reviewarticle nigella sativa l. (black cumin): a promising natural remedy...

Review ArticleNigella sativa L (Black Cumin) A Promising Natural Remedyfor Wide Range of Illnesses

EbrahimM Yimer 1 Kald Beshir Tuem 1 Aman Karim 2

Najeeb Ur-Rehman3 and Farooq Anwar4

1Department of Pharmacology and Toxicology College of Health Sciences Mekelle University Ethiopia2Department of Pharmacognosy College of Health Sciences Mekelle University Ethiopia3Department of Pharmacology College of Pharmacy Prince Sattam Bin Abdulaziz University Al-Kharj Saudi Arabia4Department of Chemistry University of Sargodha Sargodha Pakistan

Correspondence should be addressed to Ebrahim M Yimer ebrahim99muhammedgmailcom

Received 20 October 2018 Revised 26 February 2019 Accepted 30 April 2019 Published 12 May 2019

Academic Editor Nativ Dudai

Copyright copy 2019 Ebrahim M Yimer et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The seed of Nigella sativa (N sativa) has been used in different civilization around the world for centuries to treat variousanimal and human ailments So far numerous studies demonstrated the seed of Nigella sativa and its main active constituentthymoquinone to be medicinally very effective against various illnesses including different chronic illness neurological andmental illness cardiovascular disorders cancer diabetes inflammatory conditions and infertility as well as various infectiousdiseases due to bacterial fungal parasitic and viral infections In spite of limited studies conducted so far the promisingefficacy of N sativa against HIVAIDS can be explored as an alternative option for the treatment of this pandemic disease aftersubstantiating its full therapeutic efficacy Moreover the strong antioxidant property of this valued seed has recently gainedincreasing attention with regard to its potential role as dietary supplement with minimal side effects Besides when combinedwith different conventional chemotherapeutic agents it synergizes their effects resulting in reducing the dosage of concomitantlyused drugs with optimized efficacy and least andor no toxicity A number of pharmaceutical and biological properties have beenascribed to seeds of N sativa The present review focuses on the profile of high-value components along with traditional medicinaland biological principles of N sativa seed and its oil so as to explore functional food and nutraceutical potential of this valuedherb

1 Introduction

Plants have long been used as a basis of traditional remediesin the history of mankind and also act as sources of modernmedicines According to the World Health Organization(WHO) more than three-fourths of the communities inresource-limited countries rely upon medicinal plants fortheir primary health care needs because more than 60 ofthe societies are unable to have access andor afford allopathicmedicines [1 2] In line with the new progress in the area ofoptimumnutrition nowadays there is a resurgence of interestin the use of plants as a source of food and medicine [3 4]Recently the usage of phytomedicine has been amplifieddramatically for numerous ailments because of not only their

easy accessibility and low cost but also the belief that naturalremedies have fewer harmful effects as compared to syntheticmedicines [5]

The development of new products from natural sourcesis also encouraged because it is estimated that of the300000 herbal species that exist globally only 15 have beenexplored for their pharmacological potential [6] Amongseveral medicinal plants Nigella sativa L (Ranunculaceae)has been considered one of the most treasured nutrient-richherb in history around the world and numerous scientificstudies are in progress to validate the traditionally claimeduses of small seed of this species [7 8]

The maximal nutritional value of black cumin can belinked to the presence of substantial amount of vegetable

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2019 Article ID 1528635 16 pageshttpsdoiorg10115520191528635

2 Evidence-Based Complementary and Alternative Medicine

protein fiber and minerals and vitamins The nutritionalcomposition reported fromdifferent sources revealed 20-85of protein 3820 of fat 7-94 of fiber and 3194 of totalcarbohydrates Among various amino acids identified gluta-mate arginine and aspartate while cysteine and methioninewere the major and minor amino acids respectively Blackcumin seeds also contain significant levels of iron copperzinc phosphorus calcium thiamin niacin pyridoxine andfolic acid [7 8] In addition phytochemical analyses of Nsativa displayed the presence of over hundreds of phytocon-stituents which include mainly alkaloids saponins sterolsand essential oil but the composition of many of these havenot been chemically recognized nor have been biologicallyverified TheN sativa seed contain 26-34 fixed oil of whichthe major fatty acids are linoleic acid (646) and palmiticacid (204)The seed oil is comprised of 04ndash25 essentialoil [9 10] Amongst different active constituents reported sofar thymoquinone found asmajor component of the essentialoil is the most bioactive compound and exhibits wide rangingtherapeutic benefits [11]

2 High-Value BioactiveCompounds (Phytochemicals) inthe Seed of Nigella sativa

Several bioactive compounds from the seed of N sativahave been reported in the literature among those themost important bioactive ones are thymoquinones Othermain phytochemicals reported from different varieties of Nsativa include sterols and saponins phenolic compoundsalkaloids novel lipid constituents and fatty acids andvolatile oils of varying composition [12] The essential oilcomposition (04-045) reported in various studies repre-sented about forty different compounds amongst the abun-dantly constituents identified are trans-anethole p-cymenelimonene carvone 120572-thujene thymoquinone (TQ) thymo-hydroquinone (THQ) dithymoquinone carvacrol and 120573-Pinene with various concentration [13ndash15]

The quantity of most important bioactive constituentthymoquinone present in the volatile oil isolated by differentextraction methods from the seeds of N sativa varied overa wide range using SC-CO2 (106 407mgg) [16] and bySoxhlet extraction (294043mgkg) [17] and (88mgg) oil[18]

The seed oil fatty acid composition (32-40) has beenreported by various authors to contain mainly linoleiclinolenic oleic palmitoleic palmitic acids together witharachidonic eicosadienoic stearic and myristic acid [15 1619] A new dienoate and two known monoesters along withnovel lipids have been isolated from the unsaponified extractof the seed namely methylnonadeca-1517-dienoate pentylhexadec-12-enoate and pentyl pentadec-11-enoate [20]

Phytosterols are important part of human diet and aregaining greater interest due to their nutraceutical and medic-inal benefits in lowering low density lipoprotein and totalcholesterol level [21] Phytosterols are also important as char-acteristic compounds for assessing the quality of vegetableoils and food labelingThe total sterols content of black cumin

seed oil as estimated by different researchers was found to bebetween 18 and 42 of the unsaponified matter The majorsterols identified were 120573-sitosterol campesterol stigmasteroland 5-avenasterol [19 22] Tocopherols exhibited attractivescavenging potentials of free radicals which are believedto terminate lipids peroxidation [23] The total tocopherolcontents of black seed oil reported in varied quantities fromdiverse sources ranged from 915 to 2792mg100 g Amongthe foremost tocopherols recognized in black cumin seeds120572- and 120574-tocopherol and 120573-tocotrienol are well recognized[19]

Steroidal glycosides of new and known structures havebeen isolated from N sativa seeds which include 3-O-[120573-D-xylopyranosyl-(1997888rarr2)-120572-L-rhamnopyranosyl-(1997888rarr2)-120573-D-glucopyranosyl]-11-methoxy-16 23-dihydroxy-28-methylol-ean-12-enoate stigma-522-dien-3-120573-D-glucopyranoside[24]and 3-O-[120573-D-xylopyranosyl-(1997888rarr3)-120572-L-rhamnopyrano-syl-(1997888rarr4)-120573-D-glucopy-ranosyl]-11-methoxy-16-hydroxy-17-acetoxy hederagenin [25] Moreover alkaloids of diversetypes have been isolated from the seeds of black cuminwhich include novel Dolabellane-type diterpene alkaloidsnigellamines A1 A2 B1 and B2 and nigellamines A3 A4 A5and C [26 27] possessing lipid metabolizing property andindazole class of alkaloids nigellidine nigellicine [28 29]and nigellidine-4-O-sulfite [30]

3 Traditional Uses of Nigella sativa inFolk Remedies

Nigella sativa has been widely used as a spice and flavoringagent in variety of food preparations such as in breadyogurt pickles sauces and salads Black seed or blackcumin (English) Habbatul Barakah (Arabic) Tikur azmud(Amharic) has long been used in traditional remedy in theArabian countries Far East Asia Europe and Africa [31]Nigella sativa has also been described as the miraculous plantand considered by earliest herbal specialists as ldquoThe herbfrom heavenrdquo [32] The Prophet Mohammed (PBUH) haddescribed the curative powers of the black seed as ldquoHold onto use this black seed as it has a remedy for every illnessexcept deathrdquo [33] Avicenna a well-known physician of 10thcentury famous for his book ldquoThe Canon of Medicinerdquo hasrecommended use ofNigella seeds for enhancement of bodyrsquosenergy and also support during recovery from fatigue anddispiritednessNigella sativa is also mentioned for its curativeproperty in the Holy Bible and is also labelled asMelanthionby Hippocrates and Dioscorides [34 35]

The medicinal use of black cumin seeds in varioustraditional herbal systems is known for a wide range ofailments which include different airway disorders for painsuch as chronic headache and back pain diabetes paralysisinfection inflammation hypertension and digestive tractrelated problems administered in different kind of prepa-rations It has also been used topically where it is applieddirectly to the blisters nasal abscesses orchitis eczema andswollen joints [33]

Keeping in view of the numerous traditional medic-inal uses of N sativa seeds and its active component

Evidence-Based Complementary and Alternative Medicine 3

thymoquinone this valuable herb can be explored as an effec-tive folk medicine with multiple pharmacological actions

4 Pharmacological Activities of Nigella sativa

Nigella sativa has been broadly studied in the last few decadesand studies have reported that it possesses a number ofmedicinal properties and pharmacological actions In orderto retrieve the relevant literatures with respective subtopicswe have used PubMed Science Direct Scopus GoogleScholar and grey literatures using different searching termssuch as ldquoNigella sativardquo or ldquoBlack cuminrdquo or ldquoBlack seedrdquoand respective disease conditions In the case of PubMedsearching we have used the respective ldquoMeshrdquo terms andtext words ldquotwrdquo in order to retrieve all the relevant articlesregardless of time boundaries

41 Antioxidant Activity Oxidative stress and an intensifica-tion in the levels of free radicals are amongst the foremostcentral markers associated with several progressive patho-logical conditions including neurological disorder canceraging and endocrine illness [36] To date there has been agrowing importance in the therapeutic option of medicinalplants as natural antioxidants Among the various naturallyoccurringmedicinal plantsN sativa has been reported for itseffective antioxidant activities of invivo and invitro studies[37]

The concomitant usage of Allium sativum and N sativaseed in thirty postmenopausal women after two monthsof consumption revealed a significant reduction in plasmamalondialdehyde (MDA) levelswith increased activity in ery-throcyte glutathione peroxidase (GSH-Px) and superoxidedismutase [38] Likewise the fixed and essential oil of blackcumin seed revealed a significant increment of Glutathione-S-transferase (GST) glutathione reductase and GSH-Pxagainst oxidative stress brought by potassium bromate in ratsrsquomodel [39]

The separate administration of N sativa and nanosizedclinoptilolite to Wistar rats also showed significant improve-ment on antioxidant parameters than concomitant usesof both extracts and diabetic groups [40] A randomizedcontrolled clinical trial in fifty volunteer obese subjectsalso demonstrated that N sativa seed oil along with a lesscaloric diet significantly diminished the superoxide dismu-tase (SOD) level and body weight as compared to the placebogroup in eight weeksrsquo trial [41] Moreover the methanolicextract and essential oil fractioned from N sativa seed inatherogenic suspension nourished rats has been reportedeffectively replenished the plasma total antioxidant power byeighty-eight percent against free radicals [42] Similarly theoil of N sativa and thymoquinone administration markedlyameliorated cisplatin-induced alteration on carbohydratebiotransformation and enzymatic and nonenzymatic antiox-idant defense system in the gastric mucosa [43] Hence themarked antioxidant activity of N sativa and thymoquinonemight be a potential newer antioxidant agent and used asessential nutrients for life for health promotion and diseasesprevention

42 Antidiabetic Activity Even with the advancement in themanagement of diabetes mellitus exploration for innovativeagents continues since the existing synthetic agents havenumerous limitations [44] The administration of blackcumin seed for one month to streptozotocin-induced dia-betic rats displayed a significant reduction of fasting plasmaglucose serum MDA interleukin-6 and immunoglobulinA G and M while substantial increment of endogenousantioxidant enzymes SOD Glutathione-S-transferase andcatalase expression were noticed The histology of pancreasin N sativa treated group also revealed an improvementin the pancreatic 120573-cells degeneration inflammation andcongestion as compared to diabetic control [45] The com-bination of administration of N sativa and Cinnamomumcassia extracts (NSCCe) to experimentally STZ-induced dia-betic rats also showed significantly stabilized serum glucoseconcentrations lipid profile and renal function parametersas compared to the diabetic control Significant effects wereobserved in animals that received combined extract andmetformin on these parameters A substantial reversal of thehistopathological pancreatic cell injury was also observed inanimals receiving the concomitant extracts of NSCCe [46]The marked antidiabetic activity upon three-month supple-mentation of N sativa (2 gday) along with oral antidiabeticagent in type 2 DM patients has also been reported In thisstudy N sativa received group showed significant reductionof fasting plasma glucose hemoglobin A1c and TBARBswhilemarked elevation of the total antioxidant capacity SODand glutathione levels were noted [47]

Furthermore an experimental randomized controlledtrial of 99 diabetes patients received the placebo and twotreatment groups received oral black seed oil Administrationof 15 and 3mLday of black seed oil for 20 days showedmeaningful reduction of glycated hemoglobin A1c and ran-dom blood sugar levels [48] The effect of N sativa seed onthe glycemic control of patients with type-2 diabetes (DM-2)was also used as an adjunctive treatment added to their oralhypoglycemic agents N sativa at a dose of two gday alsoinfluenced substantial reductions in fasting plasma glucoseand glycated hemoglobin (HbA1c) without major alterationin body weight [49] The oil of N sativa (NSO) at 2mLkgalso was showed to reduce fasting plasma glucose andintensification of insulin levels in diabetic rats compared tocontrol Diabetic rats that received NSO exhibited substantialimprovements in lipid profile and expressive increment ofpancreatic and hepatic antioxidant enzymes also augmentedthe histological image and glycogen contents other thanimprovements of average pancreatic islet extent than thediabetic groups [50]

The different doses of N sativa seed (1 2 and 3 gday)in patients with DM-2 were also evaluated A one gdayadministration increased high-density lipoprotein choles-terol (HDL-c) levels after 3months while two and three gdayof N sativa seed significantly decreased serum levels of totalcholesterol (TC) and triglyceride (TG) as well as low-densitylipoprotein cholesterol (LDL-c) and increased plasma HDL-c[51] In reference to modern scholarsrsquo devotion to the likelyeffects of medicinal herbs in diabetic management a recentmeta-analysis of antidiabetic effects of N sativa [44] also


exhibited the maintenance of glucose homeostasis and serumlipid profiles in diabetic human subjects [44 51]

Generally the possible antidiabetic mechanisms of Nsativa might be mediated via modulation of oxidative status(either through upregulation of endogenous antioxidantsor reduction of oxidative species) [45 47] attenuation ofinflammation [45] improvement of lipid profiles increasedgood cholesterol (HDL-c) while reducing bad cholesterols(LDL-c TC and TG) and body weight [44 46 51]

43 Antihypertensive Activity Numerous antihypertensiveagents have been clinically used to control hypertensionand to relieve associated comorbid conditions However theeffectiveness of these agents is only in 40-60of hypertensivepatients and commonly combination of two or more bloodlowering agents from diverse antihypertensive classes isrequired to attain the desired outcomes [52] This eventuallyincreases the likelihoods of untoward effects and also raisesthe cost of therapy A number of herbal products such as theseed ofN sativa have been used and claimed to have positiveeffects against elevated blood pressure (BP)

According to a nonrandomized controlled trials 57patients who were allocated to receive 2 g daily supplemen-tations of black cumin for one year displayed a noticeablereduction in systolic diastolic and mean arterial BP heartrate TC LDL-c the fractions of TCHDL-c and LDL-cHDL-c while serum HDL-c was suggestively raised com-pared with the corresponding baseline values and the controlgroup [53] Although a trend towards reduction in BP wasobserved after N sativa administration one randomizedcontrolled clinical trial failed to show a significant reductionof BP in elderly patients with hypertension [54] This mightbe because of the sample size dosage (300mg BID for4 weeks) of the N sativa used in this study the severityof hypertension and study population used For instanceprevious clinical studies conducted by Dehkordi et al [55]and Qidwai et al [56] conducted on mild hypertensivepatients with the dosage of 200mg BID for 4 weeks and500mg BID for 6 weeks respectively showed a significantreduction of SPB

