radix Bupleuri (Figure 2)[44ndash54] Among them saikosaponins a c and d are themajor bioactive constituents found in Radix Bupleurihowever a variety of minor saikosaponins have also been
isolated [16] The cytotoxic and antiproliferative effects ofsaikosaponins a and d have been attracting much interest inrecent years [55] Additionally more information about theintimate relationship between the structural characterizationof saikosaponins and their cytotoxic evaluations is verynecessary
43 Polyacetylenes Four polyacetylene compounds fromRadix Bupleuri have been identified including (2Z8Z10E)-pentadecatriene-46-diyne-1-ol (36) (2Z8E10E)-pentadec-atriene-46-diyne-1-ol (37) (2Z8Z10E)-heptadecatriene-46-diyne-1-ol (38) and bupleurynol (39) (Figure 3) [56 57]
44 Flavonoids So far twelve flavonoids have been isolatedand identified from Radix Bupleuri including quercetin(40) isorhamnetin (41) isorhamnetin-3-O-glucoside (42)puerarin (43) rutin (44) narcissin (45) eugenin (46)saikochromeA (47) saikochromic acid (48) 741015840-dihydroxy-isoflavone-7-O-120573-D-glucoside (49) saikochromosideA (50)and saikoisoflavonoside A (51) (Figure 4) [58ndash63]
6 BioMed Research International
Table 2 Chemical compounds isolated from Radix Bupleuri
Classification Number Chemical component Reference
Saponins
1 Saikosaponin a [44]2 Saikosaponin c [44]3 Saikosaponin d [44]4 Saikosaponin e [45]5 Prosaikogenin G [46]6 Prosaikogenin F [46]7 210158401015840-O-Acetylsaikosaponin a [47]8 310158401015840-O-Acetylsaikosaponin a [48]9 610158401015840-O-Acetylsaikosaponin a [49]10 23-O-Acetylsaikosaponin a [50]11 610158401015840-O-Acetylsaikosaponin d [51]
12 23-Hydroxy-13120573 28120573-epoxy-olean-11-ene-16-one3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside [52]
13 312057316120573-Dihydroxy-23-O-acetyl-13120573 28120573-epoxy-olean-11-ene3-O-120573-D-fucopyranoside [47]
14 Bupleuroside I [45]15 Saikosaponin b1 [45 49]16 Saikosaponin b2 [45 49]17 610158401015840-O-Acetyl-saikosaponin b2 [51]18 Saikosaponin h [47 53]19 Prosaikogenin D [54]20 Prosaikogenin A [47]
2131205732328-Trihydroxy-11 13(18)-diene-16-one
3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside
[47]
22 Bupleuroside V [45]23 Bupleuroside X [45]24 Bupleuroside XII [45]25 Saikosaponin v-1 [51]26 Saikosaponin b3 [44 53]27 Saikosaponin b4 [44 53]28 Saikosaponin f [45]
29 3120573161205732328-Tetrahydroxy-11120572-methoxy-olean-12-ene3-O-120573-D-fucopyranoside [47]
30 31205731612057328-Trihydroxyl-11120572-methoxy-olean-12-ene-O-120573-D-fucopyranoside [47]
31 Bupleuroside VII [45]32 Saikosaponin g [53]33 Saikosaponin i [53]34 Bupleuroside VIII [45]35 Bupleuroside XI [45]
Polyacetylenes
36 (2Z8Z10E)-pentadecatriene-46-diyne-1-ol [56]37 (2Z8E10E)-pentadecatriene-46-diyne-1-ol [56 57]38 (2Z8Z10E)-heptadecatriene-46-diyne-1-ol [56]39 Bupleurynol [56 57]
BioMed Research International 7
Table 2 Continued
Classification Number Chemical component Reference
Flavonoids
40 Quercetin [60]41 Isorhamnetin [60]42 Isorhamnetin-3-O-glucoside [60]43 Puerarin [60]44 Rutin [60]45 Narcissin [59]46 Eugenin [62]47 Saikochrome A [62 63]48 Saikochromic acid [60]49 741015840-Dihydroxy-isoflavone-7-O-120573-D-glucoside [60]50 Saikochromoside A [59]51 Saikoisoflavonoside A [61]
Lignans
52 Nortrachelogenin [63]53 Nemerosin [62]54 Kaerophyllin [62]55 Isochaihulactone [62]56 Isokaerophyllin [62]57 (minus)-yatein [62]58 Chinensinaphthol [62]59 Chaihunaphthone [62]
Fatty acids
60 Fumaric acid [64]61 Butanedioic acid [64]62 Pentadecanoic acid [65]63 Palmitoleic acid [65]64 Palmitic acid [65]65 Oleic acid [65]66 Stearic acid [65]67 11-Hexadecenoic acid [65]68 13-Octadecenoic acid [65]69 Linoleic acid [65]70 Tetracosanoic acid [64]71 9S12S13S-Trihydroxy-10E-octadecenoic acid [63]
Sterols72 120572-Spinasterol [64]73 24120585-Methylcholesta-7 22E-diene-312057351205726120573-triol [63]74 24120585-Ethylcholest-22E-end-312057351205726120573-Triol [63]
45 Ligans Lignans existing in numerous plants weredetected in the roots of Bupleurum scorzonerifolium WilldThese lignans included nortrachelogenin (52) nemerosin(53) kaerophyllin (54) isochaihulactone (55) isokaero-phyllin (56) (minus)-yatein (57) chinensinaphthol (58) andchaihunaphthone (59) (Figure 5) [62 63]
46 Other Compounds There are also other components inRadix Bupleuri including 12 fatty acids fumaric acid (60)butanedioic acid (61) pentadecanoic acid (62) palmitoleicacid (63) palmitic acid (64) oleic acid (65) stearic acid(66) 11-hexadecenoic acid (67) 13-octadecenoic acid (68)
linoleic acid (69) tetracosanoic acid (70) and 9S12S13S-trihydroxy-10E-octadecenoic acid (71) Three sterols com-pounds namely 120572-spinasterol (72) 24120585-methylcholesta-7 22E-diene-312057351205726120573-triol (73) and 24120585-ethylcholest-22E-end-312057351205726120573-triol (74) were also isolated and identified fromthis plant (Figure 6) [63ndash65]
5 Pharmacological Effects
Radix Bupleuri exerts a great variety of pharmacologi-cal activities due to its complexbioactive compounds Anoverview of the pharmacological studies on Radix Bupleuriispresented in detail in the following sections
8 BioMed Research International
O
R1
R1 R2 R3 R4
R2R1
R1 R2
R1 R2
R3
R3 R4
R1
R1
R2
R2
R3
R1
R1
R1
R2
R3
CH2R2
CH2R3
CH2R2
CH2OH
CH2OH
CH2OH
CH2OH
R3O
R4O
R4O
R3O
R2O
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH훽-OH훽-OH훽-OH훽-OH
훽-OH
훽-OH훽-OH
훽-OH훽-OH훽-OH훽-OH
훽-OH훽-OH
훼-OH
훼-OH
훼-OH
훼-OH훼-OH훼-OH
훼-OH
훼-OH
훼-OH
훼-OH
OH
OH
OHOHOHOHOH
OHOH
OH
1234567891011121314
1516171819202122232425
262728293031
3233
3435
H
H
OAc
OAc=O
=O
=O
COOH
COOH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Fuc-훽-D-Fuc-
2㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-3㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-2)-훽-D-Glc-(1-3)-훽-D-Fuc-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
COOCH2-(CHOH)3-CH2OHCH2OH
CH2OH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
6㰀㰀-acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-
OCH3
OCH3
OCH3
OHOH
OH
OH
OCH3
H
HH
H
H
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-2)-훽-D-Ara-(1-3)-훽-D-GlcA-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
Figure 2 Chemical structures of triterpenoid saponins
BioMed Research International 9
OH
OH
3736
3938
OH
OH
Figure 3 Chemical structures of polyacetylenes
51 Anti-inflammatory Effects Radix Bupleuri has beenwidely used for the treatment of several types of chronicinflammatory diseases The crude polysaccharides(80mgkg) isolated from the roots of Bupleurum chinenseDC significantly attenuated lung injury by inhibiting thelevel of myeloperoxidase (MPO) tumor necrosis factor-120572(TNF-120572) and serum nitric oxide (NO) [66] Chun et alreported that saikosaponins from Radix Bupleuri exhibitedanti-inflammatory activity on inflammatory processesincluding inhibition of inflammatory exudation capillarypermeability inflammatory mediators release migrationof white cells connective tissue hyperplasia and a varietyof allergic inflammation [67] Ma et al was the first toshow that saikosaponins exerted anti-inflammatory activityon paw edema mainly via regulating the nicotinate andnicotinamide metabolism and arachidonic acid metabolism[5] Zhu et al found that saikosaponin a (SSa) exhibitedan inhibitory effect on proinflammatory cytokines inLPS-stimulated macrophages The mechanism of theseactions involved the regulation of MAPK and NF-120581B signalspathways [68] In another study SSa dose-dependentlyinhibited the production of ROS TNF-120572 IL-8 COX-2 andiNOS in LPS-stimulated human umbilical endothelial cells(HUVECs) by upregulating of the LXR120572-ABCA1 signalingpathway [69] Moreover Lee et al showed that saikosaponinc (SSc) was also shown to inhibited LPS-induced apoptosis inHUVECs via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation [70] Zhao et al showed thatSSa also suppressed TNF-120572 and IL-6 concentrations inthe intestines of septic rats through the inhibition of thenucleotide-binding oligomerization domain 2 (NOD2)NF-120581B signaling pathway [71] Saikosaponin d (SSd) has beenreported to inhibit PGE2 production and intracellular freeCa2+ concentration ([Ca2+]i) in a concentration-dependentmanner with an IC50 value of 3 120583m in C6 rat glioma cells[72]
In addition several studies showed that a widerange of Radix Bupleuri preparations also exhibited anti-inflammatory effects in in vitro and in vivo model Li et alshowed that Saireito and its active components (SSd) couldsuppress the proliferation of mesangial cells and expansionof the mesangial matrix in the rat glomerulonephritismodel [73] In experimental chronic pancreatitis rats modelldquoChai-hu-shu-gan powderrdquo exerted anti-inflammatory andantifibrotic effects by inhibiting the expression of nuclearfactor-120581B (NF-120581B) and TNF-120572 mRNA in the pancreas [74]Furthermore it also reduced the abnormally high plasmalevel of cholecystokinin improved the gastricmovement andavoided nausea and flatulence [75] In another experimenta Chinese herbal formula called ldquoRCM-101rdquo (containingFlos magnoliae Radix Bupleuri Radix Glycyrrhizae RadixAngelicae Sinensis etc) inhibited the NO production andiNOS protein expression in LPS-stimulated rat aorta andRaw 2647 macrophages [76]
52 Anticancer Effects The extracts and compounds ofRadix Bupleuri also possessed anticancerantitumor effectThe acetone extract of Bupleurum scorzonerifolium couldinhibit the proliferation of A549 human lung cancer cellsin a dose-dependent manner via causing cell cycle arrestin the G2M phase increasing microtubule stabilizationsuppressing telomerase activity activating ERK 12 andcaspase-39 in A549 cells [77ndash79] Saponins isolated fromRadix Bupleuri also exhibited significantly anti-proliferativeactivity in human non-small cell lung cancer A549 cellsthrough Fas-dependent apoptotic pathway [80] Su et alfound that thewater extracts ofRadix Bupleuri could enhance5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cellsthrough cell arrest at the late G1early S phase while pro-tecting normal blood lymphocytes [6] SSd showed verypotent activity against the HepG2 cell line with an IC50value of 125mgml The mechanism of cytotoxicity was
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
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[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
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20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
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the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
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[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
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[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
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[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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Pharmaceutics
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MEDIATORSINFLAMMATION
of
BioMed Research International 5
Table 1 Continued
Preparation name Compositions Traditional uses
Ruzengning capsuleRadix Bupleuri Folium Artemisiae Argyi FoliumEpimedii Fructus Toosendan Radix AsparagiRhizoma bolbostemmatis
Curing lump in breast and mammary gland hyperplasia
Mangan Jieyu capsule
Radix Bupleuri Radix Angelicae sinensis RadixPaeoniae Alba Atractylodis Macrocephalae RhizomaPoria Radix Glycyrrhizae Herba menthae haplocalycisRadix et Rhizoma Salviae miltiorrhizae FructusToosendan Fructus citri Rhizoma Corydalis andothers
Curing chest congestion inappetence abdominaldistention and chronic hepatitis
Biyuanshu capsule
Radix Bupleuri Radix Scutellariae Herba menthaehaplocalycis Radix Angelicae dahuricae FlosMagnoliae Fructus Xanthii Fructus Gardeniae Radixet Rhizoma Asari Rhizoma Chuanxiong RadixAstragali Radix Platycodonis Poria Caulis Akebiae
Curing rhinitis and nasosinusitis
Figure 1The whole plant of Bupleurum chinenseDC (A) the whole plant of Bupleurum scorzonerifoliumWilld (B) the roots of Bupleurumchinense DC (C) the roots of Bupleurum scorzonerifoliumWilld (D)
bioactive compounds owing to their antifungal and anti-inflammatory activities [37 38] In one study the essentialoils in Radix Bupleuri were extracted by steam distillationand solvent extraction and then analyzed by GCMS 78peaks were identified Among these peaks the major volatilecompounds were 3-methylbutanal (724) pentanal (574)hexanal (2011) furan-2-carbaldehyde (2523) and hep-tanal (1207) [39] However in another study the resultsshowed that E-2-heptanal furan 2-pentyl and E-2-nonenalwere some of the main compounds of the oil [40]
42 Triterpenoid Saponins Triterpenoid saponins are themain active components of Radix Bupleuri which exhibit abroad spectrum of biological and pharmacological effectsincluding analgesic immunomodulatory hepatoprotectiveimmunomodulatory anti-inflammatory antitumor andantiviral activities [3 41ndash43] Currently approximately 35saponins have been isolated from Radix Bupleuri (Figure 2)[44ndash54] Among them saikosaponins a c and d are themajor bioactive constituents found in Radix Bupleurihowever a variety of minor saikosaponins have also been
isolated [16] The cytotoxic and antiproliferative effects ofsaikosaponins a and d have been attracting much interest inrecent years [55] Additionally more information about theintimate relationship between the structural characterizationof saikosaponins and their cytotoxic evaluations is verynecessary
