exploring pharmacological mechanisms of xuefu zhuyu...

Research ArticleExploring Pharmacological Mechanisms of Xuefu ZhuyuDecoction in the Treatment of Traumatic Brain Injury viaa Network Pharmacology Approach

Yuanyuan Zhong1 Jiekun Luo 1 Tao Tang 1 Pengfei Li1 Tao Liu12 Hanjin Cui1

YangWang 13 and Zebing Huang 3

1 Institute of Integrative Medicine Xiangya Hospital Central South University Changsha 410008 China2Department of Gerontology Traditional Chinese Medicine Hospital Affiliated to XinjiangMedical University Urumqi 830000China3Department of Infectious Disease Hunan Key Laboratory of Viral Hepatitis Xiangya Hospital Central South UniversityChangsha 410008 China

Correspondence should be addressed to YangWang wangyang xy87csueducn and ZebingHuang huangabing0330csueducn

Received 22 June 2018 Accepted 17 September 2018 Published 4 October 2018

Academic Editor Darren R Williams

Copyright copy 2018 Yuanyuan Zhong 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

Objectives Xuefu Zhuyu decoction (XFZYD) a traditional Chinesemedicine (TCM) formula has been demonstrated to be effectivefor the treatment of traumatic brain injury (TBI)However the underlying pharmacologicalmechanisms remain unclearThis studyaims to explore the potential action mechanisms of XFZYD in the treatment of TBI and to elucidate the combination principle ofthis herbal formula Methods A network pharmacology approach including ADME (absorption distribution metabolism andexcretion) evaluation target prediction known therapeutic targets collection network construction and molecule docking wasused in this study Results A total of 119 bioactive ingredients from XFZYD were predicted to act on 47 TBI associated specificproteins which intervened in several crucial pathological processes including apoptosis inflammation antioxidant and axongenesis Almost each of the bioactive ingredients targeted more than one protein The molecular docking simulation showedthat 91 pairs of chemical components and candidate targets had strong binding efficiencies The ldquoJunrdquo ldquoChenrdquo and ldquoZuo-Shirdquoherbs from XFZYD triggered their specific targets regulation respectively Conclusion Our work successfully illuminates theldquomulticompounds multitargetsrdquo therapeutic action of XFZYD in the treatment of TBI by network pharmacology with moleculedocking methodThe present workmay provide valuable evidence for further clinical application of XFZYD as therapeutic strategyfor TBI treatment

1 Introduction

Traumatic brain injury (TBI) is a major cause of deathand disability [1] At least 10 million severe TBIs result indeath or hospitalization annually worldwide [2] Approx-imately 17 million Americans sustain a TBI each yearleading to over 14 million emergency department visits275 000 hospital admissions and 50 000 deaths that con-tribute to one-third of all injury-related deaths [3] In theEuropean Union alone an estimated 15 million hospitaladmissions and 57000 deaths annually attribute to TBI[4] In China TBI-related mortality remains a high levelranging from 1299 to 1706 per population of 100 000

persons [5]Thus TBI has afforded huge social and economicburden

TBI is a diverse group of sterile injuries induced byprimary and secondary mechanisms that give rise to celldeath inflammation and neurologic dysfunction in patientsof all demographics [6 7]The primary injury is caused by themechanical stress or shear force on tissues with no therapeu-tic agents [8] The secondary injury includes a wide varietyof processes like activation of inflammatory and immuneresponse [9 10] calciumoverload [11] glutamate toxicity [12]and mitochondrial dysfunction [13] among others Currentguidelines for the management of the secondary injury areprimarily supportive including the emphasis on surveillance

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2018 Article ID 8916938 20 pageshttpsdoiorg10115520188916938

2 Evidence-Based Complementary and Alternative Medicine

(ie intracranial pressure) and the preventive measures toreduce morbidity and mortality [14] Despite the fact thatdetailed medicines contain free-radical scavengers antago-nists of N-methyl-D-aspartate and calcium channel blockers[15] the results of the controlled clinical trials of these drugsare disappointing [16] Neuroscientists and doctors tend tosearch for potential novel drugs from traditional Chinesemedicine (TCM) library to treat TBI [17]