In addition it has been employed to determine the bloodpressure lowering potential and possible mechanisms of Nsativa in ratsrsquo model and it was found that the seed oil andnicardipine received groupsrsquo revealed substantial reductionin BP The BP diminishing effect was related with a reduc-tion in cardiac lipid peroxidation product and inhibitoryactivity of angiotensin converting enzyme in both groupsbut plasma nitric oxide level significantly increased in Nsativa oil received group than the placebo and nicardipinereceived groups [57] Black cumin and its active componentthymoquinone exhibited a reduction in oxidative stressvia calcium channel blockade and increasing urine outputactivity which might have been linked to reduction in bloodpressure [58] Based on majority of these reports variouspreparation of N sativa showed a sustainable reduction ofthe BP in animal models and clinical studies hence can beexplored as a promising basis of natural antihypertensivedrugs

44 Neuroprotective Effects Neurological disorder such asdepression is amongst the most prevailing illnesses glob-ally It is principally affected by the hypoactivity of neu-rotransmitters particularly owing to inadequate activity ofserotonin [59] Stress is the chief triggering aspect in theinitiation of depression and this premise is steadily supportedby various clinical observations Studies in experimentalanimals displayed that overwhelming stress conditions pro-duce neurochemical modifications and behavioral deficits[60] A large number of medicinal herbs and their isolatedcompounds have been revealed to have medicinal benefitsand therapeutic potential Among the promising medicinalplants black cumin is a worthwhile herb with a rich historicaland religious basis to manage depression and many otherneurological disorders

The intragastric supplementation of TQ (20mgmL) inaluminum trichloride and D-galactose induced neurotoxi-city in rats showed a meaningful improvement of cogni-tion SOD and total antioxidant capacity while reducingacetylcholinesterase activities It also exhibited a reductionin MDA nitric oxide levels and tumor necrosis factor-120572immunoreactivity and amplified brain derived neurotrophicfactor and Bcl-2 levels [61] While the effects of repeatedadministration ofN sativa in rats indicated that there was animprovement in learning and recall status [62] In additionflavonoids isolated from black cumin have been shown tomodulate critical neuronal signaling paths involved in theprocesses ofmemory and are likely to affect synaptic plasticityand long-standing potentiating mechanisms [63] The neu-ropharmacological effects of the seed and oils ofN sativa andits active component TQ are described in Table 1 Based onthe wide ranging neuropharmacological effects black cuminseed its oil and the active principle thymoquinone (TQ) canbe explored as a promising natural remedy for improvementof numerous neurological disorders

45 Anti-Inflammatory and Analgesic Effects Inflammationhas a key role in various medical conditions such as cysticfibrosis rheumatoid arthritis osteoarthritis asthma aller-gies and cancer which all are associated with acute andorchronic pain The existing anti-inflammatory agents com-monly comprise classes of drugs that produce severe adverseeffects such as gastric ulcer bone marrow depression waterand salt retention resulting from the extended use [80]Medicinal herbs including black cumin might be a potentialsource of novel biological compounds that are safer andwith fewer side effects The volatile oil of black cumin andthymoquinone at various doses revealed a dose-reliant anti-inflammatory activity against carrageenan-induced hind pawedema in ratsrsquo parallel to indomethacin [81] The volatileoil of N sativa seed also displayed a substantial pain-relieving effect in acetic acid-induced writhing formalinand tail flick tests [82] As stated by Al-Ghamdi the waterextract of black cumin also retained anti-inflammatory effectsin carrageenan-induced paw edema comparable to acetylsalicylic acid at corresponding doses but failed to displayantipyretic activity against yeast-induced pyrexia [83] Fur-thermore the alcoholic extract of black cumin exhibited


Table 1 The effects of N sativa and its active component thymoquinone (TQ) on neurological and mental disorders

Neurologicalor mentalDisorders

Model used and intervention (s) Finding (mechanism) References

Alzheimerrsquosdisease (AD)

Lipopolysaccharide-induced AD in mice receivedTQ (25 amp 5mgkg) for 7 days

(i) darr TBARS amp 5-LOX levels(ii) uarr GSH extent and SOD action(iii) Causes disaggregation of A120573 peptide(iv) prevents declining of neurons(v) Slows degeneration of cognitive ability

[64 65]

A120573-induced neurotoxicity (analyzed by culturinghippocampus and cortical neurons)TQ is administered along with A1205731minus42 for 72 hours

(i) Reducing A120573-induced neurotoxicity(Improved cell viability) by(ii) Inhibiting mitochondrial membrane potentialdepolarization(iii) Hindering reactive oxygen species generation

[66]

Parkinsonrsquosdisease (PD)

1-methyl-4-phenylpyridinium (MPP+) androtenone-induced neurotoxicity in PDmodelcultures were treated with TQ (001 01 1 and 10120583M) on day 8th for 4 days

(i) Rescued dopaminergic neurons through(ii) Its antioxidant and anti-inflammatory effects

[67]

Experimental model of early PD induced by6-hydroxydopamine neurotoxicity pretreatmentof daily TQ (5 amp 10 mgkg) and one additionaldose after surgery were used

(i) darrMDA level(ii) Prevents loss of neurons in substantia nigra(iii) Protects hippocampal amp human inducedpluripotent stem cell against 120572-synuclein inducedsynaptic toxicity

[68 69]

Depressionand anxiety

(i) Open field and elevated plus maze modelsforced swim test(ii) Locomotor behavior in familiar and newenvironment in rats N sativa oil (01 mLday)aqueous seed extract (2 mLday) orally for 4-6weeks

(i) uarr in open field activity amp struggling time(ii) uarr 5-HT(iii) darr 5HIAA level in the brain(iv) uarr tryptophan level in plasma amp brain(v) uarr locomotors activity in novel environment(vi) uarr brain DA level

[59 70 71]

Stressed and unstressed mice 10 and 20 mgkg ofTQ for 4 weeks

Unstressed mice at 10 amp 20 mgKg showedanti-anxiety(i) without altering nitrite levels(ii) uarr GABA content (only 20mgKg)Stressed mice 20 mgkg showed anxiolytic effectswith(i) darr plasma nitrite level(ii) Reversal of reduced GABA

[72]

Randomized control trial on healthy humansubjects N sativa capsule (500 mg) daily for 4weeks

(i) Stabilize disturbed mood(ii) darr anxiety(iii) Modulate memory positively

[73]

Epilepsy

Pentylenetetrazole-induced seizure N sativa oilTQ

(i) Prevented seizure occurrence(ii) darr Reactive oxygen species generation(iii) Reduced seizure score(iv) Showed additive effects with phenobarbitone

[74ndash76]

Double-blinded placebo randomized control trial(refractory epilepsy) TQ as adjunctive therapy for4 weeks

(i) Significant reduction of seizure frequency(those who received combination therapy) [77]

OpioiddependenceandTolerance

Morphine brought tolerance and dependency inmice 4mLkg of N sativa oil along withmorphine (5mgkg)

(i) Attenuated the development of tolerance(ii) Inhibited nitric oxide overproduction(iii) darr in brain MDA level

[78]

Randomized trial (on 35 known addicts ofopiates) 500 mg N Sativa three times daily

(i) darr the withdrawal effects significantly(ii) uarr appetite (no significant weight gain)(iii) No changes in physiological parameters(blood pressure pulse and respiratory rate)

[79]

TBARs=Thiobarbituric acid reactive substances GABA= gamma amino butyric acid 5-HT= 5 hydroxytryptamine MDA=malondialdehyde DA= dopamine5HIAA=5 hydroxyindoleacetic acid GSH= glutathione peroxidase SOD= superoxide dismutase TQ= thymoquinone A120573= beta amyloid peptides uarr=increasedarr=decrease


a noteworthy pain-relieving effect in mice as comparedto diclofenac sodium [84] Additional study also showedthat essential oil of black cumin has notable activity as apainkiller in acetic acid-induced writing formalin and tailflick tests It was also revealed that this extract might elevatea significant swimming and anoxia tolerance time [85] Theanti-inflammatory action of TQmight be related to inhibitionof the oxidative product of arachidonic acid formationsuch as thromboxane B2 and leukotriene by blocking bothcyclooxygenase and lipoxygenase enzymes [86 87]

In addition the action of black cumin seed on trachealsensitivity and pulmonary inflammation of guinea pigswhich were exposed to breathe Sulphur mustard togetherwith black cumin displayed expressively lower magnitudecompared to that of only Sulphur mustard exposed group[88] The bronchial relaxation effects of the boiled extractof N sativa in contrast with theophylline were assessedin asthmatic patients and it was found that black cuminextract caused substantial rises in entirely measured respi-ratory function tests and the starting time of bronchodilatoraction of the extract was comparable to that of theophylline[89] The various extracts oil and active constituent (120572-hederin) ofN sativa also showed an improvement of trachealresponsiveness and significant anti-inflammatory activity viadecreasing the release of histamine and leukotrienes whileincreasing the PGE2 from themast cells and perfused lungs inanima model of allergic asthma [90ndash93] This antiasthmaticeffect is further substantiated by different clinical studiesand majority of them reported that different N sativa prepa-rations showed an improvements of clinical symptoms andpulmonary function as well as various asthma biomarkers[89 94ndash97] These preclinical and clinical studies evidencedthe potential antiasthmatic effects of N sativa but furtherinvestigations are required to assure its efficacy

The efficacy of black cumin oil in patients with rheuma-toid arthritis (RA) was also evaluated and data from 40female patients diagnosed with RA who took N sativaoil capsules (500mg) twice daily exhibited improvementin disease activity score compared to placebo (P lt 005)Correspondingly a noticeable improvement was displayed innumber of inflamed joints incidence of morning stiffnessand disease activity after the consumption of black cumin[98]

Chronic inflammation has been implicated in variouschronic illnesses [(cancer cardiovascular disorders diabetesAlzheimerrsquos disease epilepsy amyotrophic lateral sclerosisrheumatoid arthritis and asthma) that involve progressiveand irreversible damage to the cell andor neurons] as wellas in many infectious conditions [99 100] Therefore thecrucial role of anti-inflammatory actions of differentN sativapreparations and TQ might be the possible sources for thedevelopment of a new generation of anti-inflammatory agentto treat these wide ranging conditions

46 Antimicrobial Activity Antimicrobials have been thebases of clinical medicine since the second half of the20th century and have saved prominent number of peoplefrom serious microbial infections Nevertheless in the late

20th century and the earliest 21st century it has perceivedthe advent and widespread of antimicrobial resistance inpathogenic microorganisms throughout the globe [101 102]The ever-increasing terrorization of microbial infections andantimicrobial resistant bacteria demands for a global struggleto discover for novel solutions that might be groundedon the natural products such as plants which are selectedon the basis of renowned ethnomedicinal use [103 104]Among the inspiring medicinal plants black cumin is the onethat displayed strong antibacterial antifungal antiviral andantiparasitic actions

461 Antibacterial Activity Thymoquinone obtained fromseeds of N sativa revealed broader spectrum activitiesagainst multiple strains of gram-positive and gram-negativebacteria including Bacillus Listeria Enterococcus Micrococ-cus Staphylococcus Pseudomonas Escherichia SalmonellaSerovar and Vibrio parahaemolyticus in addition to inhibit-ing bacterial biofilm formation [105] The methyl alcoholicextract of the seed also displayed a larger inhibition zone ongram-positive (S pyogenes) as compared to gram-negativebacteria (P aeruginosa K pneumoniae and P vulgaris) [106]For different isolates ofmethicillin-resistant S aureus variousconcentrations of (100 80 50 40 30 and 20) Nsativa oils displayed an expressively higher zone of inhibitionsagainst all the tested bacterial strains [107] Thymoquinonealso revealed a significant bactericidal activity against gram-positive cocci with MICs ranging from 8 to 32120583gmL andproved the minimum biofilm inhibition concentration at 22and 60120583gmL for S aureus and S epidermidis respectively[108] Moreover black seed (2 gday) owed clinically valuableanti-H pylori effect comparable to triple therapy [109] andthis can provide a scientific basis for the exploration ofpotential uses of this valued seed for the treatment of Hpylori-induced gastric ulcers

462 Antifungal Activity The essential oil of N sativa ofdifferent origins has been reported to possess moderateinhibitory action against pathogenic strains of yeasts der-matophytes and nondermatophytic filamentous fungi alongwith aflatoxin-producing fungi The N sativa treatmenttargeted the cell wall plasma membrane and membranousorganelles mainly in the nuclei and mitochondria as wereevident in the morphology of these toxigenic fungi [110]Moreover different extracts of black cumin and TQ exhibitedpowerful fungicidal activity against dermatophyte strainsincluding Trichophyton mentagrophytes and Microsporumgypseum superior to fluconazole but lesser than that ofketoconazole [111] Thymoquinone also arrested the growthof Aspergillus niger and Fusarium solani comparable toAmphotericin-B [112] and was effective against C albicansC tropicalis and C krusei [113] Similarly as stated by Tahaet al the active constituent of black cumin such as TQthymohydroquinone and thymol revealed potent antifungaleffect against several clinically isolated fungal strains includ-ing dermatophytes molds and yeasts [114] As a potentialcandidate with multiple antimicrobial activities N sativa canalso be explored as a natural preservative and food additiveto protect foods from spoilage


463 Antiviral Activity N sativa seed oil was found to sup-press viral load in murine model cytomegalovirus infectedmice to undetectable level in the liver and spleen in 10daysrsquo intraperitoneal administration This was possibly dueto the increase in number and function of CD4+ve T cellsand increased production of interferon- (INF-) gamma [115]Interestingly patients (30) with hepatitis C virus (HCV)infection who were not eligible for IFN-120572ribavirin therapyshowed significant improvement in HCV viral load (1667became seronegative and 50 showing significant decre-ment) and proved laboratory parameter like total proteinred blood cell and platelet count decreased fasting bloodglucose and postprandial glucose in both diabetic andnondiabetic HCV patients and reduced lower-limb edemaafter they are managed with black cumin seed oil [116]

According to a case report conducted by Onifade et alafter treatment with 10mL of black seed twice daily for 6months a complete regaining and seroreversion of a 46-year-old HIV positive patient was evidenced [117] In additiona 27-year-old HIV infected woman was diagnosed duringante-natal care she was not eligible for antiretroviral therapyhence herbal therapist initiated her on black cumin andhoney mixture (10mL) thrice daily for a year The repeatserology assessments for HIV infection became negative withundetectable viral loadThe woman also got 3 children (20072010 and 2012) that all were breastfed and none of thechildren infected with HIV and her repeat CD4 count wasnot less than 750 cells120583L [118] Nowadays HIVAIDS is aserious global threat and in this regard N sativa can be apromising natural therapy to cure such a chronic infectiousdisease after validating its full therapeutic efficacy by furtherinvestigations

464 Antiparasitic Activity Nigella sativa seeds have shownschistosomicidal properties against Schistosoma mansoni (invitro) through a strong biocidal effect against all stages ofthe parasite and an inhibitory effect on egg-laying of adultfemale worms [119 120] An ointment ofN sativa seed signif-icantly contracted and inhibited the inflammatory reactionsto cutaneous leishmaniasis produced experimentally in miceby a subcutaneous inoculation of Leishmania major at theabaxial base of the tail [121] N sativa extract at a dose of125 gkg prominently lowered Plasmodium yoelii infection inmice by 94 however the effect of chloroquine was only 86as compared to the untreated group In addition methanolicextract of N sativa revealed higher parasite clearance andrestoration of altered biochemical indicators by P yoeliiinfection than chloroquine [122] Thus considering N sativafor future antiparasitic agents will have a very importantinput after conduction of further investigation of its curativeprophylactic and chemopreventive activity particularly in theera of emerging antimalarial drug resistance

47 Anticancer Activity Cancer is a bigger challenge inmedical science as the incidence of this health disorder israpidly growing across the world This prompts the effortsto search some effective natural anticancer therapies alter-native to currently employed chemotherapies with limited

applications The effect of black seed in different types ofcancer cells is summarized in Table 2 As there are ten cancerhallmarks which are common to most tumors TQ a majoractive component of N sativa plays great role in affecting allmarkers of cancer [123]