43 Polyacetylenes Four polyacetylene compounds fromRadix Bupleuri have been identified including (2Z8Z10E)-pentadecatriene-46-diyne-1-ol (36) (2Z8E10E)-pentadec-atriene-46-diyne-1-ol (37) (2Z8Z10E)-heptadecatriene-46-diyne-1-ol (38) and bupleurynol (39) (Figure 3) [56 57]
44 Flavonoids So far twelve flavonoids have been isolatedand identified from Radix Bupleuri including quercetin(40) isorhamnetin (41) isorhamnetin-3-O-glucoside (42)puerarin (43) rutin (44) narcissin (45) eugenin (46)saikochromeA (47) saikochromic acid (48) 741015840-dihydroxy-isoflavone-7-O-120573-D-glucoside (49) saikochromosideA (50)and saikoisoflavonoside A (51) (Figure 4) [58ndash63]
6 BioMed Research International
Table 2 Chemical compounds isolated from Radix Bupleuri
Classification Number Chemical component Reference
Saponins
1 Saikosaponin a [44]2 Saikosaponin c [44]3 Saikosaponin d [44]4 Saikosaponin e [45]5 Prosaikogenin G [46]6 Prosaikogenin F [46]7 210158401015840-O-Acetylsaikosaponin a [47]8 310158401015840-O-Acetylsaikosaponin a [48]9 610158401015840-O-Acetylsaikosaponin a [49]10 23-O-Acetylsaikosaponin a [50]11 610158401015840-O-Acetylsaikosaponin d [51]
12 23-Hydroxy-13120573 28120573-epoxy-olean-11-ene-16-one3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside [52]
13 312057316120573-Dihydroxy-23-O-acetyl-13120573 28120573-epoxy-olean-11-ene3-O-120573-D-fucopyranoside [47]
14 Bupleuroside I [45]15 Saikosaponin b1 [45 49]16 Saikosaponin b2 [45 49]17 610158401015840-O-Acetyl-saikosaponin b2 [51]18 Saikosaponin h [47 53]19 Prosaikogenin D [54]20 Prosaikogenin A [47]
2131205732328-Trihydroxy-11 13(18)-diene-16-one
3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside
[47]
22 Bupleuroside V [45]23 Bupleuroside X [45]24 Bupleuroside XII [45]25 Saikosaponin v-1 [51]26 Saikosaponin b3 [44 53]27 Saikosaponin b4 [44 53]28 Saikosaponin f [45]
29 3120573161205732328-Tetrahydroxy-11120572-methoxy-olean-12-ene3-O-120573-D-fucopyranoside [47]
30 31205731612057328-Trihydroxyl-11120572-methoxy-olean-12-ene-O-120573-D-fucopyranoside [47]
31 Bupleuroside VII [45]32 Saikosaponin g [53]33 Saikosaponin i [53]34 Bupleuroside VIII [45]35 Bupleuroside XI [45]
Polyacetylenes
36 (2Z8Z10E)-pentadecatriene-46-diyne-1-ol [56]37 (2Z8E10E)-pentadecatriene-46-diyne-1-ol [56 57]38 (2Z8Z10E)-heptadecatriene-46-diyne-1-ol [56]39 Bupleurynol [56 57]
BioMed Research International 7
Table 2 Continued
Classification Number Chemical component Reference
Flavonoids
40 Quercetin [60]41 Isorhamnetin [60]42 Isorhamnetin-3-O-glucoside [60]43 Puerarin [60]44 Rutin [60]45 Narcissin [59]46 Eugenin [62]47 Saikochrome A [62 63]48 Saikochromic acid [60]49 741015840-Dihydroxy-isoflavone-7-O-120573-D-glucoside [60]50 Saikochromoside A [59]51 Saikoisoflavonoside A [61]
Lignans
52 Nortrachelogenin [63]53 Nemerosin [62]54 Kaerophyllin [62]55 Isochaihulactone [62]56 Isokaerophyllin [62]57 (minus)-yatein [62]58 Chinensinaphthol [62]59 Chaihunaphthone [62]
Fatty acids
60 Fumaric acid [64]61 Butanedioic acid [64]62 Pentadecanoic acid [65]63 Palmitoleic acid [65]64 Palmitic acid [65]65 Oleic acid [65]66 Stearic acid [65]67 11-Hexadecenoic acid [65]68 13-Octadecenoic acid [65]69 Linoleic acid [65]70 Tetracosanoic acid [64]71 9S12S13S-Trihydroxy-10E-octadecenoic acid [63]
Sterols72 120572-Spinasterol [64]73 24120585-Methylcholesta-7 22E-diene-312057351205726120573-triol [63]74 24120585-Ethylcholest-22E-end-312057351205726120573-Triol [63]
45 Ligans Lignans existing in numerous plants weredetected in the roots of Bupleurum scorzonerifolium WilldThese lignans included nortrachelogenin (52) nemerosin(53) kaerophyllin (54) isochaihulactone (55) isokaero-phyllin (56) (minus)-yatein (57) chinensinaphthol (58) andchaihunaphthone (59) (Figure 5) [62 63]
46 Other Compounds There are also other components inRadix Bupleuri including 12 fatty acids fumaric acid (60)butanedioic acid (61) pentadecanoic acid (62) palmitoleicacid (63) palmitic acid (64) oleic acid (65) stearic acid(66) 11-hexadecenoic acid (67) 13-octadecenoic acid (68)
linoleic acid (69) tetracosanoic acid (70) and 9S12S13S-trihydroxy-10E-octadecenoic acid (71) Three sterols com-pounds namely 120572-spinasterol (72) 24120585-methylcholesta-7 22E-diene-312057351205726120573-triol (73) and 24120585-ethylcholest-22E-end-312057351205726120573-triol (74) were also isolated and identified fromthis plant (Figure 6) [63ndash65]
5 Pharmacological Effects
Radix Bupleuri exerts a great variety of pharmacologi-cal activities due to its complexbioactive compounds Anoverview of the pharmacological studies on Radix Bupleuriispresented in detail in the following sections
8 BioMed Research International
O
R1
R1 R2 R3 R4
R2R1
R1 R2
R1 R2
R3
R3 R4
R1
R1
R2
R2
R3
R1
R1
R1
R2
R3
CH2R2
CH2R3
CH2R2
CH2OH
CH2OH
CH2OH
CH2OH
R3O
R4O
R4O
R3O
R2O
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH훽-OH훽-OH훽-OH훽-OH
훽-OH
훽-OH훽-OH
훽-OH훽-OH훽-OH훽-OH
훽-OH훽-OH
훼-OH
훼-OH
훼-OH
훼-OH훼-OH훼-OH
훼-OH
훼-OH
훼-OH
훼-OH
OH
OH
OHOHOHOHOH
OHOH
OH
1234567891011121314
1516171819202122232425
262728293031
3233
3435
H
H
OAc
OAc=O
=O
=O
COOH
COOH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Fuc-훽-D-Fuc-
2㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-3㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-2)-훽-D-Glc-(1-3)-훽-D-Fuc-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
COOCH2-(CHOH)3-CH2OHCH2OH
CH2OH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
6㰀㰀-acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-
OCH3
OCH3
OCH3
OHOH
OH
OH
OCH3
H
HH
H
H
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-2)-훽-D-Ara-(1-3)-훽-D-GlcA-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
Figure 2 Chemical structures of triterpenoid saponins
BioMed Research International 9
OH
OH
3736
3938
OH
OH
Figure 3 Chemical structures of polyacetylenes
51 Anti-inflammatory Effects Radix Bupleuri has beenwidely used for the treatment of several types of chronicinflammatory diseases The crude polysaccharides(80mgkg) isolated from the roots of Bupleurum chinenseDC significantly attenuated lung injury by inhibiting thelevel of myeloperoxidase (MPO) tumor necrosis factor-120572(TNF-120572) and serum nitric oxide (NO) [66] Chun et alreported that saikosaponins from Radix Bupleuri exhibitedanti-inflammatory activity on inflammatory processesincluding inhibition of inflammatory exudation capillarypermeability inflammatory mediators release migrationof white cells connective tissue hyperplasia and a varietyof allergic inflammation [67] Ma et al was the first toshow that saikosaponins exerted anti-inflammatory activityon paw edema mainly via regulating the nicotinate andnicotinamide metabolism and arachidonic acid metabolism[5] Zhu et al found that saikosaponin a (SSa) exhibitedan inhibitory effect on proinflammatory cytokines inLPS-stimulated macrophages The mechanism of theseactions involved the regulation of MAPK and NF-120581B signalspathways [68] In another study SSa dose-dependentlyinhibited the production of ROS TNF-120572 IL-8 COX-2 andiNOS in LPS-stimulated human umbilical endothelial cells(HUVECs) by upregulating of the LXR120572-ABCA1 signalingpathway [69] Moreover Lee et al showed that saikosaponinc (SSc) was also shown to inhibited LPS-induced apoptosis inHUVECs via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation [70] Zhao et al showed thatSSa also suppressed TNF-120572 and IL-6 concentrations inthe intestines of septic rats through the inhibition of thenucleotide-binding oligomerization domain 2 (NOD2)NF-120581B signaling pathway [71] Saikosaponin d (SSd) has beenreported to inhibit PGE2 production and intracellular freeCa2+ concentration ([Ca2+]i) in a concentration-dependentmanner with an IC50 value of 3 120583m in C6 rat glioma cells[72]
In addition several studies showed that a widerange of Radix Bupleuri preparations also exhibited anti-inflammatory effects in in vitro and in vivo model Li et alshowed that Saireito and its active components (SSd) couldsuppress the proliferation of mesangial cells and expansionof the mesangial matrix in the rat glomerulonephritismodel [73] In experimental chronic pancreatitis rats modelldquoChai-hu-shu-gan powderrdquo exerted anti-inflammatory andantifibrotic effects by inhibiting the expression of nuclearfactor-120581B (NF-120581B) and TNF-120572 mRNA in the pancreas [74]Furthermore it also reduced the abnormally high plasmalevel of cholecystokinin improved the gastricmovement andavoided nausea and flatulence [75] In another experimenta Chinese herbal formula called ldquoRCM-101rdquo (containingFlos magnoliae Radix Bupleuri Radix Glycyrrhizae RadixAngelicae Sinensis etc) inhibited the NO production andiNOS protein expression in LPS-stimulated rat aorta andRaw 2647 macrophages [76]
52 Anticancer Effects The extracts and compounds ofRadix Bupleuri also possessed anticancerantitumor effectThe acetone extract of Bupleurum scorzonerifolium couldinhibit the proliferation of A549 human lung cancer cellsin a dose-dependent manner via causing cell cycle arrestin the G2M phase increasing microtubule stabilizationsuppressing telomerase activity activating ERK 12 andcaspase-39 in A549 cells [77ndash79] Saponins isolated fromRadix Bupleuri also exhibited significantly anti-proliferativeactivity in human non-small cell lung cancer A549 cellsthrough Fas-dependent apoptotic pathway [80] Su et alfound that thewater extracts ofRadix Bupleuri could enhance5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cellsthrough cell arrest at the late G1early S phase while pro-tecting normal blood lymphocytes [6] SSd showed verypotent activity against the HepG2 cell line with an IC50value of 125mgml The mechanism of cytotoxicity was
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
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[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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MEDIATORSINFLAMMATION
of
6 BioMed Research International
Table 2 Chemical compounds isolated from Radix Bupleuri
Classification Number Chemical component Reference
Saponins
1 Saikosaponin a [44]2 Saikosaponin c [44]3 Saikosaponin d [44]4 Saikosaponin e [45]5 Prosaikogenin G [46]6 Prosaikogenin F [46]7 210158401015840-O-Acetylsaikosaponin a [47]8 310158401015840-O-Acetylsaikosaponin a [48]9 610158401015840-O-Acetylsaikosaponin a [49]10 23-O-Acetylsaikosaponin a [50]11 610158401015840-O-Acetylsaikosaponin d [51]
12 23-Hydroxy-13120573 28120573-epoxy-olean-11-ene-16-one3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside [52]
13 312057316120573-Dihydroxy-23-O-acetyl-13120573 28120573-epoxy-olean-11-ene3-O-120573-D-fucopyranoside [47]
14 Bupleuroside I [45]15 Saikosaponin b1 [45 49]16 Saikosaponin b2 [45 49]17 610158401015840-O-Acetyl-saikosaponin b2 [51]18 Saikosaponin h [47 53]19 Prosaikogenin D [54]20 Prosaikogenin A [47]
2131205732328-Trihydroxy-11 13(18)-diene-16-one
3-O-120573-D-glucopyranosyl-(1rarr3)-120573-D-fucopyranoside
[47]
22 Bupleuroside V [45]23 Bupleuroside X [45]24 Bupleuroside XII [45]25 Saikosaponin v-1 [51]26 Saikosaponin b3 [44 53]27 Saikosaponin b4 [44 53]28 Saikosaponin f [45]
29 3120573161205732328-Tetrahydroxy-11120572-methoxy-olean-12-ene3-O-120573-D-fucopyranoside [47]
30 31205731612057328-Trihydroxyl-11120572-methoxy-olean-12-ene-O-120573-D-fucopyranoside [47]
31 Bupleuroside VII [45]32 Saikosaponin g [53]33 Saikosaponin i [53]34 Bupleuroside VIII [45]35 Bupleuroside XI [45]
Polyacetylenes
36 (2Z8Z10E)-pentadecatriene-46-diyne-1-ol [56]37 (2Z8E10E)-pentadecatriene-46-diyne-1-ol [56 57]38 (2Z8Z10E)-heptadecatriene-46-diyne-1-ol [56]39 Bupleurynol [56 57]
BioMed Research International 7
Table 2 Continued
Classification Number Chemical component Reference
Flavonoids
40 Quercetin [60]41 Isorhamnetin [60]42 Isorhamnetin-3-O-glucoside [60]43 Puerarin [60]44 Rutin [60]45 Narcissin [59]46 Eugenin [62]47 Saikochrome A [62 63]48 Saikochromic acid [60]49 741015840-Dihydroxy-isoflavone-7-O-120573-D-glucoside [60]50 Saikochromoside A [59]51 Saikoisoflavonoside A [61]
Lignans
52 Nortrachelogenin [63]53 Nemerosin [62]54 Kaerophyllin [62]55 Isochaihulactone [62]56 Isokaerophyllin [62]57 (minus)-yatein [62]58 Chinensinaphthol [62]59 Chaihunaphthone [62]
Fatty acids
60 Fumaric acid [64]61 Butanedioic acid [64]62 Pentadecanoic acid [65]63 Palmitoleic acid [65]64 Palmitic acid [65]65 Oleic acid [65]66 Stearic acid [65]67 11-Hexadecenoic acid [65]68 13-Octadecenoic acid [65]69 Linoleic acid [65]70 Tetracosanoic acid [64]71 9S12S13S-Trihydroxy-10E-octadecenoic acid [63]
Sterols72 120572-Spinasterol [64]73 24120585-Methylcholesta-7 22E-diene-312057351205726120573-triol [63]74 24120585-Ethylcholest-22E-end-312057351205726120573-Triol [63]
45 Ligans Lignans existing in numerous plants weredetected in the roots of Bupleurum scorzonerifolium WilldThese lignans included nortrachelogenin (52) nemerosin(53) kaerophyllin (54) isochaihulactone (55) isokaero-phyllin (56) (minus)-yatein (57) chinensinaphthol (58) andchaihunaphthone (59) (Figure 5) [62 63]
46 Other Compounds There are also other components inRadix Bupleuri including 12 fatty acids fumaric acid (60)butanedioic acid (61) pentadecanoic acid (62) palmitoleicacid (63) palmitic acid (64) oleic acid (65) stearic acid(66) 11-hexadecenoic acid (67) 13-octadecenoic acid (68)
linoleic acid (69) tetracosanoic acid (70) and 9S12S13S-trihydroxy-10E-octadecenoic acid (71) Three sterols com-pounds namely 120572-spinasterol (72) 24120585-methylcholesta-7 22E-diene-312057351205726120573-triol (73) and 24120585-ethylcholest-22E-end-312057351205726120573-triol (74) were also isolated and identified fromthis plant (Figure 6) [63ndash65]
5 Pharmacological Effects