TCM is a comprehensive medicinal system that has beenused in clinical practice for thousands of years and playsan important role in the health maintenance for people allover the world [18 19] The validated curative effects of TCMmake it a feasible alternative therapeutic agent for diseasetreatment Xuefu Zhuyu decoction (XFZYD) a representa-tive TCM formula was first recorded in Correction of Errorsin Medical Works by Qing-ren Wang XFZYD consists of11 crude herbs Persicae Semen (Tao ren) Carthami Flos(Hong hua) Radix Paeoniae Rubra (Chi shao) ChuanxiongRhizoma (Chuan xiong) Achyranthis Bidentatae Radix (Niuxi) Angelicae Sinensis Radix (Dang gui) Rehmannia glutinosaLibosch (Sheng di huang) Platycodon Grandiforus (Jie geng)Aurantii Fructus (zhi qiao) Radix Bupleuri (chai hu) andlicorice (Gan cao)Themain chemicals from XFZYD includeflavonoids organic acids terpenoids and steroidal saponins[20ndash22] The formula has been proven reliable and effectivefor curing various diseases including unstable angina pectoris[23 24] coronary artery disease [25] thromboembolic stroke[26] ischemic stroke [27] and TBI The therapeutic agent ofXFZYD is to promote blood circulation and remove bloodstasis according to the TCM theory Several randomizedcontrolled clinical trials and animal experiments have showeddefinite therapeutic effects of XFZYD for the treatment ofTBI [28ndash31] Recent researches demonstrate that XFZYDprovides neuroprotection via anti-inflammatory pathway andcognitive improvement through synaptic regulation [32 33]However merely these evidences to explain the multipletherapeutic mechanisms of TCM for TBI treatment areunavailable Because the effects of TCM are always contro-versial in terms of their abstract theory unclear basis com-plex interactions between various ingredients and complexinteractive biological systems [25] it is essential to developan advanced technique to deeply uncover the synthesizedpharmacological effects of XFZYD in the treatment of TBI

With the development of TCM modernization networkpharmacology has become a novel method to elucidate themulti-druggable targets effects of TCM [34] TCM networkpharmacology first proposed by Shao Li [35] makes itfeasible to understand the effective constituents and targetsof the herbs from TCM formula This analytical methodintegrates bioinformatics systems biology and polypharma-cology and further utilizes network analysis to imply themultiple actions of drugs across multiple scales ranging frommolecularcellular to tissueorganism levels [36 37] Coin-ciding with the holistic and systemic characteristics of TCMnetwork pharmacology is expected to bridge the gap betweenTCM and modern medicine [25] Previous researches haveclarified the scientific basis and systematic features of herbalmedicine to treat diseases through network pharmacologysuch asQing-Luo-Yin andMa-HuangDecoction etc [38 39]

In the present work we explored the pharmacologicalmechanisms of XFZYD acting on TBI via a network pharma-cology approach Network analyses and molecular dockingmethod were used to reveal candidate drug targets relatedto TBI Target analysis suggested that XFZYD regulatedseveral key biological processes of TBI development suchas apoptosis inflammation blood coagulation and axongenesis These processes contributed to the clarifying of themolecular mechanisms of XFZYD for TBI treatment Thiswill help to improve the effectiveness and specificity of TCMclinical usage (Figure 1 depicts a flowchart of the entireresearch procedure)

2 Methods

21 Database Construction The chemical ingredients of11 herbs in XFZYD were screened from Traditional Chi-nese Medicine Systems Pharmacology database (TCMSPhttplspnwueducntcmspphp) [40] As a chemically ori-ented herbal encyclopedia TCMSP can provide comprehen-sive information about herb ingredients including chemicalstructural data oral bioavailability drug targets and theirrelationships with diseases as well as the biological or physio-logical consequences of drug actions involving drug-likenessintestinal epithelial permeability and aqueous solubility [40]The structures of these compoundswere saved asmol2 formatfor further analysis Discovery studio 25 was employed tooptimize these molecules with a Merck molecular force field(MMFF) All detailed information about these ingredients isprovided in Table S1

22 Pharmacokinetic Prediction Due to the disadvantagesof biological experiments as being time-consuming and ofhigh cost identification of ADME (absorption distributionmetabolism and excretion) properties by in silico toolshas now become a necessary paradigm in pharmaceuticalresearch In this study 2 ADME-related models includingthe evaluation of oral bioavailability (OB) and drug-likeness(DL) were employed to identify the potential bioactivecompounds of XFZYD

Oral bioavailability (OB) one of the most importantpharmacokinetic parameters represents the speed of a drugof becoming available to the body and the eventuallyabsorbed extent of the oral dose [41] which is particularly sig-nificant in drug discovery of TCM formost oral Chinese herbformulas Poor OB is indeed the main reason responsible forthe unsuccessful development of compounds into therapeuticdrugs in drug screening cascades Here a reliable in silicomodel OBioavail 11 [42] which integrates the metabolism(P450 3A4) and transport (P-glycoprotein) information wasemployed to calculate the OB values of herbal ingredientsIn this study OBge30 (a suggested criterion by TCMSPdatabase) was regarded as one threshold for screening pos-sible candidate drugs presently while 2 compounds withOB le 30 were also taken into consideration due to theirtherapeutic effects according to literatures such as amygdalinand hydroxysafflor yellow A [43 44]

Drug-likeness (DL) is a qualitative profile used in drugdesign to evaluate whether a compound is chemically suitable