48 Effects onMale Infertility Infertility is the incapability ofa copulate to attain offspring after 12 months of intercoursewithout contraception It is more prevalent among men thanwomen [142] Sperm dysfunction is the main problem relatedwith men infertility which accounts 60 of all reasonsThe structure function motility and survival of sperm aredeleteriously affected by oxidative stress that prominentlyleads to infertility Hence increasing spermatozoa countsfunctionality and sperm quality using antioxidants canimprove fertility status [143 144] Evidence proves that someherbal medicines can reduce negative effects of oxidativestress by salvaging free radicals [145] Among the varioustraditional plants N sativa was found to exhibit remarkableantioxidant effect [146]

Alcoholic extract of N sativa indicated remarkableincrement in the production of viable and motile spermcells enhanced epididymal sperm reservation weight gain-ing of reproductive organs blood testosterone densitygonadotropins content amount of mature Leydig cells andfertility indexes compared to the control group in male rats[147] According to Mohammad et al black cumin thoughtto trigger a rise in spermatogenesis hormones on pituitarygland and an increase in the weight of reproductive organsThe study also reveals that N sativa can affect oxidativephosphorylation enzymes and increase sperm motility [147]In addition a randomized double-blind placebo-controlledclinical trial was conducted on 68 Iranian infertile menand half of them receive 25mL of black seed oil and theremaining received placebo twice daily for two months Theamount and the motility of sperm and the content of semenvolume were raised significantly in black seed oil treatedgroup compared with placebo group after two months oftherapy [148] This indicates that N sativa can be a potentialsource for development of natural aphrodisiac agents

5 Toxicological Properties

The acute oral toxicity of active constituents of black cuminseed TQ lethal dose 50 (LD50) value has been reported tobe 24 g per kg of body weight of Swiss albino mice whereasthe instant behavioral alteration at two and three g per kg ofbody weight of the composite was hypoactivity and troublein breathing while late toxicities comprising a substantiallessening in the virtual organ weight and glutathione dis-tribution of the hepatic renal and cardiovascular systemhave been reported [149] Daily administration of aqueousextract (AqE) of N sativa to mice for six weeks led to deathof one mouse after 2 weeks of treatment with 64 gkg ofAqE On the other hand 2 and 3 mice experienced death at3rd and 5th weeks while they received 21 gkg and 60 gkgof the extract respectively Otherwise no other deaths wererecorded for the application of other doses used [150] In


Table2Eff

ectsof

Nsativaandthym

oquino

neagainstv

arious

typeso

fcancerm

odelsa

ndtheire

ffectso

nantic

ancera

gents

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Invitro

studies

Doxorub

icin-resistant

human

breastcancer

cells

line(MCF

-7D

OXcells)

TQ(2550

or100120583M)for

48ho

ursamp

NSO

Nano

emulsio

n

(i)Con

centratio

ndepend

entgrowth

inhibitio

n(ii)Ind

ucea

poptosis

p53protein

(iii)Upregulationof

PTEN

(inhibitP

I3K

Akt

pathway)

[124125]

Hum

ancervicalsquamou

scancer

cells

TQ(10to

30120583gmL)

for

2448and72

hours

(i)Morec

ytotoxicthan

cisplatin

towards

thiscancerou

scell(but

lesscytotoxicitytowards

norm

alcells)

(ii)D

ownregulates

Bcl-2

protein

[126]

Myeloblastic

leuk

emia

(HL-60

cells)

TQ(i)

Indu

cesa

poptosis

disrup

tsmito

chon

drial

mem

branep

otentia

ltriggersthea

ctivationof

caspases

38amp9in

HL-60

cells

[127]

Hum

anbladderc

ancerc

ells

(T24

and253J)

TQ(20-160120583molL)for

different

perio

ds(24h

48h

and72h)

(i)TQ

show

edmarkedcytotoxicityon

bladderc

ancer

cells

(ii)Itinh

ibitedcancerou

scellsrapidmultip

licationand

evoked

apop

tosis

viaa

ctivationof

caspase

(iii)TQ

also

resultedin

activ

ationof

ERstr

ess

mito

chon

drialdisturbancea

ndenhanced

mito

chon

drialm

ediatedapop

totic

path

[128]

Renalcellcancer(RC

C)cell

lines

(786-O

andAC

HN)

TQ(40120583molL)for

24ho

urs

(i)TQ

supp

ressed

migratio

ninvasio

nand

epith

elial-m

esenchym

altransitionin

RCCcells

(ii)T

Qexhibitedsig

nificantinh

ibition

ofthem

etastasis

ofRC

Ccells

throug

hindu

ctionof

autoph

agyv

iaAMPK

mTO

Rsig

nalling

[129]

Hum

anrenaltub

ular

epith

elialcell(HK2

)and

theh

uman

RCCcelllin

es(769-P

amp786-O)

TQ(0512551015

amp20

120583M)a

tvarious

duratio

ns(02448

amp72

h)

(i)TQ

markedlyinhibitedthem

igratio

nandinvasio

nof

theh

uman

RCC769-Pand786-Ocelllin

es

(ii)T

Qalso

increasedthee

xpressionof

E-cadh

erin

and

redu

cedthee

xpressionof

SnailZE

B1andvimentin

atthem

RNAas

wellas

proteinlevelsin

dose-dependent

fashion

(iii)Asa

result

thee

xtentsof

phosph

orylationof

hepatic

kinase

B1andAMPK

were

upregu

lated

[130]

Hum

anprostatecancer

cell

lines

(DU145andC3

)TQ

(2550amp10120583M)for

24ho

urs

(i)TQ

substantially

arreste

dthep

roliferationof

prostatecancer

(ii)Itinh

ibitedthem

igratin

gandinvading

capabilityof

prostatecancer

DU145andPC

3cells

(iii)TQ

also

downregulated

thee

xpressionof

TGF-120573

Smad2andSm

ad3in

prostatecancer

cells

[131]

Hepatocellularc

ancerc

ell

line(HepG2)

TQ(3ndash24120583M)for

24ho

urs

(i)Decreased

both

then

oof

viableHepG2cells

andthe

levels

(ii)T

Qindu

cedcellcyclea

rrestand

apop

tosis

(iii)Increasedtotalantioxidant

status(do

sedepend

ently

)(iv

)TQredu

cedther

elease

ofVEG

Fof

HepG2cells

[132]


Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Invivo

studies

Diethylnitro

samine

indu

cedh

epatocarcino

gen-

esisin

Wistar

rats

Ethano

licextracto

fNS

(250

mgkg)for

5consecutived

ays

(i)Th

echemicalindu

cedincrem

entofliver

weight

hepato-som

aticindicesserum

AFP

andVEG

Flevels

andhepatic

HGF120573

proteinexpressio

nwe

resig

nificantly

reversed

bythee

xtract

(ii)Th

ehistop

atho

logicalalteratio

nof

theliversd

ueto

thec

hemicalwas

decreasedin

NSextractreceivedrats

with

outh

armfuleffects

[133]

Ortho

topicm

odelinmice

[triple-negativeb

reast

cancer

(TNBC

)celllines]

TQ(20or

100mgk)

once

every3

days

(i)TQ

markedlyredu

cedtheg

rowth

ofMDA-

MB-231

tumor

(ii)T

QdecreasedTN

BCcellviability

andproliferatio

nas

wellas

them

igratio

nandinvasio

nof

TNBC

cells

(iii)TQ

also

downregulated

thee

xpressionof

eEF-2K

(viamod

ulationof

theN

F-120581BmiR-603)SrcFA

Kand

Akt

inTN

BCcells

[134]

Colon

carcinogenesisof

ratsmod

elNSO

for14we

eks

(i)NSO

revealed

asignificantantiproliferativea

ctivity

inbo

thinitiationandpo

st-initiationph

ases

(ii)Inh

ibitedcoloncarcinogenesisof

ratsmainlyin

the

post-

initiationsta

gewith

noevidento

fadverse

effects

[135]

Mou

semod

elof

colorectal

carcinogenesisampC2

6cell

TQ(5

mgkg)for

3we

eksamp

TQ(02040

60120583M)in

vitro

(i)TQ

redu

cedtumor

multip

licity

(ii)T

Qim

pededtumor

grow

thandindu

ceapop

tosis

inHCT

116xeno

graft

s(iii)Sub-cytotoxicc

oncof

TQ(40120583

M)a

lsoredu

ced

C26cellinvasio

n(iv

)Anti-n

eoplastic

andpro-apop

totic

p53-depend

ent

mechanism

[136]

Ratm

ulti-organ

carcinogenesis

NSO

for3

0we

eks

(i)Re

ductionin

malignant

andbenign

colontumor

sizestum

orsinthelun

gsandin

diversep

artsof

the

alim

entary

canalprin

cipally

theo

esop

hagu

sand

fore

stomach

[137]


Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Effecto

nanti-cancer

drug

s

Cyclop

hosphamide

Indu

cedtoxicity(abn

ormal

RFampLF

Tandredu

ced

Hgb)inrat

NSO

(1mlk

g)andTQ

(10

mgkg)E

ODfor12days

(i)Substantialreductio

nin

overallcycloph

osph

amide

indu

cedtoxicityin

both

NSO

andTQ

treated

grou

ps

[138]

Antitu

mor

Effecto

fTQand

gemcitabine

onxeno

graft

mou

seandPA

NC-

1AsPC-

1and

BxPC

-3cell

lines

ofpancreaticcancer

mod

els

TQ(0ndash50120583molL)amp

10mg

mou

sedaily

(i)TQ

pre-tre

atmentsyn

ergistically

increasedthe

gemcitabine

actio

nsof

apop

totic

andtumor

grow

thinhibitio

nof

pancreaticcancer

cells

(ii)C

oncomitant

uses

resultedin

thec

hangeo

fseveral

molecular

signalin

ginclu

ding

thed

ownregulationof

Notch1NICDassociated

with

up-regulationof

PTEN

viathe

inactiv

ationof

Aktm

TORS6

signalin

g(iii)TQ

andgemcitabine

also

indu

cedsupp

ressionof

anti-apop

totic

Bcl-2

Bcl-xLXIAPandoverexpressio

nandactiv

ationCaspase-3C

aspase-9amp

Bax

[139]

Cytotoxicityassayof

TQandpaclita

xelonmou

sebreastcancer

celllin

e(4T

1)andanim

almod

els

TQ(6251252550amp

100

120583M)for

24amp48

hours

(06424amp32mgkg

ofmou

sebo

dywe

ight)

(i)TQ

indu

cedmarkedcytotoxicityandapop

tosis

whileinhibitin

gwo

undhealingandmigratio

nof

4T1

cells

(ii)C

o-administratio

nof

TQandpaclita

xel

significantly

indu

cedcytotoxicityandapop

tosis

comparedto

separateadministratio

n(iii)Th

ecom

binatio

nof

paclita

xeland

thelow

erdo

seTQ

markedlyinhibitedthetum

orgrow

th

(iv)B

othagentsalso

mod

ulated

thea

poptosisgenes

p53andJAK-

STAT

signalin

gwhileoverexpressin

gthe

levelsof

Caspase-3C

aspase-7and

Caspase-12

[140]

Anti-tum

oractiv

ityof

TQandtopo

tecanin

colorectal

cancer

celllin

e(HT-29)

TQ(4055

amp60120583M)

(i)TQ

significantly

enhanced

thea

nti-tum

oreffecto

fno

n-cytotoxicd

oseo

ftop

otecan

(ii)B

othdrug

sind

uced

apop

tosis

viaa

p53-independ

entm

echanism

whilethee

xpressionof

p21w

ason

lyno

tedin

TQtherapy

(iii)TQ

improved

thee

ffectivenesso

ftop

otecan

byinhibitin

gproliferatio

nand

lowe

ringtoxicityviap

53-

andBa

xBc

l2-in

depend

entm

echanism

s

[141]

AMPK

Adeno

sinem

onop

hosphate-activated

proteinkinaseN

SNigellasativaNSO

NigellasativaoilT

QTh

ymoq

uino

neP

TENpho

sphataseandtensin

homolog

MCF

-7M

ichiganCancerF

ound

ation-7EO

D

everyotherd

aym

TOR

Mam

malianTargetof

Rapamycin


addition the subchronic toxicity study in mice treated with30 60 and 90mgkgday of TQ for 90 days resulted inno mortality or signs of toxicity but substantial decrementof fasting plasma glucose and also showed no change intoxicological significance in body organs and histologicalinvestigation [149]The toxicity of the fixed oil of black cuminin mice and rats was also examined and the LD50 values werefound to be 288mlkg and 206mlkg when given by oral andintraperitoneal routes respectively Chronic toxicity was alsostudied in rats treated daily with an oral dose of 2mlkg for 12weeksrsquo black cumin oil while alterations in vital liver enzymelevels and histopathological modifications (heart liver kid-neys and pancreas) were not detected [151]Theminor andornegligible toxicological effects and wider therapeutic marginof N sativa and its active constituents thymoquinone asevident by various scientific studies support its safe use forthe long-term traditional food and medicinal purposes

6 Conclusion and Future Prospects

Traditional medicinal plants have received much attentiondue to several factors such as low cost ease of accessand lower adverse effect profiles as compared to syntheticmedicines Besides various medicinal floras and their prod-ucts are used on the basis of religious and cultural tradi-tions Among various plants black cumin has been usedby diverse human cultures around the world especially inMuslim population for centuries to treat numerous ailmentsTo date a number of studies showed that black seed andits component including TQ have revealed a remarkablenatural therapy for treatment of a wide range of illnessesincluding chronic noninfectious (neurologic disorders DMhypertension dyslipidemia inflammatory disorders canceretc) and infectious disease (bacterial fungal viral andparasitic infections) Both animal and human studies alsoshowed that black seed and TQ have potential to treat maleinfertility and their antioxidant activities have recently gainedgreater attention due to their role as dietary supplementswith minimal side effects Furthermore when combinedwith different conventional chemotherapeutic agents theysynergize the effects which may reduce the dosage of theconcomitantly usedmedicines and optimizing efficacy versustoxicity and it might also overcome drug resistance problemTherefore having wider safety margins and praiseworthyefficacy againstwide range ofmaladies it would be a potentialherbal remedy to be assessed under clinical trial for numerousconditions Isolation of novel bioactive components fromblack cumin and its oil and studies of their therapeutic effectsusing specific clinical models are further recommended

Abbreviations

AqE Aqueous extractN sativa Nigella sativaTQ ThymoquinoneLD Lethal dosePTEN Phosphatase and tensin homologMCF-7 Michigan Cancer Foundation-7TBARs Thiobarbituric acid

GABA Gamma amino butyric acid5-HT 5-HydroxytryptamineMDA MalondialdehydeDA Dopamine5HIAA 5 Hydroxyindoleacetic acidGSH-Px Glutathione peroxidaseSOD Superoxide dismutaseA120573 Beta amyloid peptidesHCV Hepatitis C virusINF InterferonMIC Minimum inhibitory concentrationRA Rheumatoid arthritisBP Blood pressureDM Diabetic mellitusCQ Chloroquine

Conflicts of Interest

The authors declare no conflict of interest

Authorsrsquo Contributions

Ebrahim M Yimer developed the research conception andtook the initiatives of this work and drafted the manuscriptKald Beshir Tuem Aman Karim Najeeb Ur-Rehman andFarooq Anwar provide greater contribution towards collect-ing extracting and organizing relevant data and also revisingthe review paper and agreed to be accountable for all aspectsof the work

References

[1] World Health Organization Traditional Medicine Fact sheetNo 134 2017 httpwwwsiav-itvasorgimagesstoriesdocWHO Traditional medicine 2008pdf

[2] F Jamshidi-Kia Z Lorigooini andHAmini-Khoei ldquoMedicinalplants Past history and future perspectiverdquo Journal of HerbMedPharmacology vol 7 no 1 pp 1ndash7 2018

[3] F Anwar F Anwar G Muhammad et al ldquoCapparis spinosa LA plant with high potential for development of functional foodsand nutraceuticalspharmaceuticalsrdquo International Journal ofPharmacology vol 12 no 3 pp 201ndash219 2016

[4] M F R Hassanien A M A Assiri A M Alzohairy and H FOraby ldquoHealth-promoting value and food applications of blackcumin essential oil an overviewrdquo Journal of Food Science andTechnology vol 52 no 10 pp 6136ndash6142 2015

[5] M Adib-Hajbaghery and S Rafiee ldquoMedicinal plants use byelderly people in Kashan Iranrdquo Nursing and Midwifery Studiesvol 7 no 2 pp 67ndash73 2018