Radix Bupleuri exerts a great variety of pharmacologi-cal activities due to its complexbioactive compounds Anoverview of the pharmacological studies on Radix Bupleuriispresented in detail in the following sections
8 BioMed Research International
O
R1
R1 R2 R3 R4
R2R1
R1 R2
R1 R2
R3
R3 R4
R1
R1
R2
R2
R3
R1
R1
R1
R2
R3
CH2R2
CH2R3
CH2R2
CH2OH
CH2OH
CH2OH
CH2OH
R3O
R4O
R4O
R3O
R2O
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH훽-OH훽-OH훽-OH훽-OH
훽-OH
훽-OH훽-OH
훽-OH훽-OH훽-OH훽-OH
훽-OH훽-OH
훼-OH
훼-OH
훼-OH
훼-OH훼-OH훼-OH
훼-OH
훼-OH
훼-OH
훼-OH
OH
OH
OHOHOHOHOH
OHOH
OH
1234567891011121314
1516171819202122232425
262728293031
3233
3435
H
H
OAc
OAc=O
=O
=O
COOH
COOH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Fuc-훽-D-Fuc-
2㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-3㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-2)-훽-D-Glc-(1-3)-훽-D-Fuc-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
COOCH2-(CHOH)3-CH2OHCH2OH
CH2OH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
6㰀㰀-acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-
OCH3
OCH3
OCH3
OHOH
OH
OH
OCH3
H
HH
H
H
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-2)-훽-D-Ara-(1-3)-훽-D-GlcA-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
Figure 2 Chemical structures of triterpenoid saponins
BioMed Research International 9
OH
OH
3736
3938
OH
OH
Figure 3 Chemical structures of polyacetylenes
51 Anti-inflammatory Effects Radix Bupleuri has beenwidely used for the treatment of several types of chronicinflammatory diseases The crude polysaccharides(80mgkg) isolated from the roots of Bupleurum chinenseDC significantly attenuated lung injury by inhibiting thelevel of myeloperoxidase (MPO) tumor necrosis factor-120572(TNF-120572) and serum nitric oxide (NO) [66] Chun et alreported that saikosaponins from Radix Bupleuri exhibitedanti-inflammatory activity on inflammatory processesincluding inhibition of inflammatory exudation capillarypermeability inflammatory mediators release migrationof white cells connective tissue hyperplasia and a varietyof allergic inflammation [67] Ma et al was the first toshow that saikosaponins exerted anti-inflammatory activityon paw edema mainly via regulating the nicotinate andnicotinamide metabolism and arachidonic acid metabolism[5] Zhu et al found that saikosaponin a (SSa) exhibitedan inhibitory effect on proinflammatory cytokines inLPS-stimulated macrophages The mechanism of theseactions involved the regulation of MAPK and NF-120581B signalspathways [68] In another study SSa dose-dependentlyinhibited the production of ROS TNF-120572 IL-8 COX-2 andiNOS in LPS-stimulated human umbilical endothelial cells(HUVECs) by upregulating of the LXR120572-ABCA1 signalingpathway [69] Moreover Lee et al showed that saikosaponinc (SSc) was also shown to inhibited LPS-induced apoptosis inHUVECs via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation [70] Zhao et al showed thatSSa also suppressed TNF-120572 and IL-6 concentrations inthe intestines of septic rats through the inhibition of thenucleotide-binding oligomerization domain 2 (NOD2)NF-120581B signaling pathway [71] Saikosaponin d (SSd) has beenreported to inhibit PGE2 production and intracellular freeCa2+ concentration ([Ca2+]i) in a concentration-dependentmanner with an IC50 value of 3 120583m in C6 rat glioma cells[72]
In addition several studies showed that a widerange of Radix Bupleuri preparations also exhibited anti-inflammatory effects in in vitro and in vivo model Li et alshowed that Saireito and its active components (SSd) couldsuppress the proliferation of mesangial cells and expansionof the mesangial matrix in the rat glomerulonephritismodel [73] In experimental chronic pancreatitis rats modelldquoChai-hu-shu-gan powderrdquo exerted anti-inflammatory andantifibrotic effects by inhibiting the expression of nuclearfactor-120581B (NF-120581B) and TNF-120572 mRNA in the pancreas [74]Furthermore it also reduced the abnormally high plasmalevel of cholecystokinin improved the gastricmovement andavoided nausea and flatulence [75] In another experimenta Chinese herbal formula called ldquoRCM-101rdquo (containingFlos magnoliae Radix Bupleuri Radix Glycyrrhizae RadixAngelicae Sinensis etc) inhibited the NO production andiNOS protein expression in LPS-stimulated rat aorta andRaw 2647 macrophages [76]
52 Anticancer Effects The extracts and compounds ofRadix Bupleuri also possessed anticancerantitumor effectThe acetone extract of Bupleurum scorzonerifolium couldinhibit the proliferation of A549 human lung cancer cellsin a dose-dependent manner via causing cell cycle arrestin the G2M phase increasing microtubule stabilizationsuppressing telomerase activity activating ERK 12 andcaspase-39 in A549 cells [77ndash79] Saponins isolated fromRadix Bupleuri also exhibited significantly anti-proliferativeactivity in human non-small cell lung cancer A549 cellsthrough Fas-dependent apoptotic pathway [80] Su et alfound that thewater extracts ofRadix Bupleuri could enhance5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cellsthrough cell arrest at the late G1early S phase while pro-tecting normal blood lymphocytes [6] SSd showed verypotent activity against the HepG2 cell line with an IC50value of 125mgml The mechanism of cytotoxicity was
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
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Medicinal ChemistryInternational Journal of
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AddictionJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
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Autoimmune Diseases
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Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
BioMed Research International 7
Table 2 Continued
Classification Number Chemical component Reference
Flavonoids
40 Quercetin [60]41 Isorhamnetin [60]42 Isorhamnetin-3-O-glucoside [60]43 Puerarin [60]44 Rutin [60]45 Narcissin [59]46 Eugenin [62]47 Saikochrome A [62 63]48 Saikochromic acid [60]49 741015840-Dihydroxy-isoflavone-7-O-120573-D-glucoside [60]50 Saikochromoside A [59]51 Saikoisoflavonoside A [61]
Lignans
52 Nortrachelogenin [63]53 Nemerosin [62]54 Kaerophyllin [62]55 Isochaihulactone [62]56 Isokaerophyllin [62]57 (minus)-yatein [62]58 Chinensinaphthol [62]59 Chaihunaphthone [62]
Fatty acids
60 Fumaric acid [64]61 Butanedioic acid [64]62 Pentadecanoic acid [65]63 Palmitoleic acid [65]64 Palmitic acid [65]65 Oleic acid [65]66 Stearic acid [65]67 11-Hexadecenoic acid [65]68 13-Octadecenoic acid [65]69 Linoleic acid [65]70 Tetracosanoic acid [64]71 9S12S13S-Trihydroxy-10E-octadecenoic acid [63]
Sterols72 120572-Spinasterol [64]73 24120585-Methylcholesta-7 22E-diene-312057351205726120573-triol [63]74 24120585-Ethylcholest-22E-end-312057351205726120573-Triol [63]
45 Ligans Lignans existing in numerous plants weredetected in the roots of Bupleurum scorzonerifolium WilldThese lignans included nortrachelogenin (52) nemerosin(53) kaerophyllin (54) isochaihulactone (55) isokaero-phyllin (56) (minus)-yatein (57) chinensinaphthol (58) andchaihunaphthone (59) (Figure 5) [62 63]
46 Other Compounds There are also other components inRadix Bupleuri including 12 fatty acids fumaric acid (60)butanedioic acid (61) pentadecanoic acid (62) palmitoleicacid (63) palmitic acid (64) oleic acid (65) stearic acid(66) 11-hexadecenoic acid (67) 13-octadecenoic acid (68)
linoleic acid (69) tetracosanoic acid (70) and 9S12S13S-trihydroxy-10E-octadecenoic acid (71) Three sterols com-pounds namely 120572-spinasterol (72) 24120585-methylcholesta-7 22E-diene-312057351205726120573-triol (73) and 24120585-ethylcholest-22E-end-312057351205726120573-triol (74) were also isolated and identified fromthis plant (Figure 6) [63ndash65]
5 Pharmacological Effects
Radix Bupleuri exerts a great variety of pharmacologi-cal activities due to its complexbioactive compounds Anoverview of the pharmacological studies on Radix Bupleuriispresented in detail in the following sections
8 BioMed Research International
O
R1
R1 R2 R3 R4
R2R1
R1 R2
R1 R2
R3
R3 R4
R1
R1
R2
R2
R3
R1
R1
R1
R2
R3
CH2R2
CH2R3
CH2R2
CH2OH
CH2OH
CH2OH
CH2OH
R3O
R4O
R4O
R3O
R2O
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH훽-OH훽-OH훽-OH훽-OH
훽-OH
훽-OH훽-OH
훽-OH훽-OH훽-OH훽-OH
훽-OH훽-OH
훼-OH
훼-OH
훼-OH
훼-OH훼-OH훼-OH
훼-OH
훼-OH
훼-OH
훼-OH
OH
OH
OHOHOHOHOH
OHOH
OH
1234567891011121314
1516171819202122232425
262728293031
3233
3435
H
H
OAc
OAc=O
=O
=O
COOH
COOH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Fuc-훽-D-Fuc-
2㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-3㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-2)-훽-D-Glc-(1-3)-훽-D-Fuc-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
COOCH2-(CHOH)3-CH2OHCH2OH
CH2OH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
6㰀㰀-acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-
OCH3
OCH3
OCH3
OHOH
OH
OH
OCH3
H
HH
H
H
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-2)-훽-D-Ara-(1-3)-훽-D-GlcA-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
Figure 2 Chemical structures of triterpenoid saponins
BioMed Research International 9
OH
OH
3736
3938
OH
OH
Figure 3 Chemical structures of polyacetylenes
51 Anti-inflammatory Effects Radix Bupleuri has beenwidely used for the treatment of several types of chronicinflammatory diseases The crude polysaccharides(80mgkg) isolated from the roots of Bupleurum chinenseDC significantly attenuated lung injury by inhibiting thelevel of myeloperoxidase (MPO) tumor necrosis factor-120572(TNF-120572) and serum nitric oxide (NO) [66] Chun et alreported that saikosaponins from Radix Bupleuri exhibitedanti-inflammatory activity on inflammatory processesincluding inhibition of inflammatory exudation capillarypermeability inflammatory mediators release migrationof white cells connective tissue hyperplasia and a varietyof allergic inflammation [67] Ma et al was the first toshow that saikosaponins exerted anti-inflammatory activityon paw edema mainly via regulating the nicotinate andnicotinamide metabolism and arachidonic acid metabolism[5] Zhu et al found that saikosaponin a (SSa) exhibitedan inhibitory effect on proinflammatory cytokines inLPS-stimulated macrophages The mechanism of theseactions involved the regulation of MAPK and NF-120581B signalspathways [68] In another study SSa dose-dependentlyinhibited the production of ROS TNF-120572 IL-8 COX-2 andiNOS in LPS-stimulated human umbilical endothelial cells(HUVECs) by upregulating of the LXR120572-ABCA1 signalingpathway [69] Moreover Lee et al showed that saikosaponinc (SSc) was also shown to inhibited LPS-induced apoptosis inHUVECs via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation [70] Zhao et al showed thatSSa also suppressed TNF-120572 and IL-6 concentrations inthe intestines of septic rats through the inhibition of thenucleotide-binding oligomerization domain 2 (NOD2)NF-120581B signaling pathway [71] Saikosaponin d (SSd) has beenreported to inhibit PGE2 production and intracellular freeCa2+ concentration ([Ca2+]i) in a concentration-dependentmanner with an IC50 value of 3 120583m in C6 rat glioma cells[72]
In addition several studies showed that a widerange of Radix Bupleuri preparations also exhibited anti-inflammatory effects in in vitro and in vivo model Li et alshowed that Saireito and its active components (SSd) couldsuppress the proliferation of mesangial cells and expansionof the mesangial matrix in the rat glomerulonephritismodel [73] In experimental chronic pancreatitis rats modelldquoChai-hu-shu-gan powderrdquo exerted anti-inflammatory andantifibrotic effects by inhibiting the expression of nuclearfactor-120581B (NF-120581B) and TNF-120572 mRNA in the pancreas [74]Furthermore it also reduced the abnormally high plasmalevel of cholecystokinin improved the gastricmovement andavoided nausea and flatulence [75] In another experimenta Chinese herbal formula called ldquoRCM-101rdquo (containingFlos magnoliae Radix Bupleuri Radix Glycyrrhizae RadixAngelicae Sinensis etc) inhibited the NO production andiNOS protein expression in LPS-stimulated rat aorta andRaw 2647 macrophages [76]
52 Anticancer Effects The extracts and compounds ofRadix Bupleuri also possessed anticancerantitumor effectThe acetone extract of Bupleurum scorzonerifolium couldinhibit the proliferation of A549 human lung cancer cellsin a dose-dependent manner via causing cell cycle arrestin the G2M phase increasing microtubule stabilizationsuppressing telomerase activity activating ERK 12 andcaspase-39 in A549 cells [77ndash79] Saponins isolated fromRadix Bupleuri also exhibited significantly anti-proliferativeactivity in human non-small cell lung cancer A549 cellsthrough Fas-dependent apoptotic pathway [80] Su et alfound that thewater extracts ofRadix Bupleuri could enhance5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cellsthrough cell arrest at the late G1early S phase while pro-tecting normal blood lymphocytes [6] SSd showed verypotent activity against the HepG2 cell line with an IC50value of 125mgml The mechanism of cytotoxicity was
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
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[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
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Medicinal ChemistryInternational Journal of
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AddictionJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Pharmaceutics
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MEDIATORSINFLAMMATION
of
8 BioMed Research International
O
R1
R1 R2 R3 R4
R2R1
R1 R2
R1 R2
R3
R3 R4
R1
R1
R2
R2
R3
R1
R1
R1
R2
R3
CH2R2
CH2R3
CH2R2
CH2OH
CH2OH
CH2OH
CH2OH
R3O
R4O
R4O
R3O
R2O
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH
훽-OH훽-OH훽-OH훽-OH훽-OH
훽-OH
훽-OH훽-OH
훽-OH훽-OH훽-OH훽-OH
훽-OH훽-OH
훼-OH
훼-OH
훼-OH
훼-OH훼-OH훼-OH
훼-OH
훼-OH
훼-OH
훼-OH
OH
OH
OHOHOHOHOH
OHOH
OH
1234567891011121314
1516171819202122232425
262728293031
3233
3435
H
H
OAc
OAc=O
=O
=O
COOH
COOH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Fuc-훽-D-Fuc-
2㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-3㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-6㰀㰀-Acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-2)-훽-D-Glc-(1-3)-훽-D-Fuc-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
COOCH2-(CHOH)3-CH2OHCH2OH
CH2OH
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
6㰀㰀-acetyl-훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-
OCH3
OCH3
OCH3
OHOH
OH
OH
OCH3
H
HH
H
H
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-3)-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-훽-D-Fuc-훽-D-Fuc-
훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-3)-훽-D-Fuc-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
훽-D-Glc-(1-2)-훽-D-Ara-(1-3)-훽-D-GlcA-훽-D-Glc-(1-6)-[훼-L-rha-(1-4)]-훽-D-Glc-
Figure 2 Chemical structures of triterpenoid saponins
BioMed Research International 9
OH
OH
3736
3938
OH
OH
Figure 3 Chemical structures of polyacetylenes
51 Anti-inflammatory Effects Radix Bupleuri has beenwidely used for the treatment of several types of chronicinflammatory diseases The crude polysaccharides(80mgkg) isolated from the roots of Bupleurum chinenseDC significantly attenuated lung injury by inhibiting thelevel of myeloperoxidase (MPO) tumor necrosis factor-120572(TNF-120572) and serum nitric oxide (NO) [66] Chun et alreported that saikosaponins from Radix Bupleuri exhibitedanti-inflammatory activity on inflammatory processesincluding inhibition of inflammatory exudation capillarypermeability inflammatory mediators release migrationof white cells connective tissue hyperplasia and a varietyof allergic inflammation [67] Ma et al was the first toshow that saikosaponins exerted anti-inflammatory activityon paw edema mainly via regulating the nicotinate andnicotinamide metabolism and arachidonic acid metabolism[5] Zhu et al found that saikosaponin a (SSa) exhibitedan inhibitory effect on proinflammatory cytokines inLPS-stimulated macrophages The mechanism of theseactions involved the regulation of MAPK and NF-120581B signalspathways [68] In another study SSa dose-dependentlyinhibited the production of ROS TNF-120572 IL-8 COX-2 andiNOS in LPS-stimulated human umbilical endothelial cells(HUVECs) by upregulating of the LXR120572-ABCA1 signalingpathway [69] Moreover Lee et al showed that saikosaponinc (SSc) was also shown to inhibited LPS-induced apoptosis inHUVECs via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation [70] Zhao et al showed thatSSa also suppressed TNF-120572 and IL-6 concentrations inthe intestines of septic rats through the inhibition of thenucleotide-binding oligomerization domain 2 (NOD2)NF-120581B signaling pathway [71] Saikosaponin d (SSd) has beenreported to inhibit PGE2 production and intracellular freeCa2+ concentration ([Ca2+]i) in a concentration-dependentmanner with an IC50 value of 3 120583m in C6 rat glioma cells[72]
In addition several studies showed that a widerange of Radix Bupleuri preparations also exhibited anti-inflammatory effects in in vitro and in vivo model Li et alshowed that Saireito and its active components (SSd) couldsuppress the proliferation of mesangial cells and expansionof the mesangial matrix in the rat glomerulonephritismodel [73] In experimental chronic pancreatitis rats modelldquoChai-hu-shu-gan powderrdquo exerted anti-inflammatory andantifibrotic effects by inhibiting the expression of nuclearfactor-120581B (NF-120581B) and TNF-120572 mRNA in the pancreas [74]Furthermore it also reduced the abnormally high plasmalevel of cholecystokinin improved the gastricmovement andavoided nausea and flatulence [75] In another experimenta Chinese herbal formula called ldquoRCM-101rdquo (containingFlos magnoliae Radix Bupleuri Radix Glycyrrhizae RadixAngelicae Sinensis etc) inhibited the NO production andiNOS protein expression in LPS-stimulated rat aorta andRaw 2647 macrophages [76]
52 Anticancer Effects The extracts and compounds ofRadix Bupleuri also possessed anticancerantitumor effectThe acetone extract of Bupleurum scorzonerifolium couldinhibit the proliferation of A549 human lung cancer cellsin a dose-dependent manner via causing cell cycle arrestin the G2M phase increasing microtubule stabilizationsuppressing telomerase activity activating ERK 12 andcaspase-39 in A549 cells [77ndash79] Saponins isolated fromRadix Bupleuri also exhibited significantly anti-proliferativeactivity in human non-small cell lung cancer A549 cellsthrough Fas-dependent apoptotic pathway [80] Su et alfound that thewater extracts ofRadix Bupleuri could enhance5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cellsthrough cell arrest at the late G1early S phase while pro-tecting normal blood lymphocytes [6] SSd showed verypotent activity against the HepG2 cell line with an IC50value of 125mgml The mechanism of cytotoxicity was
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
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[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
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20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
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[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
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the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
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[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
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[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
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[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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MEDIATORSINFLAMMATION
of
BioMed Research International 9
OH
OH
3736
3938
OH
OH
Figure 3 Chemical structures of polyacetylenes
51 Anti-inflammatory Effects Radix Bupleuri has beenwidely used for the treatment of several types of chronicinflammatory diseases The crude polysaccharides(80mgkg) isolated from the roots of Bupleurum chinenseDC significantly attenuated lung injury by inhibiting thelevel of myeloperoxidase (MPO) tumor necrosis factor-120572(TNF-120572) and serum nitric oxide (NO) [66] Chun et alreported that saikosaponins from Radix Bupleuri exhibitedanti-inflammatory activity on inflammatory processesincluding inhibition of inflammatory exudation capillarypermeability inflammatory mediators release migrationof white cells connective tissue hyperplasia and a varietyof allergic inflammation [67] Ma et al was the first toshow that saikosaponins exerted anti-inflammatory activityon paw edema mainly via regulating the nicotinate andnicotinamide metabolism and arachidonic acid metabolism[5] Zhu et al found that saikosaponin a (SSa) exhibitedan inhibitory effect on proinflammatory cytokines inLPS-stimulated macrophages The mechanism of theseactions involved the regulation of MAPK and NF-120581B signalspathways [68] In another study SSa dose-dependentlyinhibited the production of ROS TNF-120572 IL-8 COX-2 andiNOS in LPS-stimulated human umbilical endothelial cells(HUVECs) by upregulating of the LXR120572-ABCA1 signalingpathway [69] Moreover Lee et al showed that saikosaponinc (SSc) was also shown to inhibited LPS-induced apoptosis inHUVECs via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation [70] Zhao et al showed thatSSa also suppressed TNF-120572 and IL-6 concentrations inthe intestines of septic rats through the inhibition of thenucleotide-binding oligomerization domain 2 (NOD2)NF-120581B signaling pathway [71] Saikosaponin d (SSd) has beenreported to inhibit PGE2 production and intracellular freeCa2+ concentration ([Ca2+]i) in a concentration-dependentmanner with an IC50 value of 3 120583m in C6 rat glioma cells[72]
In addition several studies showed that a widerange of Radix Bupleuri preparations also exhibited anti-inflammatory effects in in vitro and in vivo model Li et alshowed that Saireito and its active components (SSd) couldsuppress the proliferation of mesangial cells and expansionof the mesangial matrix in the rat glomerulonephritismodel [73] In experimental chronic pancreatitis rats modelldquoChai-hu-shu-gan powderrdquo exerted anti-inflammatory andantifibrotic effects by inhibiting the expression of nuclearfactor-120581B (NF-120581B) and TNF-120572 mRNA in the pancreas [74]Furthermore it also reduced the abnormally high plasmalevel of cholecystokinin improved the gastricmovement andavoided nausea and flatulence [75] In another experimenta Chinese herbal formula called ldquoRCM-101rdquo (containingFlos magnoliae Radix Bupleuri Radix Glycyrrhizae RadixAngelicae Sinensis etc) inhibited the NO production andiNOS protein expression in LPS-stimulated rat aorta andRaw 2647 macrophages [76]
52 Anticancer Effects The extracts and compounds ofRadix Bupleuri also possessed anticancerantitumor effectThe acetone extract of Bupleurum scorzonerifolium couldinhibit the proliferation of A549 human lung cancer cellsin a dose-dependent manner via causing cell cycle arrestin the G2M phase increasing microtubule stabilizationsuppressing telomerase activity activating ERK 12 andcaspase-39 in A549 cells [77ndash79] Saponins isolated fromRadix Bupleuri also exhibited significantly anti-proliferativeactivity in human non-small cell lung cancer A549 cellsthrough Fas-dependent apoptotic pathway [80] Su et alfound that thewater extracts ofRadix Bupleuri could enhance5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cellsthrough cell arrest at the late G1early S phase while pro-tecting normal blood lymphocytes [6] SSd showed verypotent activity against the HepG2 cell line with an IC50value of 125mgml The mechanism of cytotoxicity was
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
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[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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Advances in Pharmacological Sciences
Tropical MedicineJournal of
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Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
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BioMed Research International
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Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
10 BioMed Research International
O
O
O
O
HOHO
HO
HO
HOHO
HOHO
HO
HO
HO
HOHO
HO
HO
HO
HO
HO
HO
HO
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OHOH
OH
OH
OHOH
OH
OH
OH
OHOH
OH
OHOH
OH
OHOH
OHOH
OH
OH
OH
OH
OHOH
4140
4342
O
OO
O
O
O
O
O
OO
HO
O
O
O
O
OO
O
O
O
44 45
O
O
O
O
O
O
COOH
46 4847
O O
O
O O
O
O
49 50
O
O
OO
O
O
51
CH2O
CH2OH
CH2OH
CH2OH
CH3
CH2OH
CH2OH
HOH2C
H3C
H3CO
H3CO
H3CO
H3C
OCH3
OCH3
OCH3
OCH3
Figure 4 Chemical structures of flavonoids
attributed to the induction of apoptosis through activationof caspase-3 and caspase-7 which subsequently resultedin poly-ADP-ribose polymerase (PARP) cleavage [81] Thestudy by Hou et al demonstrated that SSd exerted its
antitumor effect in human hepatocellular carcinoma cellline SMMC-7721 through the HIF-1120572COX-2 pathway [82]Furthermore SSd was also reported to induce autophagyin HeLa and MCF-7 cancer cells by direct inhibition of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
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[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Autoimmune Diseases
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Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
BioMed Research International 11
O OHO
HHO
HO
52
H
O
OO
O
RH
OH
OO
O
R
H
OO
O O
H H
53 5556
5754
O
OO
OH
O
O
O
OO
58 59
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
R = OCH3
R = HR = OCH3
R = H
Figure 5 Chemical structures of lignans
sarcoplasmicendoplasmic reticulumCa2+ ATPase (SERCA)leading to the increase of intracellular calcium ion levels andactivating the Ca2+calmodulin-dependent kinase kinase-120573- (CaMKK120573-) AMP-activated protein kinase- (AMPK-)mammalian target of rapamycin (mTOR) signaling cascadeendoplasmic reticulum (ER) stress and unfolded proteinresponses (UPR) [43]
Several Chinese medicine preparations containing RadixBupleuri also have been traditionally used in the treatmentof tumors and cancer The water extracts of ldquoLong DanXie Gan Wanrdquo exerted a significant growth inhibitory effectin HL60 and HT29 cancer cell lines indicating that thisformulation may possess some chemotherapeutic potential[83] Treatment with ldquoxiao-chai-hu decoctionrdquo exhibited asignificantly lower incidence of hepatocellular carcinoma andreductions in cancer pain and tumor size The underlyingmechanismof the antitumor activities is based on stimulationof the reticuloendothelial system (RES) and is closely relatedof TNF production [84ndash86]
53 Antiviral Effects Wen et al reported that the acetoneextract of Radix Bupleuri possessed a significant antiviruseffect on acute respiratory tract infections with H1N1 virusinfection and suppressed influenzaAvirus-inducedRANTESsecretion in H1N1-infected A549 cells at a concentration of