[6] V De Luca V Salim S M Atsumi and F Yu ldquoMining thebiodiversity of plants A revolution in the makingrdquo Science vol336 no 6089 pp 1658ndash1661 2012

[7] H R H Takruri and M A F Dameh ldquoStudy of the nutritionalvalue of black cumin seeds (Nigella sativa L)rdquo Journal of theScience of Food andAgriculture vol 76 no 3 pp 404ndash410 1998

[8] M F Ramadan ldquoNutritional value functional properties andnutraceutical applications of black cumin (Nigella sativa L) anoverviewrdquo International Journal of Food Science amp Technologyvol 42 no 10 pp 1208ndash1218 2007


[9] M A Mamun and N Absar ldquoMajor nutritional compositionsof black cumin seeds cultivated in Bangladesh and the physic-ochemical characteristics of its oilrdquo International Food ResearchJournal vol 25 no 6 pp 2634ndash2639 2018

[10] K H Ghahramanloo B Kamalidehghan H Akbari Javar RTeguh Widodo K Majidzadeh and M I Noordin ldquoCompara-tive analysis of essential oil composition of iranian and indiannigella sativa L Extracted using supercritical fluid extractionand solvent extractionrdquoDrugDesign Development andTherapyvol 11 pp 2221ndash2226 2017

[11] S Haseena M Aithal K K Das and S H Saheb ldquoPhyto-chemical analysis of Nigella sativa and its effect on reproductivesystemrdquo Journal of Pharmaceutical Sciences and Research vol 7no 8 pp 514ndash517 2015

[12] I Botnick W Xue E Bar et al ldquoDistribution of primary andspecialized metabolites in Nigella sativa seeds a spice with vasttraditional and historical usesrdquo Molecules vol 17 no 9 pp10159ndash10177 2012

[13] T Ainane Z Askaoui M Elkouali et al ldquoChemical composi-tion and antibacterial activity of essential oil of Nigella sativaseeds from Beni Mellal (Morocco)What is the most importantpart Essential Oil or the rest of seedsrdquo Journal of Materials andEnvironmental Science vol 5 no 6 pp 2017ndash2020 2014

[14] F Benkaci-Ali R Akloul A Boukenouche and E D PauwldquoChemical composition of the essential oil of nigella sativa seedsextracted by microwave steam distillationrdquo Journal of EssentialOil Bearing Plants vol 16 no 6 pp 781ndash794 2013

[15] S Isik M Kartal and S A Erdem ldquoQuantitative analysis ofthymoquinone in Nigella Sativa L (Black Cumin) seeds andcommercial seed oils and seed oil capsules fromTurkeyrdquoAnkaraUniversitesi Eczacılık Fakultesi Dergisi vol 41 no 1 pp 34ndash412017

[16] Z Solati B S Baharin and H Bagheri ldquoAntioxidant propertythymoquinone content and chemical characteristicsof differentextracts fromNigella sativa L seedsrdquo Journal of the AmericanOilChemistsrsquo Society vol 91 no 2 pp 295ndash300 2014

[17] Herlina S A Aziz A Kurniawati and D N Faridah ldquoChangesof thymoquinone thymol and malondialdehyde content ofblack cumin (Nigella sativa L) in response to Indonesia trop-icalrdquo Journal of Biosciences vol 24 no 3 pp 156ndash161 2017

[18] R Salea E Widjojokusumo A W Hartanti B Veriansyahand R R Tjandrawinata ldquoSupercritical fluid carbon dioxideextraction of Nigella sativa (black cumin) seeds using taguchimethod and full factorial designrdquo Biochemical Compounds vol1 no 1 p 1 2013

[19] B Matthaus and M M Ozcan ldquoFatty acids tocopherol andsterol contents of some nigella species seed oilrdquo Czech Journalof Food Sciences vol 29 no 2 pp 145ndash150 2011

[20] B KMehtaM Verma andMGupta ldquoNovel lipid constituentsidentified in seeds of Nigella sativa (Linn)rdquo Journal of theBrazilian Chemical Society vol 19 no 3 pp 458ndash462 2008

[21] I San Mauro-Martın J A Blumenfeld-Olivares E Garicano-Vilar M A Cuadrado M J Ciudad-Cabanas and L Collado-Yurrita ldquoDifferences in the effect of plant sterols on lipidmetabolism in men and womenrdquo Topics in Clinical Nutritionvol 33 no 1 pp 31ndash40 2018

[22] S Cheikh-Rouhou S Besbes B Hentati C Blecker CDeroanne and H Attia ldquoNigella sativa L chemical composi-tion and physicochemical characteristics of lipid fractionrdquo FoodChemistry vol 101 no 2 pp 673ndash681 2007

[23] M Zaunschirm M Pignitter J Kienesberger et al ldquoContribu-tion of the ratio of tocopherol homologs to the oxidative stability

of commercial vegetable oilsrdquo Molecules vol 23 no 1 p 2062018

[24] B K Mehta P Mehta and M Gupta ldquoA new naturallyacetylated triterpene saponin fromNigella sativardquoCarbohydrateResearch vol 344 no 1 pp 149ndash151 2009

[25] B K Mehta V Pandit and M Gupta ldquoNew principles fromseeds of Nigella sativardquo Natural Product Research (FormerlyNatural Product Letters) vol 23 no 2 pp 138ndash148 2009

[26] T Morikawa F Xu Y Kashima H Matsuda K NinomiyaandM Yoshikawa ldquoNovel dolabellane-type diterpene alkaloidswith lipid metabolism promoting activities from the seeds ofNigella sativardquo Organic Letters vol 6 no 6 pp 869ndash872 2004

[27] T Morikawa F Xu K Ninomiya H Matsuda and MYoshikawa ldquoNigellamines A3 A4 A5 and C new dolabellane-type diterpene alkaloids with lipid metabolism-promotingactivities from the Egyptian medicinal food black cuminrdquoChemical amp Pharmaceutical Bulletin vol 52 no 4 pp 494ndash4972004

[28] M S Atta-ur-Rahman H Cun-Heng and J Clardy ldquoIsolationand structure determination of Nigellicine a novel alkaloidfrom the seeds of Nigella sativardquo Journal of Natural Productsvol 55 no 5 pp 676ndash678 1992

[29] M S Atta-ur-Rahman S S Hasan M I Choudhary C-Z Niand J Clardy ldquoNigellidine - A new indazole alkaloid from theseeds of Nigella sativardquo Tetrahedron Letters vol 36 no 12 pp1993ndash1996 1995

[30] Z Ali D Ferreira P Carvalho M A Avery and I A KhanldquoNigellidine-4-o-sulfite the first sulfated indazole-type alkaloidfrom the seeds of Nigella sativardquo Journal of Natural Productsvol 71 no 6 pp 1111-1112 2008

[31] S Javed A A Shahid and M S Haider ldquoNutritional phyto-chemical potential and pharmacological evaluation of NigellaSativa (Kalonji) and Trachyspermum Ammi (Ajwain)rdquo Journalof Medicinal Plants Research vol 6 no 5 pp 768ndash775 2010

[32] I Ahmad J Tripathi S Manik L Umar and J Rabia ldquoPre-liminary phytochemical studies of the miracle herb of thecentury Nigella sativa L (black seed)rdquo Indo American Journalof Pharmaceutical Research vol 3 no 4 pp 3000ndash3007 2013

[33] A A Bukhari ldquoSahih-ul-Bukharirdquo httpquranxcomSearchq=Black+cuminampcontext=Hadith 2018

[34] K Nadkarni ldquoCrocus sativusNigella sativardquo in Indian MaterialMedica K M Nadkarni Ed pp 386ndash411 Popular PrakashanBombay India 1976

[35] M Tariq ldquoNigella sativa seeds folklore treatment in modernday medicinerdquo Saudi Journal of Gastroenterology vol 14 no 3pp 105-106 2008

[36] F Lupoli T Vannocci G Longo N Niccolai and A PastoreldquoThe role of oxidative stress in Friedreichrsquos ataxiardquo FEBS Lettersvol 592 no 5 pp 718ndash727 2018

[37] N Ozdemir M N Kantekin-Erdogan T Tat and A TekinldquoEffect of black cumin oil on the oxidative stability and sensorycharacteristics of mayonnaiserdquo Journal of Food Science andTechnology vol 55 no 4 pp 1562ndash1568 2018

[38] R M Mostafa Y M Moustafa Z Mirghani G M AlKusayerand K M Moustafa ldquoAntioxidant effect of garlic (Alliumsativum) and black seeds (Nigella sativa) in healthy post-menopausal womenrdquo SAGE Open Medicine vol 1 Article ID2050312113517501 2013

[39] M T Sultan M S Butt R Karim et al ldquoNigella sativa fixed andessential oil modulates glutathione redox enzymes in potassiumbromate induced oxidative stressrdquo BMC Complementary andAlternative Medicine vol 15 no 1 article no 330 2015


[40] H Omidi S Khorram M Mesgari M Asghari-Jafarabadiand A Tarighat-Esfanjani ldquoEffects of separate and concurrentsupplementation of Nano-sized clinoptilolite and Nigella sativaon oxidative stress anti-oxidative parameters and body weightin rats with type 2 diabetesrdquo Biomedicine amp Pharmacotherapyvol 96 pp 1335ndash1340 2017

[41] N Namazi R Mahdavi M Alizadeh and S Farajnia ldquoOxida-tive stress responses to Nigella sativa oil concurrent with alow-calorie diet in obese women A randomized double-blindcontrolled clinical trialrdquo Phytotherapy Research vol 29 no 11pp 1722ndash1728 2015

[42] S Ahmad and Z H Beg ldquoEvaluation of therapeutic effectof omega-6 linoleic acid and thymoquinone enriched extractsfrom Nigella sativa oil in the mitigation of lipidemic oxidativestress in ratsrdquoNutrition Journal vol 32 no 6 pp 649ndash655 2016

[43] F Shahid Z Farooqui A A Khan and F Khan ldquoOral Nigellasativa oil and thymoquinone administration ameliorates theeffect of long-term cisplatin treatment on the enzymes of carbo-hydrate metabolism brush border membrane and antioxidantdefense in rat intestinerdquo Naunyn-Schmiedebergrsquos Archives ofPharmacology vol 391 no 2 pp 145ndash157 2018

[44] R Daryabeygi-Khotbehsara M Golzarand M P Ghaffari andK Djafarian ldquoNigella sativa improves glucose homeostasis andserum lipids in type 2 diabetes A systematic review and meta-analysisrdquo Complementary Therapies in Medicine vol 35 pp 6ndash13 2017

[45] H A El Rabey M N Al-Seeni and A S BakhashwainldquoThe antidiabetic activity of Nigella sativa and propolis onstreptozotocin-induced diabetes and diabetic nephropathy inmale ratsrdquo Evidence-Based Complementary and AlternativeMedicine vol 2017 Article ID 5439645 14 pages 2017

[46] G Kaur M Invally M K Khan and P Jadhav ldquoA nutraceuticalcombination of Cinnamomum cassia ampNigella sativa for Type 1diabetesmellitusrdquo Journal of Ayurveda and IntegrativeMedicinevol 9 no 1 pp 27ndash37 2018

[47] H Kaatabi A O Bamosa A Badar et al ldquoNigella sativaimproves glycemic control and ameliorates oxidative stressin patients with type 2 diabetes mellitus Placebo controlledparticipant blinded clinical trialrdquo PLoS ONE vol 10 no 2 2015

[48] P N R Rachman Akrom and E Darmawan ldquoThe efficacy ofblack cumin seed (Nigella sativa) oil and hypoglycemic drugcombination to reduce HbA1c level in patients with metabolicsyndrome riskrdquo in Proceedings of the International PharmacyConference vol 259 Indonesia 2017

[49] A Bamosa H Kaatabi A Badar et al ldquoNigella sativa Apotential natural protective agent against cardiac dysfunctionin patients with type 2 diabetes mellitusrdquo Journal of Family andCommunity Medicine (JFCM) vol 22 no 2 pp 88ndash95 2015

[50] H M A Abdelrazek O E Kilany M A A MuhammadH M Tag and A M Abdelazim ldquoBlack seed and thymo-quinone improved insulin secretion hepatic glycogen storageand oxidative stress in streptozotocin-induced diabetic malewistar ratsrdquo Oxidative Medicine and Cellular Longevity vol2018 Article ID 8104165 10 pages 2018

[51] H Kaatabi A O Bamosa F M Lebda A H Al ELq and Al-Sultan ldquoFavorable impact of Nigella sativa seeds on lipid profilein type 2 diabetic patientsrdquo Journal of Family and CommunityMedicine vol 19 no 3 pp 155ndash160 2012

[52] O K Vasant B G Vijay S R Virbhadrappa N T DilipM V Ramahari and B S Laxamanrao ldquoAntihypertensive anddiuretic effects of the aqueous extract of Colocasia esculenta

Linn leaves in experimental paradigmsrdquo Iranian Journal ofPharmaceutical Research vol 11 no 2 pp 621ndash634 2012

[53] A Badar H Kaatabi A Bamosa et al ldquoEffect of Nigella sativasupplementation over a one-year period on lipid levels bloodpressure and heart rate in type-2 diabetic patients receiving oralhypoglycemic agents Nonrandomized clinical trialrdquo Annals ofSaudi Medicine vol 37 no 1 pp 56ndash63 2017

[54] A Rizka S Setiati A Lydia and E Dewiasty ldquoEffect of Nigellasativa seed extract for hypertension in elderly a double-blindrandomized controlled trialrdquo Acta Medica Indonesiana vol 49no 4 pp 307ndash313 2017

[55] F R Dehkordi and A F Kamkhah ldquoAntihypertensive effect ofNigella sativa seed extract in patients with mild hypertensionrdquoFundamental amp Clinical Pharmacology vol 22 no 4 pp 447ndash452 2008

[56] W Qidwai H B Hamza R Qureshi and A Gilani ldquoEffective-ness safety and tolerability of powdered Nigella sativa (kalonji)seed in capsules on serum lipid levels blood sugar bloodpressure and body weight in adults results of a randomizeddouble-blind controlled trialrdquo Journal of Alternative and Com-plementary Medicine vol 15 no 6 pp 639ndash644 2009

[57] K Jaarin W D Foong M H Yeoh et al ldquoMechanisms ofthe antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive ratsrdquo Clinics vol 70 no 11 pp 751ndash7572015

[58] X F Leong M Rais Mustafa and K Jaarin ldquoNigella sativaand its protective role in oxidative stress and hypertensionrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 120732 9 pages 2013

[59] T Perveen S Haider N A Zuberi S Saleem S Sadaf and ZBatool ldquoIncreased 5-HT levels following repeated administra-tion of Nigella sativa L (black seed) oil produce antidepressanteffects in ratsrdquo Scientia Pharmaceutica vol 82 no 1 pp 161ndash1702014

[60] M A Wilson C A Grillo J R Fadel and L P Reagan ldquoStressas a one-armed bandit Differential effects of stress paradigmson the morphology neurochemistry and behavior in the rodentamygdalardquo Neurobiology of Stress vol 1 pp 195ndash208 2015

[61] Y S Abulfadl N N El-Maraghy A A E Ahmed S Nofaland O A Badary ldquoProtective effects of thymoquinone on D-galactose and aluminum chloride induced neurotoxicity in ratsbiochemical histological and behavioral changesrdquoNeurologicalResearch vol 40 no 4 pp 324ndash333 2018

[62] M Hosseini T Mohammadpour R Karami Z Rajaei HR Sadeghnia and M Soukhtanloo ldquoEffects of the hydro-alcoholic extract of Nigella Sativa on scopolamine-inducedspatialmemory impairment in rats and its possiblemechanismrdquoChinese Journal of Integrative Medicine vol 21 no 6 pp 438ndash444 2015

[63] M K A Sahak N Kabir G Abbas S Draman N H Hashimand D S Hasan Adli ldquoThe Role of Nigella sativa and itsactive constituents in learning and memoryrdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6075679 6 pages 2016

[64] R Sharaf M N Elsayed and L Mahran ldquoNeuroprotectiveeffect of thymoquinone against lipopolysaccharide-inducedAlzheimerrsquos disease in an animal modelrdquo European GeriatricMedicine vol 5 no 1 pp S83ndashS158 2014

[65] M S B Sayeed M Asaduzzaman H MorshedM M HossainM F Kadir and M R Rahman ldquoThe effect of Nigella sativaLinn seed on memory attention and cognition in healthy


human volunteersrdquo Journal of Ethnopharmacology vol 148 no3 pp 780ndash786 2013