100 and 200120583gml suggesting that Radix Bupleuri might bebeneficial for the treatment of chronic inflammatory condi-tions followed by viral infection [10] SSc has been reportedto show effective anti-HBV activity through inhibiting DNAexpression of HBsAg HBeAg and HBV [81] Treatmentwith ldquoxiao-chai-hu decoctionrdquo (20120583gml 3 days 20120583gml6 days) could inhibit the production of HBV (119875 lt 00001)and the expression of HBeAg Moreover crude saponinsof Bupleurum chinense DC could inhibit the replication ofHBV (119875 lt 00001) [87] Similarly in another study Yinet al showed that SSd isolated from the MeOH extract ofBupleurum chinense DC exhibited significant bioactivity ininhibitingDNA replication ofHBV [88]The antiviral activityof saikosaponins (a b2 c and d) and their mode of actinwere examined The results showed that all saikosaponinsexerted antiviral activity on human coronavirus-229E atconcentrations of 025ndash25120583m and the strongest activity wasobserved for saikosaponin b2 with an IC50 of 17 120583m Thismechanism might involve interference in the early stage ofviral replication such as absorption and penetration of thevirus [89]
54 Antipyretic Effects The water extract of Radix Bupleuriwas reported to exert its antipyretic effect on dry yeast-induced high fever rats The mechanism is related to the
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
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[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
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20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
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[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
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[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
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[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Autoimmune Diseases
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Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
12 BioMed Research International
O
O
O
OOHOH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HOHOHO
HOHO
OH HOHO
O60 61 62
O
OH
O
63 64O
65
O
66O
67O
68
O
69O
70
O
71
H
H
HH
H
72 73
H
74
Figure 6 Chemical structures of other compounds
adjustment of synthesis and exudation of cyclic adenosinemonophosphate (cAMP) and arginine vasopressin (AVP)[90] A novel in situ gel system for nasal delivery of theessential oil from Radix Bupleuri was prepared The resultssuggested that Radix Bupleuri in situ gel can be moreeffective than the solution in the treatment of fever [91] Asimilar study showed that the essential oil extracted from the
herb exhibited dose-dependent antipyretic capacity on bothfevered rabbits and rats [92]
55 Antibacterial Effects The ethanol extract of Bupleu-rum chinense DC exerted a remarkable bacteriostaticeffect on Gram-negative microorganism Helicobacter pyloriThe bioactive minimum inhibitory concentration (MIC)
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
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[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
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[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
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20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
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the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
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[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
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[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
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BioMed Research International 21
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[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
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[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
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[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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MEDIATORSINFLAMMATION
of
BioMed Research International 13
value was 60Mm [93] Saikosaponins isolated from RadixBupleuri have been reported to exhibit antibacterial activityparticularly against Pseudomonas aeruginosa and Listeriamonocytogenes The protective effect was attributed to theimmunomodulatory action on macrophages [94] ldquoChaihuinjectionrdquo has also been tested for possible antimicrobialactivity in vitroThe results demonstrated thatmild inhibitionof Staphylococcus aureus was observed but no effects wereobserved against Staphylococcus albusNeisseria gonorrhoeaeDiplococcus pneumoniae haemolytic Streptococcus or Pseu-domonas aeruginosa [95]
56 Hepatoprotective Effects The liver protective effectsagainst CCl4 induced liver injury were investigated aftertreatment ofmicewith raw and vinegar-bakedRadix Bupleuri(5 gkgday) for 14 days The results showed that both rawand processed Radix Bupleuri showed liver protective effectsagainst CCl4 induced liver injury and the vinegar-bakedRadix Bupleuri exerted better effects than that of raw RadixBupleuri [96] Pretreated with saikosaponins especially SSaor SSd showed remarkable inhibition of D-galactosamine-induced hepatic injury through decreasing the activity ofglucose-6-phosphatase and NADPH-cytochrome C reduc-tase and increasing 51015840-nucleotidase activity [97] Similarlybupleurosides III VI IX and XIII and saikosaponin b3isolated from Bupleurum scorzonerifolium Willd were alsofound to exhibit protective effect on the D-galactosamine-induced cytotoxicity in primary cultured rat hepatocytes[98] Further studies also demonstrated that the protectiveeffects of saikosaponins isolated from Bupleurum chinenseDC could prevent hepatocyte injury through regulatingintracellular calcium levels [99] In a rat model with CCl4induced acute hepatic injury the hepatic enzyme levels (GOTGPT and ALP) and the lipid peroxidation in the liver weresignificantly reduced by the administration of SSd [100]Additionally SSd significantly reduced collagen I depositionand alanine aminotransferase level on liver fibrosis rats anddecreased the concentration of transforming growth factor1205731 (TGF-1205731) Moreover SSd was able to alleviate hepatocyteinjury from oxidative stressThe effect of SSd on liver fibrosismay be related to its ability to reduce lipid peroxidation [101]
57 Immunomodulatory Effects Yamakage et al determinedthe effects of Radix Bupleuri on spontaneous lymphaticvessel activity The results indicated that Radix Bupleurisignificantly increased the amplitude of spontaneous activityof lymphatic vessels in a concentration-dependent mannerand the mechanisms of this effect seem to be independent ofendothelial function [102] Eugenin (46) and saikochrome A(47) isolated from the MeOH extracts from Bupleurum scor-zonerifolium possessed immunosuppressive effect on humanperipheral blood T cells via inhibiting CD28-costimulatedactivation [62] SSd (10mg intraperitoneally) significantlyactivated peritoneal macrophages in terms of enhancementof phagocytic activity increased level of cellular lysosomalenzyme and suppressed the response of plaque-forming cellsto heterologous erythrocytes by stimulating T and B cells ina dose-dependent manner [103] Moreover SSd modulated
lymphocyte activity through suppressing the T cell responseand increasing the B cell response to different mitogensand the interleukin- (IL-) 2IL-4 production through areceptor-bypassed pathway [41 104 105] In another exper-iment Wong et al found that SSd was shown to inhibitOKT3CD28-costimulated human T cell proliferation andPMA PMAionomycin and Con A-induced mouse T cellactivation in vitro The underlying mechanisms involveddownregulation of NF-kB signaling by suppression of IKKand Akt activities [106]
58 Autophagic Effect Autophagy is a complex processin cells which occurs through the formation of double-membrane vesicles (autophagosomes) which are engulfedby cytoplasmic molecules Then the autophagosome fuseswith the lysosomes leading to degradation of long-livedproteins aggregated proteins and damaged organelles [107ndash109] Moreover autophagy might be triggered by hypoxianutritional deprivation radiation chemical drugs and otherstimulants [110] Autophagy contributes to the pathogenesisof diverse diseases such as neuronal degeneration inflamma-tory bowel disease aging and cancer [111 112] In the previousstudy Law et al demonstrated that the protective pharma-cological effects of Radix Bupleuri might be attributed to itsautophagy inductionThe autophagic effect of Radix Bupleuriplayed an important role in relieving liver disease-relatedsymptoms through anti-inflammatory organ-protective andaggregate removal functions Furthermore the anticancereffects of Radix Bupleuri could be attributed to its autophagyinduction Radix Bupleuri has been found to be an effectivetreatment against depression by regulating metabolite hor-mone and neurotransmitter levels via autophagy-mediatedlipid metabolism [113]
59 Other Pharmacological Effects The effect of the ethanolextract from Radix Bupleuri on cytochrome 450 isoformactivities using a six-drug cocktail approach was evaluatedthe results demonstrated that Radix Bupleuri had stronginduction activity on the CYP2E1 CYP2D6 and CYP3A4which may lead to potential plant drug-drug interactions[114] Radix Bupleuri was shown to be the inhibitor of 120573-glucuronidase The inhibition rate of Radix Bupleuri extractsRB1 (high molecular weight polysaccharides) RB2 (ethanolsolublewater insoluble component) RB3 (extracted by n-butanol soluble in water) and RB4 (low molecular weightwater soluble parts) on the activity of 120573-glucuronidase wasfound to be 4515 3394 2494 and 3454 respectively[115] In pentylenetetrazol (PTZ) induced epilepsy ratsmodelSSa isolated fromRadix Bupleuri significantly reduced seizureseverity and duration while it markedly elevated seizurelatency and downregulated the cytokines expression of p-mTOR p-70S6K L-1120573 and TNF-120572 through inhibitingmTORsignaling pathway [116] He et al demonstrated that SSa obvi-ously reduced lipoprotein uptake to block foamcell formationand the expression of LOX-1 and CD36 boosted cholesterolefflux and the expression of ABCA1 and PPAR120574 throughinhibiting PI3KAktNF-120581BNLRP3 signaling pathway [117]
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
[1] Editorial Committee of Chinese Pharmacopoeia Chinese Phar-macopoeia Medical Science and Technology Press BeijingChina 2015 edition 2015
[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
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Medicinal ChemistryInternational Journal of
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AddictionJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Autoimmune Diseases
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MEDIATORSINFLAMMATION
of
14 BioMed Research International
In another experiment SSc exerted a potent effect on induc-ing human umbilical vein endothelial cells (HUVECs) via-bility and growth Furthermore SSc also induced endothelialcells migration and capillary tube formation The underlyingmechanisms might be related to the gene expression oractivation of matrix metalloproteinase-2 (MMP-2) vascularendothelial growth factor (VEGF) and the p42p44mitogen-activated protein kinase (MAPK ERK) [118] In addition SScwas shown to exhibit inhibitory activities against Alzheimerrsquosdisease (AD) via suppressing the secretion ofA120573 peptides andabnormal tau hyperphosphorylation-mediated microtubuledepolymerization Moreover SSc suppressed A120573 peptide-induced brain endothelial apoptosis indicating that Sscmight be a novel therapeutic tool for treating human AD andother neurodegenerative diseases [119] It was shown by Liuet al for the first time that four polyacetylenes (36ndash39) fromRadix Bupleuri potently exhibited an antidepressant activityby inhibiting the reuptake of serotonin norepinephrine anddopamine The mechanism might be mediated by increasingthe level of monoamines particularly 5-HT andNE [56] Zhuet al suggested that SSa and SSd exhibited the anthelminticactivity against Dactylogyrus spp infecting goldfish Theeffective concentration (EC50) values for SSa and SSd were146 and 074mgminus1 respectively [120]
510 Summary of Pharmacological Effects Radix Bupleuripossesses awide spectrumof pharmacological effects includ-ing anti-inflammatory effect anticancer effect antiviraleffect antipyretic effect antibacterial effect hepatoprotectiveeffect and immunomodulatory effect (Table 3) Based onthese pharmacological effects we can conclude that theextracts and the compounds from this plant can preventor treat certain diseases such as cancer fever malariahepatitis and AD However there is not enough systemicdata of these chemical compounds and their pharmacologicaleffects Thus in the future the pharmacological effects andthe possible molecular mechanisms of the pharmacologicalactivities of Radix Bupleurimust be urgently explored on ourmodern understanding of these diseasesrsquo pathophysiologies
6 Toxicology
Radix Bupleuri has been used for thousands of years asan important traditional herb in China However the toxiceffects of Radix Bupleuri in clinical applications have beengradually reported Several studies have found that the liveris the main organ affected by toxicity particularly in long-term use Major symptoms of liver injury induced by RadixBupleuri included transaminase lifts hepatitis and jaundiceHowever liver functions can return to normal levels aftera specific period [121] Radix Bupleuri has been reportedto exhibit acute hepatitis and acute hepatic necrosis Themean total daily dose was 180 plusmn 335 g which was morethan the Chinese Pharmacopoeia recommended range of 3to 10 g [122] Moreover Radix Bupleuri had been implicatedinmultiple cases of acute hepatitis both as an ingredient aloneand within a particular formulation ldquoXiao-Chai-Hu-Tangrdquo(also known as Syo-Saiko-To in Japanese) [123] Lee et al
demonstrated that two Chinese herbal products containingRadix Bupleuri might increase their risks of liver injuryin HBV-infected patients However further mechanisticresearch on the hepatotoxicity of Radix Bupleuri in thepresence ofHBV infection is warranted [124] In addition theessential oil of Radix Bupleuri induced acute hepatotoxicitywith asynchronous state higher heart rate and fast breathing[125] The total saponins isolated from Radix Bupleuri couldalso cause evidently liver damage in dose-dependent mannermanifested as hepatocyte organic lesion and liver functionchanges as well as hepatocyte death [126]
7 Pharmacokinetics
A selective and sensitive LC-MSMS method was developedand validated for simultaneous determination of SSa b2 cand d in rat plasma afteroral administration of the ethanol-water (50 50 vv) extract of Radix Bupleuri for the firsttime The results demonstrated that SSa c and d wereabsorbed rapidly with 119879max less than 30min [127] In anotherpharmacokinetics experiment of rats Liu et al was the first todevelop an UPLC-PDA-MS method to determine the phar-macokinetics of four polyacetylenes after ig administrationof 95 ethanol extract of Radix Bupleuri The results showedthat compounds 36 and 38 were not detected in rat serumwhereas compounds 37 and 39 exerted a fast distributionphase followed by a relatively slow elimination phase (119905121199114ndash7 h) [56]
8 Future Perspectives and Conclusions
In traditional Chinese medicine Radix Bupleuri has longbeen used regulate the exterior and interiormetabolisms dis-perse evil heat from superficies sooth the liver and promoteyang and qi It has been widely used to treat various diseasesin China Japan Korea and other Asian countries for manycenturies A total of 74 compounds including essential oilstriterpenoid saponins polyacetylenes flavonoids lignansfatty acids and sterols have been isolated and identifiedfrom Radix Bupleuri [39ndash65] Pharmacological studies haverevealed that Radix Bupleuri possesses a variety of biologicaleffects including anti-inflammatory anticancer antiviralantipyretic antibacterial antiobesity immunomodulatoryhepatoprotective neuroprotective and autophagic effects[66ndash120] However there are some aspects that need to befurther investigated
Radix Bupleuri is an ingredient of many patent medicinesor prescriptions Although modern experiments have con-firmed that this drug alone exhibits multiple pharmacolog-ical activities it is important to investigate the molecularmechanisms of Radix Bupleuri combined with other herbsbased on traditional uses Furthermore the pharmacologicaleffects of only a few of the ingredients such as saikosaponinsflavonoids and the essential oils have been investigatedSome polyacetylenes lignans and sterols have not beensufficiently researched in terms of their pharmacologicaleffects Radix Bupleuri shows both hepatoprotection and
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
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AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
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Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
BioMed Research International 15
Table3Ph
armacologicaleffectsof
RadixBu
pleuri
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Anti-infl
ammatoryeffect
LPS-indu
cedmou
seacutelun
ginjury
Increaseslevels
ofMPO
andTN
F-120572Inh
ibits
theN
olevel
Crud
epolysaccharides
Invivo
[66]
Form
alin-in
ducedmicep
awedem
aRe
gulates
then
icotinatea
ndnicotin
amidem
etabolism
andarachido
nica
cidmetabolism
Saikosapon
ins
Invivo
[5]
LPS-stimulated
RAW
2647cells
Regu
latesM
APK
andNF-120581Bsig
nalspathways
Saikosapon
ina
Invitro
[68]
LPS-stim
ulated
human
umbilical
endo
thelialcells
Activ
ates
theL
XR120572-ABC
A1signalin
gpathway
Saikosapon
ina
Invitro
[69]
Septicratsmod
elInhibitsthen
ucleotide-bind
ingoligom
erization
domain2(N
OD2)N
F-120581Bsig
nalin
gpathway
Saikosapon
ina
Invivo
[70]
LPS-indu
cedapop
tosis
inhu
man
umbilicalvein
endo
thelialcells
Inhibitsthec
aspase-3
activ
ationand
caspase-3-mediated-FA
Kdegradation
Saikosapon
inc
Invitro
[71]
C6ratg
liomac
ells
InhibitsPG
E 2prod
uctio
nandele
vatesintracellu
larfree
Ca2+concentration
Saikosapon
ind
Invitro
[72]
Mon
oclonalantibod
yindu
ced
neph
ritis
Supp
resses
proteinu
riaproliferationof
mesangialcells
andexpansionof
them
esangialmatrix
Saikosapon
ind
Invivo
[73]
Chronicp
ancreatitisratsmod
elInhibitsthee
xpressionof
NF-120581BandTN
F-120572mRN
ACh
ai-hu-shu-ganpo
wder
Invivo
[74]
LPS-stim
ulated
rataortaandRa
w2647macroph
ages
InhibitstheN
Oprod
uctio
nandiN
OSprotein
expressio
nRC
M-101
Invivoin
vitro
[76]
Anticancere
ffect
A549hu
man
lung
cancer
cells
Supp
resses
telomerasea
ctivity
andactiv
ates
ERK12
andcaspase-39
Aceton
eextracts
Invitro
[77ndash79]
Hum
anno
n-sm
all-c
elllun
gcancer
A549cells
Regu
lates
Fas-depend
entapo
ptoticpathway
Sapo
nins
Invitro
[80]
HepG2hepatomac
ells
Indu
cesc
ellarrestatthe
lateG1e
arlySph
ase
Water
extracts
Invitro
[6]
HepG2celllin
eAc
tivates
caspase-3andcaspase-7
Saikosapon
ind
Invitro
[81]
SMMC-
7721
celllin
eRe
gulates
theH
IF-1120572C
OX-
2pathway
Saikosapon
ind
Invitro
[82]
HeLaa
ndMCF
-7cancer
cells
InhibitstheS
ERCA
Activates
the
CaMKK120573-AMP-AMPK
-mTO
Rsig
nalin
gcascadeER
stressa
ndUPR
Saikosapon
ind
Invitro
[43]
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
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[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
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[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
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20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
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the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
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[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
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[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
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BioMed Research International 21
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[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
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[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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MEDIATORSINFLAMMATION
of
16 BioMed Research International
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Antivira
leffect
H1N
1-infectedA549cells
Anti-H
1N1v
irus
Aceton
eextracts
Invitro
[10]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAexpressio
nof
HBsAgHBe
AgandHBV
Saikosapon
inc
Invitro
[81]
HBV
-transfe
cted
human
hepatoma
cells
Inhibitsthep
rodu
ctionof
HBV
andthee
xpressionof
HBe
Ag
Crud
esapon
ins
Invitro
[87]
HBV
-transfe
cted
human
hepatoma
cells
InhibitsDNAreplicationof
HBV
MeO
Hextracts
Invitro
[88]
Hum
ancoronavirus-229E
Interfe
resw
iththee
arlysta
geof
viralreplication
Saikosapon
ins
Invitro
[89]
Antipyreticeffect
Dry
yeast-ind
uced
high
feverrats
Adjusts
thes
ynthesisandexud
ationof
cAMPandAV
PWater
extracts
Invivo
[90]
Turpentin
e-indu
cedfeverrabbits
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[91]
Turpentin
e-indu
cedfeverrabbits
andrats
Decreases
body
temperature
Thee
ssentia
loil
Invivo
[92]
Antibacteria
leffect
Helicobacterpyloristrain
Anti-H
elicobacterpylori
Ethano
lextracts
Invitro
[93]
Staphylococcus
aureus
strain
Anti-S
taphylo
coccus
aureus
Chaihu
injection
Invitro
[95]
Pseudomonas
aeruginosaListeria
monocytogenesstrains
Anti-P
seud
omonas
aeruginosaA
nti-L
isteria
monocytogenes
Saikosapon
ins
Invitro
[94]
Hepatop
rotectivee
ffect
CCl 4indu
cedhepatic
damagein
rats
Hepatop
rotectivee
ffects
Methano
lextracts
Invivo
[96]
D-galactosamine-indu
cedhepatic
injury
inrats
Decreases
thea
ctivity
ofglucose-6-ph
osph
atasea
ndNADPH
-cytochrom
eCredu
ctaseincreases
51015840-nucleotidasea
ctivity
Saikosapon
ins
Invivo
[97]
D-galactosamine-indu
ced
cytotoxicityin
rath
epatocytes
Hepatop
rotectivee
ffects
Bupleurosid
esIIIVIIXand
XIII
saikosapon
inb 3
Invitro
[98]
BEL-7402
cells
Regu
latesintracellu
larc
alcium
levels
Saikosapon
ins
Invitro
[99]
CCl 4indu
cedacuteh
epaticinjury
inrats
Hepatop
rotectivee
ffects
Saikosapon
ind
Invivo
[100]
CR-1548cellliver
fibrosis
inrats
Redu
ceslipid
peroxidatio
nSaikosapon
ind
Invitro
invivo
[101]
Immun
omod
ulatoryeffect
Ratsfedwith
RadixBu
pleuri
Increasesthe
amplitu
deof
spon
taneou
sactivity
oflymph
aticvessels
Water
extracts
Invivo
[102]
Hum
anperip
heralblood
Tcells
InhibitsCD
28-costim
ulated
activ
ation
MeO
Hextracts
Invitro
[62]
BALB
cC
3HH
eand
CDF 1
mice
Stim
ulates
TandBcells
Saikosapon
ind
Invivo
[103]
Thym
ocytes
andspleen
cells
C57B
L6mice
Regu
latesreceptor-bypassed
pathway
Saikosapon
ind
Invitro
invivo
[41104105]
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[2] Y S Wang H M Chang and P P H But Pharmacologyand applications of Chinese Material Medica World ScientificSingapore 1987
[3] M L Ashour and M Wink ldquoGenus Bupleurum a review ofits phytochemistry pharmacology and modes of actionrdquo TheJournal of Pharmacy and Pharmacology vol 63 no 3 pp 305ndash321 2011
[4] B P Bermejo M J A Martinez A M S Sen et al ldquoIn vivoand in vitro antiinflammatory activity of saikosaponinsrdquo LifeSciences vol 63 no 13 pp 1147ndash1156 1998
[5] Y Ma Y Bao S Wang et al ldquoAnti-inflammation effectsand potential mechanism of saikosaponins by regulatingnicotinate and nicotinamide metabolism and arachidonic acidmetabolismrdquo Inflammation vol 39 no 4 pp 1453ndash1461 2016
[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
[9] Q Zhou S-S Wang G Yang W Zhao and H-L Li ldquoDevel-opment and evaluation of a herbal formulation with anti-pathogenic activities and probiotics stimulatory effectsrdquo Journalof Integrative Agriculture vol 15 no 5 pp 1103ndash1111 2016
[10] S Wen H F Xu and H Hao ldquoIn vitro anti-influenza A H1N1effect of extract of Bupleuri Radixrdquo Immunopharmacology andImmunotoxicology vol 33 no 3 pp 433ndash437 2011
[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
[14] S L Pan ldquoBupleurum species scientific evaluation and clinicalapplicationsrdquo Tayloc and Trancis Group FLa USA 2006
[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
[19] L-M Hsu Y-S Huang S-H Tsay F-Y Chang and S-DLee ldquoAcute hepatitis induced by Chinese hepatoprotective herbxiao-chai-hu-tangrdquo Journal of the Chinese Medical Associationvol 69 no 2 pp 86ndash88 2006
[20] B E Van Wyk and M Wink Medicinal Plants of the WorldAn Illustrated Scientific Guide to ImportantMedicinal Plants andTheir Uses vol 58 Timber Press Portland 1st edition 2004
[21] J Y Xiong N Zang C Y Zhang et al ldquoStudies on the anti-depression effect of Xiaoyao Powder in micrdquo Pharmacology andClinics of Chinese Materia Medica vol 23 no 1 pp 3ndash5 2007
[22] Y Zhou Y Ren Z Ma et al ldquoIdentification and quantificationof the major volatile constituents in antidepressant active frac-tion of xiaoyaosan by gas chromatography-mass spectrometryrdquoJournal of Ethnopharmacology vol 141 no 1 pp 187ndash192 2012
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
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[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
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20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
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[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
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[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
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AddictionJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Autoimmune Diseases
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Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
BioMed Research International 17
Table3Con
tinued
Pharmacologicaleffects
Celllinesm
odel
Detailm
echanism
(s)o
faction
Preparationsextractscompo
unds
Application
Reference
Others
MaleS
Drats
Exhibitsstrong
indu
ctionactiv
ityon
theC
YP2E
1CY
P2D6andCY
P3A4
Ethano
lextracts
Invivo
[107]
PTZ-indu
cedepilepsyratsmod
elInhibitsmTO
Rsig
nalin
gpathway
Saikosapon
ina
Invivo
[109]
THP-1C
ells
InhibitsPI3K
AktN
F-120581BNLR
P3sig
nalin
gpathway
Saikosapon
ina
Invitro
[110]
Hum
anum
bilicalvein
endo
thelial
cells
Activ
ates
MMP-2VEG
Fandthep
42p44
mito
gen-activ
ated
proteinkinase
Saikosapon
inc
Invitro
[111]
SH-SY5
YandSK
-N-SHcelllin
esSupp
resses
thes
ecretio
nof
A120573peptides
Saikosapon
inc
Invitro
[112]
MaleW
istar
rats
Increasesthe
levelof5-H
TandNE
Polyacetylenes
Invivo
[56]
Dactylogyrusspp
infectin
ggoldfish
Anthelm
intic
activ
itySaikosapon
insa
andd
Invivo
[113]
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
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[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
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20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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MEDIATORSINFLAMMATION
of
18 BioMed Research International
hepatotoxicity which appears to be contradictory This phe-nomenon is similar to that of PolygonummultiflorumThunb[128] Based on the literature the main reasons are likelythe administration dosage and delivery time High doses andlong-term drug delivery are more likely to result in livertoxicity whereas low doses and short-term drug deliverymight result in liver protection Therefore this issue needsfurther study