[66] A H Alhebshi M Gotoh and I Suzuki ldquoThymoquinoneprotects cultured rat primary neurons against amyloid 120573-induced neurotoxicityrdquo Biochemical and Biophysical ResearchCommunications vol 433 no 4 pp 362ndash367 2013

[67] K Radad R Moldzio M Taha and W-D Rausch ldquoThymo-quinone protects dopaminergic neurons against MPP+ androtenonerdquo Phytotherapy Research vol 23 no 5 pp 696ndash7002009

[68] R Sedaghat M Roghani and M Khalili ldquoNeuroprotectiveeffect of thymoquinone the nigella sativa bioactive com-pound in 6-hydroxydopamine-induced hemi-parkinsonian ratmodelrdquo Iranian Journal of Pharmaceutical Research vol 13 no1 pp 227ndash234 2014

[69] A H Alhebshi A Odawara M Gotoh and I Suzuki ldquoThy-moquinone protects cultured hippocampal andhuman inducedpluripotent stem cells-derived neurons against 120572-synuclein-induced synapse damagerdquo Neuroscience Letters vol 570 pp126ndash131 2014

[70] F Norouzi A Abareshi A Anaeigoudari et al ldquoThe effects ofNigella sativa on sickness behavior induced by lipopolysaccha-ride in male Wistar ratsrdquo Avicenna Journal of Phytomedicinevol 6 no 1 p 104 2016

[71] F Bano A Ahmed T Parveen and S Haider ldquoAnxiolytic andhyperlocomotive effects of aqueous extract of Nigella sativa Lseeds in ratsrdquo Pakistan Journal of Pharmaceutical Sciences vol27 no 5 pp 1547ndash1552 2014

[72] N Gilhotra and D Dhingra ldquoThymoquinone producedantianxiety-like effects in mice through modulation of GABAandNO levelsrdquoPharmacological Reports vol 63 no 3 pp 660ndash669 2011

[73] M S Bin Sayeed T Shams S F Hossain et al ldquoNigella sativaL seeds modulate mood anxiety and cognition in healthyadolescent malesrdquo Journal of Ethnopharmacology vol 152 no1 pp 156ndash162 2014

[74] M Seghatoleslam F Alipour R Shafieian et al ldquoThe effectsof Nigella sativa on neural damage after pentylenetetrazoleinduced seizures in ratsrdquo Journal of Traditional andComplemen-tary Medicine vol 6 no 3 pp 262ndash268 2016

[75] M Abdollahi Fard and A Shojaii ldquoEfficacy of iranian tradi-tional medicine in the treatment of epilepsyrdquo BioMed ResearchInternational vol 2013 Article ID 692751 8 pages 2013

[76] R Mostafa Y Moustafa and Z Mirghani ldquoThymoquinonealone or in combination with phenobarbital reduces the seizurescore and the oxidative burden in pentylenetetrazole-kindledratsrdquo Oxidants and Antioxidants in Medical Science vol 1 no3 pp 185ndash192 2012

[77] J Akhondian H Kianifar M Raoofziaee A Moayedpour MB Toosi and M Khajedaluee ldquoThe effect of thymoquinone onintractable pediatric seizures (pilot study)rdquo Epilepsy Researchvol 93 no 1 pp 39ndash43 2011

[78] A O Abdel-Zaher M S Abdel-Rahman and F M ElwaseildquoBlockade of nitric oxide overproduction and oxidative stressbyNigella sativa oil attenuatesmorphine-induced tolerance anddependence inmicerdquoNeurochemical Research vol 35 no 10 pp1557ndash1565 2010

[79] S Sangi S P Ahmed M A Channa M Ashfaq and S MMastoi ldquoA new and novel treatment of opioid dependenceNigella sativa 500 mgrdquo Journal of Ayub Medical College vol 20no 2 pp 118ndash124 2008

[80] B K Das U K Fatema M S Hossain R Rahman and M AAkbar ldquoAnalgesic and anti-inflammatory activities of the fruitextract of Ampelocissus latifolia(Roxb) on laboratory animalsrdquoBritish Journal of Pharmaceutical Research vol 4 no 12 pp1477ndash1485 2014

[81] H Pise and S Padwal ldquoEvaluation of anti-inflammatory activityof Nigella sativa An experimental studyrdquo National Journal ofPhysiology Pharmacy and Pharmacology vol 7 no 7 pp 707ndash711 2017

[82] A Zakaria M R Jais and R Ishak ldquoAnalgesic propertiesof Nigella Sativa and Eucheuma Cottonii extractsrdquo Journal ofNatural Science Biology and Medicine vol 9 no 1 pp 23ndash262018

[83] M S Al-Ghamdi ldquoThe anti-inflammatory analgesic andantipyretic activity of Nigella sativardquo Journal of Ethnopharma-cology vol 76 no 1 pp 45ndash48 2001

[84] MU Bashir andH J Qureshi ldquoAnalgesic effect ofNigella sativaseeds extract on experimentally induced pain in albino micerdquoJournal of the College of Physicians and Surgeons Pakistan vol20 no 7 pp 464ndash467 2010

[85] S Rajsekhar and B Kuldeep ldquoPharmacognosy and pharma-cology of Nigella sativardquo International Research Journal ofPharmacy vol 2 no 11 pp 36ndash39 2011

[86] P J Houghton R Zarka B de las Heras and J R S HoultldquoFixed oil of Nigella sativa and derived thymoquinone inhibiteicosanoid generation in leukocytes and membrane lipid per-oxidationrdquo Planta Medica vol 61 no 1 pp 33ndash36 1995

[87] M Mansour and S Tornhamre ldquoInhibition of 5-lipoxygenaseand leukotriene C4 synthase in human blood cells by thymo-quinonerdquo Journal of Enzyme Inhibition and Medicinal Chem-istry vol 19 no 5 pp 431ndash436 2004

[88] M H Boskabady N Vahedi S Amery and M R KhakzadldquoThe effect of Nigella sativa alone and in combination withdexamethasone on tracheal muscle responsiveness and lunginflammation in sulfur mustard exposed guinea pigsrdquo Journalof Ethnopharmacology vol 137 no 2 pp 1028ndash1034 2011

[89] M H Boskabady N Mohsenpoor and L Takaloo ldquoAntiasth-matic effect of Nigella sativa in airways of asthmatic patientsrdquoPhytomedicine vol 17 no 10 pp 707ndash713 2010

[90] M Ikhsan N Hiedayati K Maeyama and F NurwidyaldquoNigella sativa as an anti-inflammatory agent in asthmardquo BMCResearch Notes vol 11 no 1 article no 744 2018

[91] S Saadat M Mohammadi M Fallahi R keyhanmanesh andM R Aslani ldquoThe protective effect of 120572-hederin the activeconstituent of Nigella sativa on tracheal responsiveness andlung inflammation in ovalbumin-sensitized guinea pigsrdquo TheJournal of Physiological Sciences vol 65 no 3 pp 285ndash292 2015

[92] R Keyhanmanesh H Bagban H Nazemieh F M Bavil andM R Alipour ldquoThemain relaxant constituents of Nigella Sativamethanolic fraction on guinea pig tracheal chainsrdquo IranianJournal of Allergy Asthma and Immunology vol 12 no 2 pp136ndash143 2013

[93] M H Boskabady R Keyhanmanesh S Khamneh and MA Ebrahimi ldquoThe effect of Nigella sativa extract on trachealresponsiveness and lung inflammation in valbuminsensitizedguinea pigsrdquo Clinics vol 66 no 5 pp 879ndash887 2011

[94] A M Salem A O Bamosa H O Qutub et al ldquoEffect ofNigella sativa supplementation on lung function and inflam-matory mediators in partly controlled asthma A randomizedcontrolled trialrdquo Annals of Saudi Medicine vol 37 no 1 pp 64ndash71 2017


[95] A Koshak L Wei E Koshak et al ldquoNigella sativa supplemen-tation improves asthma control and biomarkers a randomizeddouble-blind placebo-controlled trialrdquo Phytotherapy Researchvol 31 no 3 pp 403ndash409 2017

[96] M H Boskabady and J Farhadi ldquoThe possible prophylacticeffect of Nigella sativa seed aqueous extract on respiratorysymptoms and pulmonary function tests on chemical warvictims A randomized double-blind placebo-controlled trialrdquoThe Journal of Alternative and Complementary Medicine vol 14no 9 pp 1137ndash1144 2008

[97] M H Boskabady H Javan M Sajady and H RakhshandehldquoThe possible prophylactic effect of Nigella sativa seed extractin asthmatic patientsrdquo Fundamental amp Clinical Pharmacologyvol 22 no 1 p 105 2008

[98] T A Gheita and S A Kenawy ldquoEffectiveness of Nigella sativaOil in the management of rheumatoid arthritis patients aplacebo controlled studyrdquo Phytotherapy Research vol 26 no 8pp 1246ndash1248 2012

[99] M Fathy and T Nikaido ldquoIn vivo attenuation of angiogenesisin hepatocellular carcinoma by Nigella sativardquo Turkish Journalof Medical Sciences vol 48 pp 178ndash186 2018

[100] E M Yimer A Surur D Z Wondafrash and A K Gebre ldquoTheeffect of metformin in experimentally induced animal modelsof epileptic seizurerdquo Behavioural Neurology vol 2019 pp 1ndash132019

[101] C-R Lee I H Cho B C Jeong and S H Lee ldquoStrategiesto minimize antibiotic resistancerdquo International Journal ofEnvironmental Research and Public Health vol 10 no 9 pp4274ndash4305 2013

[102] L C Ventola ldquoThe antibiotic resistance crisis causes andthreatsrdquo Pharm andTherap vol 40 no 4 pp 277ndash283 2015

[103] P H M Andrade E Schmidt Rondon C A Carollo et alldquoEffect of Powdered Shells of the Snail Megalobulimus lopesion Secondary-Intention Wound Healing in an Animal ModelrdquoEvidence-Based Complementary and Alternative Medicine vol2015 Article ID 120785 9 pages 2015

[104] U Theuretzbacher ldquoAccelerating resistance inadequateantibacterial drug pipelines and international responsesrdquoInternational Journal of Antimicrobial Agents vol 39 no 4 pp295ndash299 2012

[105] E M Abdallah ldquoBlack Seed (Nigella sativa) as antimicrobialdrug a mini-reviewrdquo Novel Approches in Drug Designing andDevelop vol 3 no 2 pp 1ndash5 2017

[106] N A Hasan M Z Nawahwi and H A Malek ldquoAntimicrobialactivity of nigella sativa seed extractrdquo Sains Malaysiana vol 42no 2 pp 143ndash147 2013

[107] A-J Maryam A-A Fatimah A-K Ebtesam A-S Abdulrah-man and B-EL Ineta ldquoIn-vitro studies on the effect of Nigellasativa Linn seed oil extract on Multidrug Resistant Grampositive and Gram negative bacteriardquo Journal of MedicinalPlants vol 4 no 2 pp 195ndash199 2016

[108] K Chaieb B Kouidhi H Jrah KMahdouani andA BakhroufldquoAntibacterial activity of Thymoquinone an active principleof Nigella sativa and its potency to prevent bacterial biofilmformationrdquo BMCComplementary andAlternativeMedicine vol1 article no 29 2011

[109] E M Salem T Yar A O Bamosa et al ldquoComparative study ofNigella Sativa and triple therapy in eradication of HelicobacterPylori in patients with non-ulcer dyspepsiardquo Saudi Journal ofGastroenterology vol 16 no 3 pp 207ndash214 2010

[110] H Shokri ldquoA review on the inhibitory potential of Nigella sativaagainst pathogenic and toxigenic fungirdquo Avicenna Journal ofPhytomedicine vol 6 no 1 pp 21ndash33 2016

[111] H Mahmoudvand A Sepahvand S Jahanbakhsh B Ezatpourand S A A Mousavi ldquoEvaluation of antifungal activities of theessential oil and various extracts of Nigella sativa and its maincomponent thymoquinone against pathogenic dermatophytestrainsrdquo Journal of Medical Mycology vol 24 no 4 pp e155ndashe161 2014

[112] S H Aljabre O M Alakloby and M A Randhawa ldquoDerma-tological effects of Nigella sativardquo Journal of Dermatology ampDermatologic Surgery vol 19 no 2 pp 92ndash96 2015

[113] A Piras A Rosa B Marongiu et al ldquoChemical compositionand in vitro bioactivity of the volatile and fixed oils of Nigellasativa L extracted by supercritical carbon dioxiderdquo IndustrialCrops and Products vol 46 pp 317ndash323 2013

[114] M Taha A Azeiz and W Saudi ldquoAntifungal effect of thymolthymoquinone and thymohydroquinone against yeasts der-matophytes and non-dermatophyte molds isolated from skinand nails fungal infectionsrdquo Egyptian Journal of Biochemistryand Molecular Biology vol 28 no 2 2010

[115] F Forouzanfar B S Fazly Bazzaz and H Hosseinzadeh ldquoBlackcumin (Nigella sativa) and its constituent (thymoquinone) Areview on antimicrobial effectsrdquo Iranian Journal of BasicMedicalSciences vol 17 no 12 pp 929ndash938 2014

[116] E M F Barakat L M El Wakeel and R S Hagag ldquoEffects ofNigella sativa on outcome of hepatitis C in EgyptrdquoWorld Journalof Gastroenterology vol 19 no 16 pp 2529ndash2536 2013

[117] A Onifade A Jewell and W Adedeji ldquoNigella Sativa Con-coction induced sustained seroreversion in HIV patientrdquoAfrican Journal of Traditional Complementary and AlternativeMedicines vol 10 no 5 pp 332ndash335 2013

[118] A A Onifade A P Jewell and A B Okesina ldquoSeronegativeconversion of anHIVpositive subject treatedwithNigella sativaand honeyrdquo African Journal of Infectious Diseases vol 9 no 2pp 47ndash50 2015

[119] M A Assi M H M Noor N F Bachek et al ldquoThe variouseffects of Nigella sativa on multiple body systems in human andanimalsrdquo Pertanika Journal of Scholarly Research Reviews vol 2no 3 pp 1ndash19 2016

[120] M E Abd El-Hack M Alagawany M R Farag R Tiwari KKarthik andKDhama ldquoNutritional healthical and therapeuticefficacy of black cumin (Nigella sativa) in animals poultry andhumansrdquo International Journal of Pharmacology vol 12 no 3pp 232ndash248 2016

[121] A F Bafghi A R Vahidi M H Anvari K Barzegar andM Ghafourzadeh ldquoThe in vivo antileishmanial activity ofalcoholic extract from Nigella sativa seedsrdquo African Journal ofMicrobiology Research vol 5 no 12 pp 1504ndash1510 2011

[122] V O Okeola O A Adaramoye C M Nneji C O Falade E OFarombi and O G Ademowo ldquoAntimalarial and antioxidantactivities of methanolic extract of Nigella sativa seeds (blackcumin) in mice infected with Plasmodium yoelli nigeriensisrdquoParasitology Research vol 108 no 6 pp 1507ndash1512 2011

[123] R Schneider-Stock I H Fakhoury A M Zaki C O El-BabaandH U Gali-Muhtasib ldquoThymoquinone fifty years of successin the battle against cancer modelsrdquo Drug Discovery Therapyvol 19 no 1 pp 18ndash30 2014

[124] E-S A Arafa Q Zhu Z I Shah et al ldquoThymoquinoneup-regulates PTEN expression and induces apoptosis indoxorubicin-resistant human breast cancer cellsrdquo Mutation


Research - Fundamental and Molecular Mechanisms of Mutage-nesis vol 706 no 1-2 pp 28ndash35 2011

[125] V S Periasamy J Athinarayanan and A A Alshatwi ldquoAnti-cancer activity of an ultrasonic nanoemulsion formulation ofNigella sativa L essential oil on human breast cancer cellsrdquoUltrasonics Sonochemistry vol 31 pp 449ndash455 2016

[126] W K Ng L S Yazan and M Ismail ldquoThymoquinone fromNigella sativa was more potent than cisplatin in eliminating ofSiHa cells via apoptosis with down-regulation of Bcl-2 proteinrdquoToxicology in Vitro vol 25 no 7 pp 1392ndash1398 2011