In conclusion this review summarized the traditionaluses botany phytochemistry pharmacology and toxicologyof Radix Bupleuri Moreover it has provided a new founda-tion for further research on its mechanism of action and thedevelopment of better therapeutic agents employing RadixBupleuri in the future It is anticipated that the comprehen-sive and detailed research on toxicity pharmacodynamicspharmacokinetics and molecular mechanism are necessaryto be explored to develop its bioactive compounds as effectivedrugs
Conflicts of Interest
The authors have declared that there are no conflicts ofinterest regarding the publication of this paper
Authorsrsquo Contributions
Fude Yang and Xiaoxv Dong contributed equally to this workand share first authorship
Acknowledgments
This work was financially supported by the CollaborativeInnovation Construction Plan of Beijing University of Chi-nese Medicine (no 2013-XTCX-03)
References
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[6] J K Su Y J Lee B M Kim et al ldquoEffect of Bupleuri RadixExtracts on the Toxicity of 5-Fluorouracil in HepG2 HepatomaCells and Normal Human Lymphocytesrdquo Basic amp ClinicalPharmacology amp Toxicology vol 103 no 4 pp 305ndash313 2008
[7] Y Motoo and N Sawabu ldquoAntitumor effects of saikosaponinsbaicalin and baicalein on human hepatoma cell linesrdquo CancerLetters vol 86 no 1 pp 91ndash95 1994
[8] M S Idris-Usman ldquoAntinociceptive and antipyretic propertiesof the pharmaceutical herbal preparation Radix bupleuri inratsrdquo Journal of Medicinal Plants Research vol 4 no 8 pp 659ndash663 2010
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[11] M Yoshikawa T Murakami K Hirano M Inadzuki KNinomiya andHMatsuda ldquoScorzonerosides A B and C noveltriterpene oligoglycosides with hepatoprotective effect fromChinese Bupleuri radix the roots of Bupleurum scorzoneri-folium Willdrdquo Tetrahedron Letters vol 38 no 42 pp 7395ndash7398 1997
[12] Z Wang H Li H Xu et al ldquoBeneficial effect of Bupleurumpolysaccharides on autoimmune disease induced by Campy-lobacter jejuni in BALBc micerdquo Journal of Ethnopharmacologyvol 124 no 3 pp 481ndash487 2009
[13] H Abe M Sakaguchi H Konishi T Tani and S ArichildquoThe effects of saikosaponins on biological membranesrdquo PlantaMedica vol 34 no 6 pp 160ndash166 1978
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[15] R-T Tian P-S Xie and H-P Liu ldquoEvaluation of traditionalChinese herbal medicine Chaihu (Bupleuri Radix) byboth high-performance liquid chromatographic and high-performance thin-layer chromatographic fingerprint andchemometric analysisrdquo Journal of Chromatography A vol 1216no 11 pp 2150ndash2155 2009
[16] H Q Huang X Zhang Z X Xu J Su and S K Yan ldquoFastdetermination of saikosaponins in Bupleurum by rapid reso-lution liquid chromatography with evaporative light scatteringdetectionrdquo Journal of Pharmaceutical amp Biomedical Analysisvol 49 no 4 pp 1048ndash1055 2009
[17] C Sui J-H Wei S-L Chen H-Q Chen L M Dong and C-M Yang ldquoConstruction of a full-length enriched cDNA libraryand analysis of 3111 ESTs from roots of Bupleurum ChinenseDCrdquo Botanical Studies vol 51 no 1 pp 7ndash16 2010
[18] H Xie K-K Huo Z Chao and S-L Pan ldquoIdentificationof crude drugs from Chinese medicinal plants of the genusBupleurum using ribosomal DNA ITS sequencesrdquo Planta Med-ica vol 75 no 1 pp 89ndash93 2009
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[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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MEDIATORSINFLAMMATION
of
BioMed Research International 19
[23] X Gao X Zheng Z Li et al ldquoMetabonomic study onchronic unpredictable mild stress and intervention effects ofXiaoyaosan in rats using gas chromatography coupled withmass spectrometryrdquo Journal of Ethnopharmacology vol 137 no1 pp 690ndash699 2011
[24] Editorial Board of Flora of China Flora of China SciencePublishing House Beijing China 1998
[25] Y Z Wang and Y Y Zhang ldquoDetermination of species ofmedical BupleunumrdquoChinese Pharmaceutical Journal no 1 pp3ndash8 1994
[26] S L Pan Q S Shun Q M Bo and X S Bao The colouredatlas of the medicinal plants from genus Bupleurum in ChinaShanghai Scientific and Technical Literature Press Shangha2002
[27] M H Yen C C Lin C H Chuang and S Y Liu ldquoEvaluationof root quality of Bupleurum species by TLC scanner andthe liver protective effects of ldquoxiao-chai-hu-tangrdquo Journal ofEthnopharmacology vol 34 no 2-3 pp 155ndash165 1991
[28] X-Q Li Q-T Gao X-H Chen and K-S Bi ldquoHigh perfor-mance liquid chromatographic assay of saikosaponins fromRadix Bupleuri in Chinardquo Biological and Pharmaceutical Bul-letin vol 28 no 9 pp 1736ndash1742 2005
[29] Q Zhou J P Hao and K Q Gao ldquoAnalysis on Saikosaponinof Sixteen Bupleurum chinense from Shanxirdquo Natural ProductResearch amp Development vol 24 no 5 pp 644ndash647 2012
[30] Y-H Tang Y-Y Zhang H-Y Zhu and C-G Huang ldquoA high-performance liquid chromatographic method for saikosaponina quantification in rat plasmardquoBiomedical Chromatography vol21 no 5 pp 458ndash462 2007
[31] H Zhang Y Zhao H Liang L Huang Q Zhang and X ZhildquoSimultaneous HPLC-ELSD determination of saikosaponins ac d f in Radix Bupleurirdquo Chinese Journal of PharmaceuticalAnalysis vol 27 no 8 pp 1150ndash1153 2007
[32] R Lucena S Cardenas and M Valcarcel ldquoEvaporative lightscattering detection Trends in its analytical usesrdquo Analyticaland Bioanalytical Chemistry vol 388 no 8 pp 1663ndash1672 2007
[33] Y Bao C Li H Shen and F Nan ldquoDetermination of saikos-aponin derivatives in Radix bupleuri and in pharmaceuticalsof the Chinese multiherb remedy Xiaochaihu-tang using liq-uid chromatographic tandem mass spectrometryrdquo AnalyticalChemistry vol 76 no 14 pp 4208ndash4216 2004
[34] B-C Liau S-S Hsiao M-R Lee T-T Jong and S-TChiang ldquoQuality control of Chinese medicinal preparationsLCESI(+)MSMS analyses of saikosaponins-a and -c as mark-ers of Bupleuri radix samplesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 43 no 3 pp 1174ndash1178 2007
[35] Y Chen J Wang L Yuan L Zhou X Jia and X Tan ldquoInter-action of the main components from the traditional chinesedrug pair chaihu-shaoyao based on rat intestinal absorptionrdquoMolecules vol 16 no 11 pp 9600ndash9610 2011
[36] X Lin L Xue H Zhang and C Zhu ldquoDetermination ofsaikosaponins a c and d in Bupleurum Chinese DC fromdifferent areas by capillary zone electrophoresisrdquoAnalytical andBioanalytical Chemistry vol 382 no 7 pp 1610ndash1615 2005
[37] A M Fernandez-Ocana M V Gomez-Rodriguez and AVelasco-Negueruela ldquoIn vivo antifungal activity of the essentialoil of Bupleurum gibraltarium against Plasmopara halstedii insunflowerrdquo Journal of Agriculturalamp FoodChemistry vol 52 no21 pp 6414ndash6417 2004
[38] M A Ocete S Risco A Zarzuelo and J Jimenez ldquoPharmaco-logical activity of the essential oil of Bupleurum gibraltaricum
Anti-inflammatory activity and effects on isolated rat uterirdquoJournal of Ethnopharmacology vol 25 no 3 pp 305ndash313 1989
[39] S H Liu S S Lu Y L Su and Y Guo ldquoAnalysis of volatilecompounds in Radix bupleuri injection by GC-MS-MSrdquo Chro-matographia vol 74 no 5-6 pp 497ndash502 2011
[40] X Li Y Jia A Song X Chen and K Bi ldquoAnalysis of theessential oil fromRadix Bupleuri using capillary gas chromatog-raphyrdquo Yakugaku Zasshi vol 125 no 10 pp 815ndash819 2005
[41] Y Ushio and H Abe ldquoThe effects of saikosaponin onmacrophage functions and lymphocyte proliferationrdquo PlantaMedica vol 57 no 6 pp 511ndash514 1991
[42] Y Ushio and H Abe ldquoInactivation of measles virus and herpessimplex virus by Saikosaponin drdquo Planta Medica vol 58 no 2pp 171ndash173 1992
[43] V K Wong T Li B Y Law et al ldquoSaikosaponin-d a novelSERCA inhibitor induces autophagic cell death in apoptosis-defective cellsrdquo Cell Death amp Disease vol 4 no 7 Article noe720 2012
[44] H Otsuka ldquoSeparation and determination of saponins ofbupleuri radix by droplet counter current chromatography(DCC)rdquo Planta Medica vol 33 no 2 pp 152ndash159 1978
[45] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 17 pp 2193ndash2198 1997
[46] J-K Ding H Fujino R Kasai et al ldquoChemical evaluation ofBupleurum species collected in Yunnan Chinardquo Chemical andPharmaceutical Bulletin vol 34 no 3 pp 1158ndash1167 1986
[47] D Q Li JWu L Y Liu et al ldquoCytotoxic triterpenoid glycosides(saikosaponins) from the roots of Bupleurum chinenserdquo Bioor-ganic amp Medicinal Chemistry Letters vol 25 no 18 pp 3887ndash3892 2015
[48] H Seto N Otake S Q Luo F G Qian and G Y Xu ldquoStudieson chemical constituents of Bupleurum genus Part II Isolationof triterpenoid glycosides (saikosaponins) from Bupleurumkunmingense and their chemical structuresrdquo Agricultural ampBiological Chemistry vol 50 no 4 pp 943ndash948 1986
[49] Y-Y Yang Y-Z Tang C-L Fan H-T Luo P-R Guo and J-XChen ldquoIdentification and determination of the saikosaponins inRadix bupleuri by accelerated solvent extraction combinedwithrapid-resolution LC-MSrdquo Journal of Separation Science vol 33no 13 pp 1933ndash1945 2010
[50] H Ishii M Nakamura S Seo K Tori T Tozyo and YYoshimura ldquoIsolation characterization and nuclear magneticresonance spectra of new saponins from the roots of Bupleurumfalcatum Lrdquo Chemical and Pharmaceutical Bulletin vol 28 no8 pp 2367ndash2373 1980
[51] Q-X Liu H Liang Y-Y Zhao B Wang W-X Yang and YYu ldquoSaikosaponin v-1 from roots of Bupleurum chinense DCrdquoJournal of AsianNatural Products Research vol 3 no 2 pp 139ndash144 2001
[52] Y Ogihara and M Nose ldquoNovel cleavage of the glycosidicbond of saponins in alcoholic alkali metal solution containinga trace of waterrdquo Journal of the Chemical Society ChemicalCommunications no 18 p 1417 1986
[53] J Lee D-H Yang J H Suh et al ldquoSpecies discriminationof Radix Bupleuri through the simultaneous determination often saikosaponins by high performance liquid chromatographywith evaporative light scattering detection and electrospray
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
20 BioMed Research International
ionization mass spectrometryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol879 no 32 pp 3887ndash3895 2011
[54] K Shimizu S Amagaya and Y Ogihara ldquoNew derivatives ofsaikosaponinsrdquo Chemical and Pharmaceutical Bulletin vol 33no 8 pp 3349ndash3355 1985
[55] R Tundis M Bonesi B Deguin et al ldquoCytotoxic activityand inhibitory effect on nitric oxide production of triter-pene saponins from the roots of Physospermum verticillatum(Waldst amp Kit) (Apiaceae)rdquo Bioorganic and Medicinal Chem-istry vol 17 no 13 pp 4542ndash4547 2009
[56] J Liu Y Fang L Yang XQin GDu andXGao ldquoA qualitativeand quantitative determination and pharmacokinetic study offour polyacetylenes from Radix Bupleuri by UPLC-PDA-MSrdquoJournal of Pharmaceutical and Biomedical Analysis vol 111 no1 pp 257ndash265 2015
[57] H Q Huang J Su X Zhang L Shan and W D ZhangldquoQualitative and quantitative determination of polyacetylenesin different Bupleurum species by high performance liquidchromatography with diode array detector and mass spectrom-etryrdquo Journal of ChromatographyA vol 1218 no 8 pp 1131ndash11382011
[58] Q C Li H Liang Y J Bai et al ldquoThe Chemical Constituentsfrom the Roots of Bupleurum chinense DCrdquo Journal of ChinesePharmaceutical Sciences vol 7 no 3 pp 98-99 1997
[59] H Liang Y Y Zhao and R Y Zhang ldquoA new chromoneglycoside from Bupleurum chinenserdquo Chinese Chemical Lettersvol 9 no 1 pp 69-70 1998
[60] H Liang Y Zhao Y Cui and Q Liu ldquoFlavonoids from theroots of Bupleurum chinense DCrdquo Journal of Beijing MedicalUniversity vol 7 no 3 pp 98-99 2000
[61] L Tan Y Y Zhao B Wang et al ldquoNew isoflavonoside fromBupleurum scorzonerifoliumrdquo Chinese Chemical Letters vol 9no 1 pp 71ndash73 1998
[62] W-L Chang L-W Chiu J-H Lai and H-C Lin ldquoImmuno-suppressive flavones and lignans from Bupleurum scorzoneri-foliumrdquo Phytochemistry vol 64 no 8 pp 1375ndash1379 2003
[63] M Kobayashi T Tawara T Tsuchida and H MitsuhashildquoStudies on the constituents of Umbelliferae plants XVIIIMinor constituents of Bupleuri Radix Occurrence of saiko-genins polyhydroxysterols a trihydroxy C18 fatty acid a lignanand a new chromonerdquo Chemical and Pharmaceutical Bulletinvol 38 no 11 pp 3169ndash3171 1990
[64] Q C Li H Liang and Y Y Zhao ldquoThe chemical constituentsfrom the roots of bupleurum chinenserdquo Journal of ChinesePharmaceutical Sciences no 6 pp 165-166 1997
[65] X Q Li A H Song W Li X and K S Bi ldquoAnalysis of the fattyacid from Bupleurum chinense DC in China by GC-MS andGC-FIDrdquo Chemical amp Pharmaceutical Bulletin vol 53 no 12pp 1613ndash1617 2006
[66] J Y Xie ldquoBupleurum chinense DC polysaccharides attenuateslipopolysaccharide-induced acute lung injury in micerdquo Phy-tomedicine International Journal of Phytotherapy amp Phytophar-macology vol 19 no 2 pp 130ndash137 2012
[67] J Chun A Tosun and Y S Kim ldquoAnti-inflammatory effectof corymbocoumarin from Seseli gummiferum subsp corym-bosum through suppression of NF-120581B signaling pathway andinduction of HO-1 expression in LPS-stimulated RAW 2647cellsrdquo International Immunopharmacology vol 31 pp 207ndash2152016
[68] J Zhu C Luo P Wang Q He J Zhou and H Peng ldquoSaikos-aponin A mediates the inflammatory response by inhibiting
the MAPK and NF-120581B pathways in LPS-stimulated RAW 2647cellsrdquo Experimental and Therapeutic Medicine vol 5 no 5 pp1345ndash1350 2013
[69] Y Fu X Hu Y Cao Z Zhang and N Zhang ldquoSaikosaponin ainhibits lipopolysaccharide-oxidative stress and inflammationin Human umbilical vein endothelial cells via preventing TLR4translocation into lipid raftsrdquo Free Radical Biology andMedicineno 89 pp 777ndash785 2015
[70] T H Lee J Chang and B M Kim ldquoSaikosaponin C inhibitslipopolysaccharide-induced apoptosis by suppressing caspase-3activation and subsequent degradation of focal adhesion kinasein human umbilical vein endothelial cellsrdquo Biochemical andBiophysical Research Communications vol 445 no 3 pp 615ndash621 2014
[71] H Zhao S Li H Zhang et al ldquoSaikosaponin a protects againstexperimental sepsis via inhibition of NOD2-mediated NF-120581Bactivationrdquo Experimental and Therapeutic Medicine vol 10 no2 pp 823ndash827 2015
[72] Y Kodama L Xiaochuan C Tsuchiya Y OhizumiM Yoshidaand N Nakahata ldquoDual effect of saikogenin D in vitroinhibition of prostaglandin E 2 production and elevation ofintracellular free Ca2+ concentration in C6 rat glioma cellsrdquoPlanta Medica vol 69 no 8 pp 765ndash767 2003
[73] P LiHKawachi TMorioka et al ldquoSuppressive effects of Sairei-to onmonoclonal antibody 1-22-3-induced glomerulonephritisAnalysis of effective componentsrdquo Pathology International vol47 no 7 pp 430ndash435 1997
[74] Y Chen X L Zhou and C R Xue ldquoTherapeutic effectsand mechanisms of chaihushugan decoction in experimentalchronic pancreatitis ratsrdquo Chinese Journal of Surgery of Inte-grated Traditional ampWesternMedicine no 3 pp 330ndash333 2010
[75] J Liu Z Zhao and C R Xue ldquoEffect of chaihu shugan pulvison dysfunction of pancreatic exocrine secretion in patients withchronic pancreatitisrdquo Chinese Journal of Surgery of IntegratedTraditional amp Western Medicine no 16 pp 275ndash277 2010
[76] G B Lenon C G Li C C Xue F C K Thien and D F StoryldquoInhibition of inducible nitric oxide production and iNOS pro-tein expression in lipopolysaccharide-stimulated rat aorta andRaw 2647 macrophages by ethanol extract of a Chinese herbalmedicine formula (RCM-101) for allergic rhinitisrdquo Journal ofEthnopharmacology vol 116 no 3 pp 547ndash553 2008
[77] Y-L Cheng W-L Chang S-C Lee et al ldquoAcetone extractof Bupleurum scorzonerifolium inhibits proliferation of A549human lung cancer cells via inducing apoptosis and suppressingtelomerase activityrdquo Life Sciences vol 73 no 18 pp 2383ndash23942003
[78] Y-L Chen S-Z LinW-L Chang Y-L Cheng andH-J HarnldquoRequirement for ERK activation in acetone extract identifiedfrom Bupleurrum scorzonerifolium induced A549 tumor cellapoptosis and keratin 8 phosphorylationrdquo Life Sciences vol 76no 21 pp 2409ndash2420 2005
[79] Y-L Cheng S-C Lee S-Z Lin et al ldquoAnti-proliferative activityof Bupleurum scrozonerifolium in A549 human lung cancercells in vitro and in vivordquoCancer Letters vol 222 no 2 pp 183ndash193 2005
[80] Y-L Hsu P-L Kuo T-C Weng M-H Yen L-C Chiang andC-C Lin ldquoThe antiproliferative activity of saponin-enrichedfraction from Bupleurum kaoi is through Fas-dependent apop-totic pathway in human non-small cell lung cancer A549 cellsrdquoBiological and Pharmaceutical Bulletin vol 27 no 7 pp 1112ndash1115 2004
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
BioMed Research International 21
[81] L-C Chiang L T Ng L-T Liu D-E Shieh and C-C LinldquoCytotoxicity and anti-hepatitis B virus activities of saikos-aponins from Bupleurum speciesrdquo Planta Medica vol 69 no8 pp 705ndash709 2003
[82] H L Hou S X He Z F Zhu et al ldquoldquoThe role of saikosaponind in regulating HIF-1120572COX-2 signal transduction pathway inhuman hepatocellular carcinoma cellsrdquo Journal of Xian JiaotongUniversity vol 32 pp 80ndash84 2011
[83] S Willimott J Barker L A Jones and E I Opara ldquoAn in vitrobased investigation of the cytotoxic effect ofwater extracts of theChinese herbal remedy LD on cancer cellsrdquo Chemistry CentralJournal vol 3 no 1 pp 1ndash16 2009
[84] T Kuroki ldquoProspective study of chemoprevention of hepatocel-lular carcinoma with sho-saiko-to (TJ-9)rdquoCancer vol 76 no 5pp 743ndash749 1995
[85] H Y Zhao ldquoClinical observation of the treatment of primaryliver cancer by using xiao-chai-hu decoctionrdquo Journal of Tradi-tional Chinese Medicine no 18 p 32 1995
[86] K Haranaka N Satomi A Sakurai R Haranaka N Okadaand M Kobayashi ldquoAntitumor activities and tumor necrosisfactor producibility of traditional Chinese medicines and crudedrugsrdquo Cancer Immunology Immunotherapy vol 20 no 1 pp1ndash5 1985
[87] J-S Chang K-C Wang H-W Liu M-C Chen L-C Chiangand C-C Lin ldquoSho-saiko-to (Xiao-Chai-Hu-Tang) and crudesaikosaponins inhibit Hepatitis B virus in a stable HBV-producing cell linerdquo American Journal of Chinese Medicine vol35 no 2 pp 341ndash351 2007
[88] F Yin R Pan R Chen and L Hu ldquoSaikosaponins fromBupleurum chinense and inhibition of HBV DNA replicationactivityrdquoNatural Product Communications vol 3 no 2 pp 155ndash157 2008
[89] P W Cheng L T Ng L C Chiang and C C Lin ldquoAntiviraleffects of saikosaponins on human coronavirus 229E in vitrordquoClinical amp Experimental Pharmacology amp Physiology vol 33 no7 pp 612ndash616 2006
[90] G T Jin L Bo and S RWang ldquoExperimental study onmaterialbasis efficacy and mechanism of antipyretic effect of BupleuriRadixrdquo Journal of Chengdu University of Traditional ChineseMedicine no 36 pp 28ndash30 2013
[91] S-L Cao E Chen Q-Z Zhang and X-G Jiang ldquoA novelnasal delivery system of a Chinese traditional medicine Radixbupleuri based on the concept of ion-activated in situ gelrdquoArchives of Pharmacal Research vol 30 no 8 pp 1014ndash10192007
[92] Y XieW Lu S Cao X JiangMYin andWTang ldquoPreparationof bupleurum nasal spray and evaluation on its safety andefficacyrdquo Chemical and Pharmaceutical Bulletin vol 54 no 1pp 48ndash53 2006
[93] Y Li C Xu Q Zhang J Y Liu and R X Tan ldquoIn vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines usedto treat ulcer diseasesrdquo Journal of Ethnopharmacology vol 98no 3 pp 329ndash333 2005
[94] Y Kumazawa T Kawakita H Takimoto and K NomotoldquoProtective effect of saikosaponin a saikosaponin d and saiko-genin D against Pseudomonas aeruginosa infection in micerdquoInternational Journal of Immunopharmacology vol 12 no 5 pp531ndash537 1990
[95] XM Du H Xie and Y Kang ldquoThe Pharmacological activity ofchinese ldquochaihurdquo-the root of bupleurum speciesrdquo Sci Eval ClinAppl no 10 pp 135ndash149 2006
[96] Z-Y Li H-M Sun J Xing X-M Qin and G-H DuldquoChemical and biological comparison of raw and vinegar-bakedRadix Bupleurirdquo Journal of Ethnopharmacology vol 165 pp 20ndash28 2015
[97] H Abe M Sakaguchi M Yamada S Arichi and S OdashimaldquoPharmacological actions of saikosaponins isolated fromBupleurum falcatum I Effects of saikosaponings on liverfunctionrdquo Planta Medica vol 40 no 4 pp 366ndash372 1980
[98] H Matsuda T Murakami K Ninomiya M Inadzuki andM Yoshikawa ldquoNew hepatoprotective saponins bupleurosidesIII VI IX and XIII from Chinese Bupleuri Radix Structure-requirements for the cytoprotective activity in primary culturedrat hepatocytesrdquo Bioorganic amp Medicinal Chemistry Letters vol28 no 52 pp 2193ndash2198 1997
[99] X H Han X D Gai Y J Xue and M Chen ldquoEffects ofthe extracts from Bupleurum Chinese DC on intracelluar freecalcium concentration and vincristine accumulation in humanhepatoma BEL-7402 cellsrdquo Tumor no 26 pp 314ndash317 2006
[100] H Abe M Sakaguchi S Odashima and S Arichi ldquoProtectiveeffect of saikosaponin-d isolated from Bupleurum falcatum LonCCl4-induced liver injury in the ratrdquoNaunyn-SchmiedebergrsquosArchives of Pharmacology vol 320 no 3 pp 266ndash271 1982
[101] J Fan X Li P Li et al ldquoSaikosaponin-d attenuates thedevelopment of liver fibrosis by preventing hepatocyte injuryrdquoBiochemistry amp Cell Biology vol 85 no 2 pp 189ndash195 2007
[102] M Yamakage J-I Hattori J-I Satoh and A Namiki ldquoEffectsof the Chinese herbal medicines Bupleuri radix Ginseng radixand Zingiberis rhizoma on lymphatic vessel activity in ratsrdquoAmerican Journal of Chinese Medicine vol 34 no 6 pp 1063ndash1068 2006
[103] Y Kumazawa H Takimoto C Nishimura T Kawakita andK Nomoto ldquoActivation of murine peritoneal macrophages bysaikosaponin a saikosaponin d and saikogenin drdquo InternationalJournal of Immunopharmacology vol 11 no 1 pp 21ndash28 1989
[104] M Kato M-Y Pu K-I Isobe T Hattori N Yanagita and INakashima ldquoCell type-oriented differential modulatory actionsof saikosaponin-d on growth responses and DNA fragmen-tation of lymphocytes triggered by receptor-mediated andreceptor-bypassed pathwaysrdquo Immunopharmacology vol 29no 3 pp 207ndash213 1995
[105] M Kato M-Y Pu K-I Isobe et al ldquoCharacterization ofthe immunoregulatory action of saikosaponin-drdquo CellularImmunology vol 159 no 1 pp 15ndash25 1994
[106] V K W Wong H Zhou S S F Cheung T Li and L LiuldquoMechanistic study of saikosaponin-d (Ssd) on suppression ofmurine T lymphocyte activationrdquo Journal of Cellular Biochem-istry vol 107 no 2 pp 303ndash315 2009
[107] H Yi B Long X Ye L Zhang X Liu and C ZhangldquoAutophagy A potential target for thyroid cancer therapy(Review)rdquo Molecular and Clinical Oncology vol 2 no 5 pp661ndash665 2014
[108] N Mizushima ldquoAutophagy process and functionrdquo Genes ampDevelopment vol 21 no 22 pp 2861ndash2873 2007
[109] D C Rubinsztein P Codogno and B Levine ldquoAutophagymod-ulation as a potential therapeutic target for diverse diseasesrdquoNature Reviews Drug Discovery vol 11 no 9 pp 709ndash730 2012
[110] Z J Yang C E Chee S Huang and F A Sinicrope ldquoThe roleof autophagy in cancer therapeutic implicationsrdquo MolecularCancer Therapeutics vol 10 no 9 pp 1533ndash1541 2011
[111] E-L Eskelinen ldquoThe dual role of autophagy in cancerrdquo CurrentOpinion in Pharmacology vol 11 no 4 pp 294ndash300 2011
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
22 BioMed Research International
[112] O Yamaguchi and K Otsu ldquoRole of autophagy in agingrdquoJournal of Cardiovascular Pharmacology vol 60 no 3 pp 242ndash247 2012
[113] B Y Law J F Mo and V K Wong ldquoAutophagic effects ofChaihu (dried roots of Bupleurum Chinense DC or BupleurumscorzoneraefoliumWILD)rdquoChineseMedicine vol 9 no 1 article21 2014
[114] Y Cheng Y Huang Y Tian L Xu G Q Liu and Z J ZahngldquoAssessment of the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity by a six-drugcocktail approachrdquoChinese Journal of Natural Medicines vol 11no 3 pp 302ndash308 2013
[115] X Chen T Yu Z Chen R Zhao and S Mao ldquoEffect ofsaikosaponins and extracts of vinegar-baked Bupleuri Radix onthe activity of 120573-glucuronidaserdquo Xenobiotica vol 44 no 9 pp785ndash791 2014
[116] M Ye Y-F Bi L Ding W-W Zhu and W Gao ldquoSaikosaponina functions as anti-epileptic effect in pentylenetetrazol inducedrats through inhibiting mTOR signaling pathwayrdquo Biomedicineand Pharmacotherapy vol 81 pp 281ndash287 2016
[117] D He H Wang L Xu et al ldquoSaikosaponin-a AttenuatesOxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cellsrdquo Journal of Cardiovascular Pharmacology vol 67 no 6pp 510ndash518 2016
[118] K-G Shyu S-C Tsai B-W Wang Y-C Liu and C-C LeeldquoSaikosaponin C induces endothelial cells growth migrationand capillary tube formationrdquo Life Sciences vol 76 no 7 pp813ndash826 2004
[119] T H Lee S H ParkM-H You J-H Lim S-HMin and BMKim ldquoA potential therapeutic effect of saikosaponin C as a noveldual-target anti-Alzheimer agentrdquo Journal of Neurochemistryvol 136 no 6 pp 1232ndash1245 2016
[120] S Zhu F Ling Q Zhang et al ldquoAnthelmintic activity ofsaikosaponins a and d from radix bupleuri againstDactylogyrusspp infecting goldfishrdquo Diseases of Aquatic Organisms vol 111no 2 pp 177ndash182 2014
[121] S C Cui Q Z Cao and C X Su ldquoAnalysis of 50 cases of drug-induced liver diseaserdquo Journal of Capital Medicine Universityvol 20 pp 296-297 1999
[122] D C H Teo P S L Ng S H Tan et al ldquoDrug-inducedliver injury associated with Complementary and AlternativeMedicine A review of adverse event reports in an Asiancommunity from 2009 to 2014rdquo BMC Complementary andAlternative Medicine vol 16 no 1 pp 1ndash11 2016
[123] S Itoh K Marutani T Nishijima S Matsuo and M ItabashildquoLiver injuries induced by herbal medicine Syo-saiko-to (xiao-chai-hu-tang)rdquoDigestive Diseases and Sciences vol 40 no 8 pp1845ndash1848 1995
[124] C-H Lee J-D Wang and P-C Chen ldquoRisk of Liver InjuryAssociated with Chinese Herbal Products Containing Radixbupleuri in 639 779 Patients with Hepatitis B Virus InfectionrdquoPLoS ONE vol 6 no 1 Article ID e16064 2011
[125] R Sun LWangQ YangWHuang and L L Lv ldquoAcute toxicityof volatile oil from Bupleurum chinense in rats and micerdquoChinese Journal of Experimental Traditional Medical Formulaevol 16 pp 154ndash156 2010
[126] W Huang R Sun and Z Zhang ldquoldquoDose-time-toxicityrdquo rela-tionship study onhepatotoxicity caused bymultiple dose of totalBupleurum saponin crude extracts to ratsrdquo China Journal ofChinese Materia Medica vol 35 no 35 pp 3344ndash3347 2010
[127] L Xu R Song J-X Tian Y Tian G-Q Liu and Z-JZhang ldquoAnalysis of saikosaponins in rat plasma by anionic
adducts-based liquid chromatography tandem mass spectrom-etry methodrdquo Biomedical Chromatography vol 26 no 7 pp808ndash815 2012
[128] L Lin B Ni H Lin et al ldquoTraditional usages botanyphytochemistry pharmacology and toxicology of Polygonummultiflorum Thunb a reviewrdquo Journal of Ethnopharmacologyvol 159 pp 158ndash183 2015
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Submit your manuscripts athttpswwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of