[127] K Effenberger S Breyer and R Schobert ldquoTerpene conjugatesof the Nigella sativa seed-oil constituent thymoquinone withenhanced efficacy in cancer cellsrdquoChemistry amp Biodiversity vol7 no 1 pp 129ndash139 2010

[128] M Zhang H Du Z Huang et al ldquoThymoquinone inducesapoptosis in bladder cancer cell via endoplasmic reticulumstress-dependent mitochondrial pathwayrdquo Chemico-BiologicalInteractions vol 292 pp 65ndash75 2018

[129] Y Zhang Y Fan S Huang et al ldquoThymoquinone inhibits themetastasis of renal cell cancer cells by inducing autophagy viaAMPKmTOR signaling pathwayrdquo Cancer Science vol 109 no12 pp 3865ndash3873 2018

[130] B Kou Q Kou BMa et al ldquoThymoquinone inhibitsmetastaticphenotype and epithelial-mesenchymal transition in renal cellcarcinoma by regulating the LKB1AMPK signaling pathwayrdquoOncology Reports vol 40 no 3 pp 1443ndash1450 2018

[131] B Kou W Liu W Zhao et al ldquoThymoquinone inhibitsepithelial-mesenchymal transition in prostate cancer cells bynegatively regulating the TGF-120573Smad23 signaling pathwayrdquoOncology Reports vol 38 no 6 pp 3592ndash3598 2017

[132] A Elkhoely H F Hafez AM Ashmawy et al ldquoChemopreven-tive and therapeutic potentials of thymoquinone inHepG2 cellsMechanistic perspectivesrdquo Journal of Natural Medicines vol 69no 3 pp 313ndash323 2015

[133] Y R Shahin N M Elguindy A Abdel Bary and M Bal-baa ldquo The protective mechanism of Nigella sativa againstdiethylnitrosamine-induced hepatocellular carcinoma throughits antioxidant effect and EGFRERK12 signaling rdquo Environ-mental Toxicology vol 33 no 8 pp 885ndash898 2018

[134] N Kabil R Bayraktar N Kahraman et al ldquoThymoquinoneinhibits cell proliferation migration and invasion by regulatingthe elongation factor 2 kinase (eEF-2K) signaling axis in triple-negative breast cancerrdquo Breast Cancer Research and Treatmentvol 171 no 3 pp 593ndash605 2018

[135] E I Salim and S Fukushima ldquoChemopreventive potential ofvolatile oil from black cumin (Nigella sativa L) seeds againstrat colon carcinogenesisrdquo Nutrition and Cancer vol 45 no 2pp 195ndash202 2003

[136] H Gali-Muhtasib M Ocker D Kuester et al ldquoThymoquinonereduces mouse colon tumor cell invasion and inhibits tumorgrowth in murine colon cancer modelsrdquo Journal of Cellular andMolecular Medicine vol 12 no 1 pp 330ndash342 2008

[137] E I Salim ldquoCancer chemopreventive potential of volatile oilfrom black cumin seeds Nigella sativa L in a rat multi-organcarcinogenesis bioassayrdquo Oncology Letters vol 1 no 5 pp 913ndash924 2010

[138] F Q Alenzi Y El-Sayed El-Bolkiny and M L Salem ldquoPro-tective effects of Nigella sativa oil and thymoquinone againsttoxicity induced by the anticancer drug cyclophosphamiderdquoBritish Journal of Biomedical Science vol 67 no 1 pp 20ndash282010

[139] G-G Mu L-L Zhang H-Y Li Y Liao and H-G YuldquoThymoquinone pretreatment overcomes the insensitivity andpotentiates the antitumor effect of gemcitabine through abroga-tion of notch1 PI3KAktmTOR regulated signaling pathwaysin pancreatic cancerrdquo Digestive Diseases and Sciences vol 60no 4 pp 1067ndash1080 2015

[140] C Sakalar K Izgi B Iskender et al ldquoThe combination of thy-moquinone and paclitaxel shows anti-tumor activity throughthe interplay with apoptosis network in triple-negative breastcancerrdquo Tumor Biology vol 37 no 4 pp 4467ndash4477 2016

[141] R Khalife M H Hodroj R Fakhoury and S Rizk ldquoThy-moquinone from nigella sativa seeds promotes the antitumoractivity of noncytotoxic doses of topotecan in human colorectalcancer cells in vitrordquo Planta Medica vol 82 no 4 pp 312ndash3212016

[142] S Gurunath Z Pandian R A Anderson and S BhattacharyaldquoDefining infertility-a systematic review of prevalence studiesrdquoHuman Reproduction Update vol 17 no 5 Article ID dmr015pp 575ndash588 2011

[143] R J Aitken T B Smith M S Jobling M A Baker and G NDe Iuliis ldquoOxidative stress andmale reproductive healthrdquoAsianJournal of Andrology vol 16 no 1 pp 31ndash38 2014

[144] C Wright S Milne and H Leeson ldquoSperm DNA damagecaused by oxidative stress modifiable clinical lifestyle andnutritional factors in male infertilityrdquoReproductive BioMedicineOnline vol 28 no 6 pp 684ndash703 2014

[145] F M Awah P N Uzoegwu P Ifeonu et al ldquoFree radical scav-enging activity phenolic contents and cytotoxicity of selectedNigerian medicinal plantsrdquo Food Chemistry vol 131 no 4 pp1279ndash1286 2012

[146] S S Ashraf M V Rao F S Kaneez et al ldquoNigella sativa extractas a potent antioxidant for petrochemical-induced oxidativestressrdquo Journal of Chromatographic Science (JCS) vol 49 no 4pp 321ndash326 2011

[147] R Parandin N Yousofvand and R Ghorbani ldquoThe enhancingeffects of alcoholic extract of Nigella sativa seed on fertilitypotential plasma gonadotropins and testosterone in male ratsrdquoIranian Journal of Reproductive Medicine vol 10 no 4 pp 355ndash362 2012

[148] M Kolahdooz S Nasri S Z Modarres S Kianbakht and H FHuseini ldquoEffects ofNigella sativa L seed oil on abnormal semenquality in infertile men A randomized double-blind placebo-controlled clinical trialrdquo Phytomedicine vol 21 no 6 pp 901ndash905 2014

[149] O A Badary O A Al-Shabanah M N Nagi A M Al-Bekairi and M M A Elmazar ldquoAcute and subchronic toxicityof thymoquinone in micerdquoDrug Development Research vol 44no 2-3 pp 56ndash61 1998

[150] K Bensiameur-Touati G I Kacimi E-MHaffaf S Berdja andS Aouichat-Bouguerra ldquoIn vivo subacute toxicity and antidia-betic effect of aqueous extract of Nigella sativardquo Evidence-BasedComplementary and Alternative Medicine vol 2017 Article ID8427034 13 pages 2017

[151] A Zaoui Y Cherrah N Mahassini K Alaoui H AmarouchandMHassar ldquoAcute and chronic toxicity ofNigella sativa fixedoilrdquo Phytomedicine vol 9 no 1 pp 69ndash74 2002

Stem Cells International

Hindawiwwwhindawicom Volume 2018


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Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


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Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

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Computational and Mathematical Methods in Medicine


Behavioural Neurology

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Gastroenterology Research and Practice


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Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom


protein fiber and minerals and vitamins The nutritionalcomposition reported fromdifferent sources revealed 20-85of protein 3820 of fat 7-94 of fiber and 3194 of totalcarbohydrates Among various amino acids identified gluta-mate arginine and aspartate while cysteine and methioninewere the major and minor amino acids respectively Blackcumin seeds also contain significant levels of iron copperzinc phosphorus calcium thiamin niacin pyridoxine andfolic acid [7 8] In addition phytochemical analyses of Nsativa displayed the presence of over hundreds of phytocon-stituents which include mainly alkaloids saponins sterolsand essential oil but the composition of many of these havenot been chemically recognized nor have been biologicallyverified TheN sativa seed contain 26-34 fixed oil of whichthe major fatty acids are linoleic acid (646) and palmiticacid (204)The seed oil is comprised of 04ndash25 essentialoil [9 10] Amongst different active constituents reported sofar thymoquinone found asmajor component of the essentialoil is the most bioactive compound and exhibits wide rangingtherapeutic benefits [11]

2 High-Value BioactiveCompounds (Phytochemicals) inthe Seed of Nigella sativa

Several bioactive compounds from the seed of N sativahave been reported in the literature among those themost important bioactive ones are thymoquinones Othermain phytochemicals reported from different varieties of Nsativa include sterols and saponins phenolic compoundsalkaloids novel lipid constituents and fatty acids andvolatile oils of varying composition [12] The essential oilcomposition (04-045) reported in various studies repre-sented about forty different compounds amongst the abun-dantly constituents identified are trans-anethole p-cymenelimonene carvone 120572-thujene thymoquinone (TQ) thymo-hydroquinone (THQ) dithymoquinone carvacrol and 120573-Pinene with various concentration [13ndash15]

The quantity of most important bioactive constituentthymoquinone present in the volatile oil isolated by differentextraction methods from the seeds of N sativa varied overa wide range using SC-CO2 (106 407mgg) [16] and bySoxhlet extraction (294043mgkg) [17] and (88mgg) oil[18]

The seed oil fatty acid composition (32-40) has beenreported by various authors to contain mainly linoleiclinolenic oleic palmitoleic palmitic acids together witharachidonic eicosadienoic stearic and myristic acid [15 1619] A new dienoate and two known monoesters along withnovel lipids have been isolated from the unsaponified extractof the seed namely methylnonadeca-1517-dienoate pentylhexadec-12-enoate and pentyl pentadec-11-enoate [20]

Phytosterols are important part of human diet and aregaining greater interest due to their nutraceutical and medic-inal benefits in lowering low density lipoprotein and totalcholesterol level [21] Phytosterols are also important as char-acteristic compounds for assessing the quality of vegetableoils and food labelingThe total sterols content of black cumin

seed oil as estimated by different researchers was found to bebetween 18 and 42 of the unsaponified matter The majorsterols identified were 120573-sitosterol campesterol stigmasteroland 5-avenasterol [19 22] Tocopherols exhibited attractivescavenging potentials of free radicals which are believedto terminate lipids peroxidation [23] The total tocopherolcontents of black seed oil reported in varied quantities fromdiverse sources ranged from 915 to 2792mg100 g Amongthe foremost tocopherols recognized in black cumin seeds120572- and 120574-tocopherol and 120573-tocotrienol are well recognized[19]

Steroidal glycosides of new and known structures havebeen isolated from N sativa seeds which include 3-O-[120573-D-xylopyranosyl-(1997888rarr2)-120572-L-rhamnopyranosyl-(1997888rarr2)-120573-D-glucopyranosyl]-11-methoxy-16 23-dihydroxy-28-methylol-ean-12-enoate stigma-522-dien-3-120573-D-glucopyranoside[24]and 3-O-[120573-D-xylopyranosyl-(1997888rarr3)-120572-L-rhamnopyrano-syl-(1997888rarr4)-120573-D-glucopy-ranosyl]-11-methoxy-16-hydroxy-17-acetoxy hederagenin [25] Moreover alkaloids of diversetypes have been isolated from the seeds of black cuminwhich include novel Dolabellane-type diterpene alkaloidsnigellamines A1 A2 B1 and B2 and nigellamines A3 A4 A5and C [26 27] possessing lipid metabolizing property andindazole class of alkaloids nigellidine nigellicine [28 29]and nigellidine-4-O-sulfite [30]

3 Traditional Uses of Nigella sativa inFolk Remedies

Nigella sativa has been widely used as a spice and flavoringagent in variety of food preparations such as in breadyogurt pickles sauces and salads Black seed or blackcumin (English) Habbatul Barakah (Arabic) Tikur azmud(Amharic) has long been used in traditional remedy in theArabian countries Far East Asia Europe and Africa [31]Nigella sativa has also been described as the miraculous plantand considered by earliest herbal specialists as ldquoThe herbfrom heavenrdquo [32] The Prophet Mohammed (PBUH) haddescribed the curative powers of the black seed as ldquoHold onto use this black seed as it has a remedy for every illnessexcept deathrdquo [33] Avicenna a well-known physician of 10thcentury famous for his book ldquoThe Canon of Medicinerdquo hasrecommended use ofNigella seeds for enhancement of bodyrsquosenergy and also support during recovery from fatigue anddispiritednessNigella sativa is also mentioned for its curativeproperty in the Holy Bible and is also labelled asMelanthionby Hippocrates and Dioscorides [34 35]

The medicinal use of black cumin seeds in varioustraditional herbal systems is known for a wide range ofailments which include different airway disorders for painsuch as chronic headache and back pain diabetes paralysisinfection inflammation hypertension and digestive tractrelated problems administered in different kind of prepa-rations It has also been used topically where it is applieddirectly to the blisters nasal abscesses orchitis eczema andswollen joints [33]

Keeping in view of the numerous traditional medic-inal uses of N sativa seeds and its active component



























[64 65]



[66]




[67]



[68 69]




[59 70 71]



[72]



[73]

Epilepsy



[74ndash76]






[78]



[79]






















Table2Eff

ectsof

Nsativaandthym

oquino

neagainstv

arious

typeso

fcancerm

odelsa

ndtheire

ffectso

nantic

ancera

gents

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Invitro

studies

Doxorub

icin-resistant

human

breastcancer

cells

line(MCF

-7D

OXcells)

TQ(2550

or100120583M)for

48ho

ursamp

NSO

Nano

emulsio

n

(i)Con

centratio

ndepend

entgrowth

inhibitio

n(ii)Ind

ucea

poptosis

p53protein

(iii)Upregulationof

PTEN

(inhibitP

I3K

Akt

pathway)

[124125]

Hum

ancervicalsquamou

scancer

cells

TQ(10to

30120583gmL)

for

2448and72

hours

(i)Morec

ytotoxicthan

cisplatin

towards

thiscancerou

scell(but


norm

alcells)

(ii)D

ownregulates

Bcl-2

protein

[126]

Myeloblastic

leuk

emia

(HL-60

cells)

TQ(i)

Indu

cesa

poptosis

disrup

tsmito

chon

drial

mem

branep

otentia

ltriggersthea

ctivationof

caspases

38amp9in

HL-60

cells

[127]

Hum

anbladderc

ancerc

ells

(T24

and253J)

TQ(20-160120583molL)for

different

perio

ds(24h

48h

and72h)

(i)TQ

show


bladderc

ancer

cells

(ii)Itinh

ibitedcancerou

scellsrapidmultip

licationand

evoked

apop

tosis

viaa

ctivationof

caspase

(iii)TQ

also

resultedin

activ

ationof

ERstr

ess

mito

chon

drialdisturbancea

ndenhanced

mito

chon

drialm

ediatedapop

totic

path

[128]

Renalcellcancer(RC

C)cell

lines

(786-O

andAC

HN)

TQ(40120583molL)for

24ho

urs

(i)TQ

supp

ressed

migratio

ninvasio

nand

epith

elial-m

esenchym

altransitionin

RCCcells

(ii)T

Qexhibitedsig

nificantinh

ibition

ofthem

etastasis

ofRC

Ccells

throug

hindu

ctionof

autoph

agyv

iaAMPK

mTO

Rsig

nalling

[129]

Hum

anrenaltub

ular

epith

elialcell(HK2

)and

theh

uman

RCCcelllin

es(769-P

amp786-O)

TQ(0512551015

amp20

120583M)a

tvarious

duratio

ns(02448

amp72

h)

(i)TQ


igratio

nandinvasio

nof

theh

uman


es

(ii)T

Qalso

increasedthee

xpressionof

E-cadh

erin

and

redu

cedthee

xpressionof

SnailZE

B1andvimentin

atthem

RNAas

wellas

proteinlevelsin

dose-dependent

fashion

(iii)Asa

result

thee

xtentsof

phosph

orylationof

hepatic

kinase

B1andAMPK

were

upregu

lated

[130]

Hum

anprostatecancer

cell

lines

(DU145andC3

)TQ

(2550amp10120583M)for

24ho

urs

(i)TQ

substantially

arreste

dthep

roliferationof

prostatecancer

(ii)Itinh

ibitedthem

igratin

gandinvading

capabilityof

prostatecancer

DU145andPC

3cells

(iii)TQ

also

downregulated

thee

xpressionof

TGF-120573

Smad2andSm

ad3in

prostatecancer

cells

[131]

Hepatocellularc

ancerc

ell

line(HepG2)


24ho

urs

(i)Decreased

both

then

oof

viableHepG2cells

andthe

levels

(ii)T

Qindu

cedcellcyclea

rrestand

apop

tosis


status(do

sedepend

ently

)(iv

)TQredu

cedther

elease

ofVEG

Fof

HepG2cells

[132]


Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Invivo

studies

Diethylnitro

samine

indu

cedh

epatocarcino

gen-

esisin

Wistar

rats

Ethano

licextracto

fNS

(250

mgkg)for

5consecutived

ays

(i)Th

echemicalindu

cedincrem

entofliver

weight

hepato-som

aticindicesserum

AFP

andVEG

Flevels

andhepatic

HGF120573

proteinexpressio

nwe

resig

nificantly

reversed

bythee

xtract

(ii)Th

ehistop

atho

logicalalteratio

nof

theliversd

ueto

thec

hemicalwas

decreasedin


with

outh

armfuleffects

[133]

Ortho

topicm

odelinmice

[triple-negativeb

reast

cancer

(TNBC

)celllines]

TQ(20or

100mgk)

once

every3

days

(i)TQ

markedlyredu

cedtheg

rowth

ofMDA-

MB-231

tumor

(ii)T

QdecreasedTN

BCcellviability

andproliferatio

nas

wellas

them

igratio

nandinvasio

nof

TNBC

cells

(iii)TQ

also

downregulated

thee

xpressionof

eEF-2K

(viamod

ulationof

theN


Kand

Akt

inTN

BCcells

[134]

Colon

carcinogenesisof

ratsmod

elNSO

for14we

eks

(i)NSO

revealed


ctivity

inbo

thinitiationandpo

st-initiationph

ases

(ii)Inh


ratsmainlyin

the

post-

initiationsta

gewith

noevidento

fadverse

effects

[135]

Mou

semod

elof

colorectal

carcinogenesisampC2

6cell

TQ(5

mgkg)for

3we

eksamp

TQ(02040

60120583M)in

vitro

(i)TQ

redu

cedtumor

multip

licity

(ii)T

Qim

pededtumor

grow

thandindu

ceapop

tosis

inHCT

116xeno

graft


oncof

TQ(40120583

M)a

lsoredu

ced

C26cellinvasio

n(iv

)Anti-n

eoplastic

andpro-apop

totic

p53-depend

ent

mechanism

[136]

Ratm

ulti-organ

carcinogenesis

NSO

for3

0we

eks

(i)Re

ductionin

malignant

andbenign

colontumor

sizestum

orsinthelun

gsandin

diversep

artsof

the

alim

entary

canalprin

cipally

theo

esop

hagu

sand

fore

stomach

[137]


Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Effecto

nanti-cancer

drug

s

Cyclop

hosphamide

Indu

cedtoxicity(abn

ormal

RFampLF

Tandredu

ced

Hgb)inrat

NSO

(1mlk

g)andTQ

(10

mgkg)E

ODfor12days


nin

overallcycloph

osph

amide

indu

cedtoxicityin

both

NSO

andTQ

treated

grou

ps

[138]

Antitu

mor

Effecto

fTQand

gemcitabine

onxeno

graft

mou

seandPA

NC-

1AsPC-

1and

BxPC

-3cell

lines

ofpancreaticcancer

mod

els


10mg

mou

sedaily

(i)TQ

pre-tre

atmentsyn

ergistically

increasedthe

gemcitabine

actio

nsof

apop

totic

andtumor

grow

thinhibitio

nof

pancreaticcancer

cells

(ii)C

oncomitant

uses

resultedin

thec

hangeo

fseveral

molecular

signalin

ginclu

ding

thed

ownregulationof


with

up-regulationof

PTEN

viathe

inactiv

ationof

Aktm

TORS6

signalin

g(iii)TQ

andgemcitabine

also

indu

cedsupp

ressionof

anti-apop

totic

Bcl-2


nandactiv

ationCaspase-3C

aspase-9amp

Bax

[139]

Cytotoxicityassayof

TQandpaclita

xelonmou

sebreastcancer

celllin

e(4T

1)andanim

almod

els

TQ(6251252550amp

100

120583M)for

24amp48

hours

(06424amp32mgkg

ofmou

sebo

dywe

ight)

(i)TQ

indu


tosis

whileinhibitin

gwo


nof

4T1

cells

(ii)C

o-administratio

nof

TQandpaclita

xel

significantly

indu


tosis

comparedto


n(iii)Th

ecom

binatio

nof

paclita

xeland

thelow

erdo

seTQ


orgrow

th

(iv)B

othagentsalso

mod

ulated

thea

poptosisgenes

p53andJAK-

STAT

signalin

gwhileoverexpressin

gthe

levelsof

Caspase-3C

aspase-7and

Caspase-12

[140]

Anti-tum

oractiv

ityof

TQandtopo

tecanin

colorectal

cancer

celllin

e(HT-29)

TQ(4055

amp60120583M)

(i)TQ

significantly

enhanced

thea

nti-tum

oreffecto

fno

n-cytotoxicd

oseo

ftop

otecan

(ii)B

othdrug

sind

uced

apop

tosis

viaa

p53-independ

entm

echanism

whilethee

xpressionof

p21w

ason

lyno

tedin

TQtherapy

(iii)TQ

improved

thee

ffectivenesso

ftop

otecan

byinhibitin

gproliferatio

nand

lowe

ringtoxicityviap

53-

andBa

xBc

l2-in

depend

entm

echanism

s

[141]

AMPK

Adeno

sinem

onop

hosphate-activated

proteinkinaseN

SNigellasativaNSO

NigellasativaoilT

QTh

ymoq

uino

neP

TENpho

sphataseandtensin

homolog

MCF

-7M

ichiganCancerF

ound

ation-7EO

D

everyotherd

aym

TOR

Mam

malianTargetof

Rapamycin





Abbreviations







References





































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of













































[64 65]



[66]




[67]



[68 69]




[59 70 71]



[72]



[73]

Epilepsy



[74ndash76]






[78]



[79]






















Table2Eff

ectsof

Nsativaandthym

oquino

neagainstv

arious

typeso

fcancerm

odelsa

ndtheire

ffectso

nantic

ancera

gents

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Invitro

studies

Doxorub

icin-resistant

human

breastcancer

cells

line(MCF

-7D

OXcells)

TQ(2550

or100120583M)for

48ho

ursamp

NSO

Nano

emulsio

n

(i)Con

centratio

ndepend

entgrowth

inhibitio

n(ii)Ind

ucea

poptosis

p53protein

(iii)Upregulationof

PTEN

(inhibitP

I3K

Akt

pathway)

[124125]

Hum

ancervicalsquamou

scancer

cells

TQ(10to

30120583gmL)

for

2448and72

hours

(i)Morec

ytotoxicthan

cisplatin

towards

thiscancerou

scell(but


norm

alcells)

(ii)D

ownregulates

Bcl-2

protein

[126]

Myeloblastic

leuk

emia

(HL-60

cells)

TQ(i)

Indu

cesa

poptosis

disrup

tsmito

chon

drial

mem

branep

otentia

ltriggersthea

ctivationof

caspases

38amp9in

HL-60

cells

[127]

Hum

anbladderc

ancerc

ells

(T24

and253J)

TQ(20-160120583molL)for

different

perio

ds(24h

48h

and72h)

(i)TQ

show


bladderc

ancer

cells

(ii)Itinh

ibitedcancerou

scellsrapidmultip

licationand

evoked

apop

tosis

viaa

ctivationof

caspase

(iii)TQ

also

resultedin

activ

ationof

ERstr

ess

mito

chon

drialdisturbancea

ndenhanced

mito

chon

drialm

ediatedapop

totic

path

[128]

Renalcellcancer(RC

C)cell

lines

(786-O

andAC

HN)

TQ(40120583molL)for

24ho

urs

(i)TQ

supp

ressed

migratio

ninvasio

nand

epith

elial-m

esenchym

altransitionin

RCCcells

(ii)T

Qexhibitedsig

nificantinh

ibition

ofthem

etastasis

ofRC

Ccells

throug

hindu

ctionof

autoph

agyv

iaAMPK

mTO

Rsig

nalling

[129]

Hum

anrenaltub

ular

epith

elialcell(HK2

)and

theh

uman

RCCcelllin

es(769-P

amp786-O)

TQ(0512551015

amp20

120583M)a

tvarious

duratio

ns(02448

amp72

h)

(i)TQ


igratio

nandinvasio

nof

theh

uman


es

(ii)T

Qalso

increasedthee

xpressionof

E-cadh

erin

and

redu

cedthee

xpressionof

SnailZE

B1andvimentin

atthem

RNAas

wellas

proteinlevelsin

dose-dependent

fashion

(iii)Asa

result

thee

xtentsof

phosph

orylationof

hepatic

kinase

B1andAMPK

were

upregu

lated

[130]

Hum

anprostatecancer

cell

lines

(DU145andC3

)TQ

(2550amp10120583M)for

24ho

urs

(i)TQ

substantially

arreste

dthep

roliferationof

prostatecancer

(ii)Itinh

ibitedthem

igratin

gandinvading

capabilityof

prostatecancer

DU145andPC

3cells

(iii)TQ

also

downregulated

thee

xpressionof

TGF-120573

Smad2andSm

ad3in

prostatecancer

cells

[131]

Hepatocellularc

ancerc

ell

line(HepG2)


24ho

urs

(i)Decreased

both

then

oof

viableHepG2cells

andthe

levels

(ii)T

Qindu

cedcellcyclea

rrestand

apop

tosis


status(do

sedepend

ently

)(iv

)TQredu

cedther

elease

ofVEG

Fof

HepG2cells

[132]


Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Invivo

studies

Diethylnitro

samine

indu

cedh

epatocarcino

gen-

esisin

Wistar

rats

Ethano

licextracto

fNS

(250

mgkg)for

5consecutived

ays

(i)Th

echemicalindu

cedincrem

entofliver

weight

hepato-som

aticindicesserum

AFP

andVEG

Flevels

andhepatic

HGF120573

proteinexpressio

nwe

resig

nificantly

reversed

bythee

xtract

(ii)Th

ehistop

atho

logicalalteratio

nof

theliversd

ueto

thec

hemicalwas

decreasedin


with

outh

armfuleffects

[133]

Ortho

topicm

odelinmice

[triple-negativeb

reast

cancer

(TNBC

)celllines]

TQ(20or

100mgk)

once

every3

days

(i)TQ

markedlyredu

cedtheg

rowth

ofMDA-

MB-231

tumor

(ii)T

QdecreasedTN

BCcellviability

andproliferatio

nas

wellas

them

igratio

nandinvasio

nof

TNBC

cells

(iii)TQ

also

downregulated

thee

xpressionof

eEF-2K

(viamod

ulationof

theN


Kand

Akt

inTN

BCcells

[134]

Colon

carcinogenesisof

ratsmod

elNSO

for14we

eks

(i)NSO

revealed


ctivity

inbo

thinitiationandpo

st-initiationph

ases

(ii)Inh


ratsmainlyin

the

post-

initiationsta

gewith

noevidento

fadverse

effects

[135]

Mou

semod

elof

colorectal

carcinogenesisampC2

6cell

TQ(5

mgkg)for

3we

eksamp

TQ(02040

60120583M)in

vitro

(i)TQ

redu

cedtumor

multip

licity

(ii)T

Qim

pededtumor

grow

thandindu

ceapop

tosis

inHCT

116xeno

graft


oncof

TQ(40120583

M)a

lsoredu

ced

C26cellinvasio

n(iv

)Anti-n

eoplastic

andpro-apop

totic

p53-depend

ent

mechanism

[136]

Ratm

ulti-organ

carcinogenesis

NSO

for3

0we

eks

(i)Re

ductionin

malignant

andbenign

colontumor

sizestum

orsinthelun

gsandin

diversep

artsof

the

alim

entary

canalprin

cipally

theo

esop

hagu

sand

fore

stomach

[137]


Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Effecto

nanti-cancer

drug

s

Cyclop

hosphamide

Indu

cedtoxicity(abn

ormal

RFampLF

Tandredu

ced

Hgb)inrat

NSO

(1mlk

g)andTQ

(10

mgkg)E

ODfor12days


nin

overallcycloph

osph

amide

indu

cedtoxicityin

both

NSO

andTQ

treated

grou

ps

[138]

Antitu

mor

Effecto

fTQand

gemcitabine

onxeno

graft

mou

seandPA

NC-

1AsPC-

1and

BxPC

-3cell

lines

ofpancreaticcancer

mod

els


10mg

mou

sedaily

(i)TQ

pre-tre

atmentsyn

ergistically

increasedthe

gemcitabine

actio

nsof

apop

totic

andtumor

grow

thinhibitio

nof

pancreaticcancer

cells

(ii)C

oncomitant

uses

resultedin

thec

hangeo

fseveral

molecular

signalin

ginclu

ding

thed

ownregulationof


with

up-regulationof

PTEN

viathe

inactiv

ationof

Aktm

TORS6

signalin

g(iii)TQ

andgemcitabine

also

indu

cedsupp

ressionof

anti-apop

totic

Bcl-2


nandactiv

ationCaspase-3C

aspase-9amp

Bax

[139]

Cytotoxicityassayof

TQandpaclita

xelonmou

sebreastcancer

celllin

e(4T

1)andanim

almod

els

TQ(6251252550amp

100

120583M)for

24amp48

hours

(06424amp32mgkg

ofmou

sebo

dywe

ight)

(i)TQ

indu


tosis

whileinhibitin

gwo


nof

4T1

cells

(ii)C

o-administratio

nof

TQandpaclita

xel

significantly

indu


tosis

comparedto


n(iii)Th

ecom

binatio

nof

paclita

xeland

thelow

erdo

seTQ


orgrow

th

(iv)B

othagentsalso

mod

ulated

thea

poptosisgenes

p53andJAK-

STAT

signalin

gwhileoverexpressin

gthe

levelsof

Caspase-3C

aspase-7and

Caspase-12

[140]

Anti-tum

oractiv

ityof

TQandtopo

tecanin

colorectal

cancer

celllin

e(HT-29)

TQ(4055

amp60120583M)

(i)TQ

significantly

enhanced

thea

nti-tum

oreffecto

fno

n-cytotoxicd

oseo

ftop

otecan

(ii)B

othdrug

sind

uced

apop

tosis

viaa

p53-independ

entm

echanism

whilethee

xpressionof

p21w

ason

lyno

tedin

TQtherapy

(iii)TQ

improved

thee

ffectivenesso

ftop

otecan

byinhibitin

gproliferatio

nand

lowe

ringtoxicityviap

53-

andBa

xBc

l2-in

depend

entm

echanism

s

[141]

AMPK

Adeno

sinem

onop

hosphate-activated

proteinkinaseN

SNigellasativaNSO

NigellasativaoilT

QTh

ymoq

uino

neP

TENpho

sphataseandtensin

homolog

MCF

-7M

ichiganCancerF

ound

ation-7EO

D

everyotherd

aym

TOR

Mam

malianTargetof

Rapamycin





Abbreviations







References





































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of







































Table2Eff

ectsof

Nsativaandthym

oquino

neagainstv

arious

typeso

fcancerm

odelsa

ndtheire

ffectso

nantic

ancera

gents

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Invitro

studies

Doxorub

icin-resistant

human

breastcancer

cells

line(MCF

-7D

OXcells)

TQ(2550

or100120583M)for

48ho

ursamp

NSO

Nano

emulsio

n

(i)Con

centratio

ndepend

entgrowth

inhibitio

n(ii)Ind

ucea

poptosis

p53protein

(iii)Upregulationof

PTEN

(inhibitP

I3K

Akt

pathway)

[124125]

Hum

ancervicalsquamou

scancer

cells

TQ(10to

30120583gmL)

for

2448and72

hours

(i)Morec

ytotoxicthan

cisplatin

towards

thiscancerou

scell(but


norm

alcells)

(ii)D

ownregulates

Bcl-2

protein

[126]

Myeloblastic

leuk

emia

(HL-60

cells)

TQ(i)

Indu

cesa

poptosis

disrup

tsmito

chon

drial

mem

branep

otentia

ltriggersthea

ctivationof

caspases

38amp9in

HL-60

cells

[127]

Hum

anbladderc

ancerc

ells

(T24

and253J)

TQ(20-160120583molL)for

different

perio

ds(24h

48h

and72h)

(i)TQ

show


bladderc

ancer

cells

(ii)Itinh

ibitedcancerou

scellsrapidmultip

licationand

evoked

apop

tosis

viaa

ctivationof

caspase

(iii)TQ

also

resultedin

activ

ationof

ERstr

ess

mito

chon

drialdisturbancea

ndenhanced

mito

chon

drialm

ediatedapop

totic

path

[128]

Renalcellcancer(RC

C)cell

lines

(786-O

andAC

HN)

TQ(40120583molL)for

24ho

urs

(i)TQ

supp

ressed

migratio

ninvasio

nand

epith

elial-m

esenchym

altransitionin

RCCcells

(ii)T

Qexhibitedsig

nificantinh

ibition

ofthem

etastasis

ofRC

Ccells

throug

hindu

ctionof

autoph

agyv

iaAMPK

mTO

Rsig

nalling

[129]

Hum

anrenaltub

ular

epith

elialcell(HK2

)and

theh

uman

RCCcelllin

es(769-P

amp786-O)

TQ(0512551015

amp20

120583M)a

tvarious

duratio

ns(02448

amp72

h)

(i)TQ


igratio

nandinvasio

nof

theh

uman


es

(ii)T

Qalso

increasedthee

xpressionof

E-cadh

erin

and

redu

cedthee

xpressionof

SnailZE

B1andvimentin

atthem

RNAas

wellas

proteinlevelsin

dose-dependent

fashion

(iii)Asa

result

thee

xtentsof

phosph

orylationof

hepatic

kinase

B1andAMPK

were

upregu

lated

[130]

Hum

anprostatecancer

cell

lines

(DU145andC3

)TQ

(2550amp10120583M)for

24ho

urs

(i)TQ

substantially

arreste

dthep

roliferationof

prostatecancer

(ii)Itinh

ibitedthem

igratin

gandinvading

capabilityof

prostatecancer

DU145andPC

3cells

(iii)TQ

also

downregulated

thee

xpressionof

TGF-120573

Smad2andSm

ad3in

prostatecancer

cells

[131]

Hepatocellularc

ancerc

ell

line(HepG2)


24ho

urs

(i)Decreased

both

then

oof

viableHepG2cells

andthe

levels

(ii)T

Qindu

cedcellcyclea

rrestand

apop

tosis


status(do

sedepend

ently

)(iv

)TQredu

cedther

elease

ofVEG

Fof

HepG2cells

[132]


Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Invivo

studies

Diethylnitro

samine

indu

cedh

epatocarcino

gen-

esisin

Wistar

rats

Ethano

licextracto

fNS

(250

mgkg)for

5consecutived

ays

(i)Th

echemicalindu

cedincrem

entofliver

weight

hepato-som

aticindicesserum

AFP

andVEG

Flevels

andhepatic

HGF120573

proteinexpressio

nwe

resig

nificantly

reversed

bythee

xtract

(ii)Th

ehistop

atho

logicalalteratio

nof

theliversd

ueto

thec

hemicalwas

decreasedin


with

outh

armfuleffects

[133]

Ortho

topicm

odelinmice

[triple-negativeb

reast

cancer

(TNBC

)celllines]

TQ(20or

100mgk)

once

every3

days

(i)TQ

markedlyredu

cedtheg

rowth

ofMDA-

MB-231

tumor

(ii)T

QdecreasedTN

BCcellviability

andproliferatio

nas

wellas

them

igratio

nandinvasio

nof

TNBC

cells

(iii)TQ

also

downregulated

thee

xpressionof

eEF-2K

(viamod

ulationof

theN


Kand

Akt

inTN

BCcells

[134]

Colon

carcinogenesisof

ratsmod

elNSO

for14we

eks

(i)NSO

revealed


ctivity

inbo

thinitiationandpo

st-initiationph

ases

(ii)Inh


ratsmainlyin

the

post-

initiationsta

gewith

noevidento

fadverse

effects

[135]

Mou

semod

elof

colorectal

carcinogenesisampC2

6cell

TQ(5

mgkg)for

3we

eksamp

TQ(02040

60120583M)in

vitro

(i)TQ

redu

cedtumor

multip

licity

(ii)T

Qim

pededtumor

grow

thandindu

ceapop

tosis

inHCT

116xeno

graft


oncof

TQ(40120583

M)a

lsoredu

ced

C26cellinvasio

n(iv

)Anti-n

eoplastic

andpro-apop

totic

p53-depend

ent

mechanism

[136]

Ratm

ulti-organ

carcinogenesis

NSO

for3

0we

eks

(i)Re

ductionin

malignant

andbenign

colontumor

sizestum

orsinthelun

gsandin

diversep

artsof

the

alim

entary

canalprin

cipally

theo

esop

hagu

sand

fore

stomach

[137]


Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Effecto

nanti-cancer

drug

s

Cyclop

hosphamide

Indu

cedtoxicity(abn

ormal

RFampLF

Tandredu

ced

Hgb)inrat

NSO

(1mlk

g)andTQ

(10

mgkg)E

ODfor12days


nin

overallcycloph

osph

amide

indu

cedtoxicityin

both

NSO

andTQ

treated

grou

ps

[138]

Antitu

mor

Effecto

fTQand

gemcitabine

onxeno

graft

mou

seandPA

NC-

1AsPC-

1and

BxPC

-3cell

lines

ofpancreaticcancer

mod

els


10mg

mou

sedaily

(i)TQ

pre-tre

atmentsyn

ergistically

increasedthe

gemcitabine

actio

nsof

apop

totic

andtumor

grow

thinhibitio

nof

pancreaticcancer

cells

(ii)C

oncomitant

uses

resultedin

thec

hangeo

fseveral

molecular

signalin

ginclu

ding

thed

ownregulationof


with

up-regulationof

PTEN

viathe

inactiv

ationof

Aktm

TORS6

signalin

g(iii)TQ

andgemcitabine

also

indu

cedsupp

ressionof

anti-apop

totic

Bcl-2


nandactiv

ationCaspase-3C

aspase-9amp

Bax

[139]

Cytotoxicityassayof

TQandpaclita

xelonmou

sebreastcancer

celllin

e(4T

1)andanim

almod

els

TQ(6251252550amp

100

120583M)for

24amp48

hours

(06424amp32mgkg

ofmou

sebo

dywe

ight)

(i)TQ

indu


tosis

whileinhibitin

gwo


nof

4T1

cells

(ii)C

o-administratio

nof

TQandpaclita

xel

significantly

indu


tosis

comparedto


n(iii)Th

ecom

binatio

nof

paclita

xeland

thelow

erdo

seTQ


orgrow

th

(iv)B

othagentsalso

mod

ulated

thea

poptosisgenes

p53andJAK-

STAT

signalin

gwhileoverexpressin

gthe

levelsof

Caspase-3C

aspase-7and

Caspase-12

[140]

Anti-tum

oractiv

ityof

TQandtopo

tecanin

colorectal

cancer

celllin

e(HT-29)

TQ(4055

amp60120583M)

(i)TQ

significantly

enhanced

thea

nti-tum

oreffecto

fno

n-cytotoxicd

oseo

ftop

otecan

(ii)B

othdrug

sind

uced

apop

tosis

viaa

p53-independ

entm

echanism

whilethee

xpressionof

p21w

ason

lyno

tedin

TQtherapy

(iii)TQ

improved

thee

ffectivenesso

ftop

otecan

byinhibitin

gproliferatio

nand

lowe

ringtoxicityviap

53-

andBa

xBc

l2-in

depend

entm

echanism

s

[141]

AMPK

Adeno

sinem

onop

hosphate-activated

proteinkinaseN

SNigellasativaNSO

NigellasativaoilT

QTh

ymoq

uino

neP

TENpho

sphataseandtensin

homolog

MCF

-7M

ichiganCancerF

ound

ation-7EO

D

everyotherd

aym

TOR

Mam

malianTargetof

Rapamycin





Abbreviations







References





































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Invivo

studies

Diethylnitro

samine

indu

cedh

epatocarcino

gen-

esisin

Wistar

rats

Ethano

licextracto

fNS

(250

mgkg)for

5consecutived

ays

(i)Th

echemicalindu

cedincrem

entofliver

weight

hepato-som

aticindicesserum

AFP

andVEG

Flevels

andhepatic

HGF120573

proteinexpressio

nwe

resig

nificantly

reversed

bythee

xtract

(ii)Th

ehistop

atho

logicalalteratio

nof

theliversd

ueto

thec

hemicalwas

decreasedin


with

outh

armfuleffects

[133]

Ortho

topicm

odelinmice

[triple-negativeb

reast

cancer

(TNBC

)celllines]

TQ(20or

100mgk)

once

every3

days

(i)TQ

markedlyredu

cedtheg

rowth

ofMDA-

MB-231

tumor

(ii)T

QdecreasedTN

BCcellviability

andproliferatio

nas

wellas

them

igratio

nandinvasio

nof

TNBC

cells

(iii)TQ

also

downregulated

thee

xpressionof

eEF-2K

(viamod

ulationof

theN


Kand

Akt

inTN

BCcells

[134]

Colon

carcinogenesisof

ratsmod

elNSO

for14we

eks

(i)NSO

revealed


ctivity

inbo

thinitiationandpo

st-initiationph

ases

(ii)Inh


ratsmainlyin

the

post-

initiationsta

gewith

noevidento

fadverse

effects

[135]

Mou

semod

elof

colorectal

carcinogenesisampC2

6cell

TQ(5

mgkg)for

3we

eksamp

TQ(02040

60120583M)in

vitro

(i)TQ

redu

cedtumor

multip

licity

(ii)T

Qim

pededtumor

grow

thandindu

ceapop

tosis

inHCT

116xeno

graft


oncof

TQ(40120583

M)a

lsoredu

ced

C26cellinvasio

n(iv

)Anti-n

eoplastic

andpro-apop

totic

p53-depend

ent

mechanism

[136]

Ratm

ulti-organ

carcinogenesis

NSO

for3

0we

eks

(i)Re

ductionin

malignant

andbenign

colontumor

sizestum

orsinthelun

gsandin

diversep

artsof

the

alim

entary

canalprin

cipally

theo

esop

hagu

sand

fore

stomach

[137]


Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Effecto

nanti-cancer

drug

s

Cyclop

hosphamide

Indu

cedtoxicity(abn

ormal

RFampLF

Tandredu

ced

Hgb)inrat

NSO

(1mlk

g)andTQ

(10

mgkg)E

ODfor12days


nin

overallcycloph

osph

amide

indu

cedtoxicityin

both

NSO

andTQ

treated

grou

ps

[138]

Antitu

mor

Effecto

fTQand

gemcitabine

onxeno

graft

mou

seandPA

NC-

1AsPC-

1and

BxPC

-3cell

lines

ofpancreaticcancer

mod

els


10mg

mou

sedaily

(i)TQ

pre-tre

atmentsyn

ergistically

increasedthe

gemcitabine

actio

nsof

apop

totic

andtumor

grow

thinhibitio

nof

pancreaticcancer

cells

(ii)C

oncomitant

uses

resultedin

thec

hangeo

fseveral

molecular

signalin

ginclu

ding

thed

ownregulationof


with

up-regulationof

PTEN

viathe

inactiv

ationof

Aktm

TORS6

signalin

g(iii)TQ

andgemcitabine

also

indu

cedsupp

ressionof

anti-apop

totic

Bcl-2


nandactiv

ationCaspase-3C

aspase-9amp

Bax

[139]

Cytotoxicityassayof

TQandpaclita

xelonmou

sebreastcancer

celllin

e(4T

1)andanim

almod

els

TQ(6251252550amp

100

120583M)for

24amp48

hours

(06424amp32mgkg

ofmou

sebo

dywe

ight)

(i)TQ

indu


tosis

whileinhibitin

gwo


nof

4T1

cells

(ii)C

o-administratio

nof

TQandpaclita

xel

significantly

indu


tosis

comparedto


n(iii)Th

ecom

binatio

nof

paclita

xeland

thelow

erdo

seTQ


orgrow

th

(iv)B

othagentsalso

mod

ulated

thea

poptosisgenes

p53andJAK-

STAT

signalin

gwhileoverexpressin

gthe

levelsof

Caspase-3C

aspase-7and

Caspase-12

[140]

Anti-tum

oractiv

ityof

TQandtopo

tecanin

colorectal

cancer

celllin

e(HT-29)

TQ(4055

amp60120583M)

(i)TQ

significantly

enhanced

thea

nti-tum

oreffecto

fno

n-cytotoxicd

oseo

ftop

otecan

(ii)B

othdrug

sind

uced

apop

tosis

viaa

p53-independ

entm

echanism

whilethee

xpressionof

p21w

ason

lyno

tedin

TQtherapy

(iii)TQ

improved

thee

ffectivenesso

ftop

otecan

byinhibitin

gproliferatio

nand

lowe

ringtoxicityviap

53-

andBa

xBc

l2-in

depend

entm

echanism

s

[141]

AMPK

Adeno

sinem

onop

hosphate-activated

proteinkinaseN

SNigellasativaNSO

NigellasativaoilT

QTh

ymoq

uino

neP

TENpho

sphataseandtensin

homolog

MCF

-7M

ichiganCancerF

ound

ation-7EO

D

everyotherd

aym

TOR

Mam

malianTargetof

Rapamycin





Abbreviations







References





































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table2Con

tinued

Cancerm

odelso

reffectso

fanticancer

agents

Interventio

n(s)

Find

ings

(Mechanism

s)Re

ferences

Effecto

nanti-cancer

drug

s

Cyclop

hosphamide

Indu

cedtoxicity(abn

ormal

RFampLF

Tandredu

ced

Hgb)inrat

NSO

(1mlk

g)andTQ

(10

mgkg)E

ODfor12days


nin

overallcycloph

osph

amide

indu

cedtoxicityin

both

NSO

andTQ

treated

grou

ps

[138]

Antitu

mor

Effecto

fTQand

gemcitabine

onxeno

graft

mou

seandPA

NC-

1AsPC-

1and

BxPC

-3cell

lines

ofpancreaticcancer

mod

els


10mg

mou

sedaily

(i)TQ

pre-tre

atmentsyn

ergistically

increasedthe

gemcitabine

actio

nsof

apop

totic

andtumor

grow

thinhibitio

nof

pancreaticcancer

cells

(ii)C

oncomitant

uses

resultedin

thec

hangeo

fseveral

molecular

signalin

ginclu

ding

thed

ownregulationof


with

up-regulationof

PTEN

viathe

inactiv

ationof

Aktm

TORS6

signalin

g(iii)TQ

andgemcitabine

also

indu

cedsupp

ressionof

anti-apop

totic

Bcl-2


nandactiv

ationCaspase-3C

aspase-9amp

Bax

[139]

Cytotoxicityassayof

TQandpaclita

xelonmou

sebreastcancer

celllin

e(4T

1)andanim

almod

els

TQ(6251252550amp

100

120583M)for

24amp48

hours

(06424amp32mgkg

ofmou

sebo

dywe

ight)

(i)TQ

indu


tosis

whileinhibitin

gwo


nof

4T1

cells

(ii)C

o-administratio

nof

TQandpaclita

xel

significantly

indu


tosis

comparedto


n(iii)Th

ecom

binatio

nof

paclita

xeland

thelow

erdo

seTQ


orgrow

th

(iv)B

othagentsalso

mod

ulated

thea

poptosisgenes

p53andJAK-

STAT

signalin

gwhileoverexpressin

gthe

levelsof

Caspase-3C

aspase-7and

Caspase-12

[140]

Anti-tum

oractiv

ityof

TQandtopo

tecanin

colorectal

cancer

celllin

e(HT-29)

TQ(4055

amp60120583M)

(i)TQ

significantly

enhanced

thea

nti-tum

oreffecto

fno

n-cytotoxicd

oseo

ftop

otecan

(ii)B

othdrug

sind

uced

apop

tosis

viaa

p53-independ

entm

echanism

whilethee

xpressionof

p21w

ason

lyno

tedin

TQtherapy

(iii)TQ

improved

thee

ffectivenesso

ftop

otecan

byinhibitin

gproliferatio

nand

lowe

ringtoxicityviap

53-

andBa

xBc

l2-in

depend

entm

echanism

s

[141]

AMPK

Adeno

sinem

onop

hosphate-activated

proteinkinaseN

SNigellasativaNSO

NigellasativaoilT

QTh

ymoq

uino

neP

TENpho

sphataseandtensin

homolog

MCF

-7M

ichiganCancerF

ound

ation-7EO

D

everyotherd

aym

TOR

Mam

malianTargetof

Rapamycin





Abbreviations







References





































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























Abbreviations







References





































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of















































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















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