Evidence-Based Complementary and Alternative Medicine 3

TCMSP database Molecule information ofcompounds in XFZYD

Candidate compounds profile

Candidate targets profileCandidate targets overlap analysisamong three group of herbs

Candidate compounds overlapanalysis among three group of herbs

HB-cC-cT network

Known therapeuticproteins for TBI

TBI specific proteins

OB DL

STRING

Overlap analysis of targets betweenXFZYD and TBI specific proteins

Cytoscape 340

TTD amp OMIM

HB-pC-pT network TBI specific PPInetwork

Molecule dockingGO and KEGG

pathway analysis

Binding mode between potentialtargets and compounds in XFZYD

Biological significance of potentialtargets of XFZYD on TBI

Synergistic effects ofTCM formula

HPRDTarget prediction

Figure 1 A schematic diagram of the network pharmacology-based strategies for determining the pharmacological mechanisms of the herbalformula XFZYD on TBI

for drug and how drug-like a molecule is with respect toparameters affecting its pharmacodynamic and pharmacoki-netic profiles which ultimately impacts its ADME properties[45] In this study the drug-likeness (DL) index (see (1))using the Tanimoto coefficient [46] was computed for eachcompound in XFZYD

119879 (119883119884) =119883 sdot 119884

1198832 + 1198842 minus 119883 sdot 119884(1)

where X represents the molecular descriptors of herb com-pounds and Y is the average molecular properties of all com-pounds in Drugbank database (httpwwwdrugbankca)Compounds with DL ge018 (average value for Drugbank)were selected as bioactive compounds in XFZYD

In summary compounds with OB ge30 and DLge018were selected for subsequent research and others wereexcluded The criteria used here were mainly for (1) extract-ing information from the herbs as much as possible with theleast number of components and (2) explaining the obtainedmodel by the reported pharmacological data

23 Target Prediction To obtain the molecular targets ofthese active ingredients an in-house developedmodel SysDTbased on Random Forest (RF) and Support Vector Machine(SVM) methods [47] was proposed which efficiently inte-grated large-scale information on chemistry genomics andpharmacology This approach shows impressive performanceof prediction for drug-target interactions with a concordanceof 8283 a sensitivity of 8133 and a specificity of 9362

respectively [40] UniProtKB (httpwwwuniprotorg) wasemployed to obtain the standard name of the predicted targetproteins

24 TBI-Specific Protein Collecting The known therapeutictarget proteins of TBI were screened fromTherapeutic TargetDatabase (TTD available httpbiddnusedusggroupcjttd)TTD is a publicly accessible database which provides com-prehensive information about the known therapeutic proteinand nucleic acid targets described in the literature thetargeted disease conditions the pathway information and thecorresponding drugsligands directed at each of these targets[48] We also searched for Online Mendelian Inheritancein Man database (OMIM available httpomimorg) toget proteins related to TBI OMIM catalogues all knowndiseases with a genetic component and then possibly linksthem to the relevant genes in the human genome andprovides references for further research and tools for genomicanalysis of a catalogued gene [49] Then the proteinsacquired from both databases were used as hub proteinsand submitted to Human protein Reference Database [50](HPRD available httpwwwhprdorg) and STRING [51](httpsstring-dborg) to generate the proteins interactingwith these hub proteins HPRD is a database containingcurated proteomic information pertaining to human pro-teins The human protein-protein interaction (PPI) data onHPRD (Release 9) consists of 39240 interactions among 9617genesThe STRINGdatabase provides both experimental andpredicted interaction information providing a probabilisticassociation confidence score


25 Molecule Docking The LibDock algorithm based on theCHARMm Force Field in Discovery Studio (DS) 25 wasused in this study to evaluate the potential molecular bindingmode between bioactive compounds and putative targetsThecrystal structure of the target proteins of XFZYD for treatingTBI was downloaded from the RCSB Protein Data Bank(wwwrcsborg) The 3D chemical structures of bioactivecompounds were downloaded from PubMed Compounddatabase or TCMSP database and subjected to minimize theenergy by using molecular mechanics-2 (MM2) force fieldThe protein preparation protocol was used before dockingsuch as inserting missing atoms in incomplete residuesremoving water and protonating titratable residues The lig-and preparation protocol was employed before docking suchas removing duplicates enumerating isomers and generating3D conformations The protein-ligand docking active sitewas defined by the location of the original ligand All otherdocking and consequent scoring parameters were kept attheir default settings The compound was considered to be apotentially active ingredient if the LibDock score was higherthan the original ligand

26 Network Construction and Analysis Network construc-tion was performed as follows

(1) The herbs candidate compounds and candidate tar-gets of XFZYD were used to construct an herb-candidate compound-candidate target (HB-cC-cT)network

(2) The PPI data obtained above was used to establish theTBI-specific protein interaction network

(3) Herbs potential compounds and putative targetsfrom XFZYD for treating TBI were used to builda herb-potential compounds-potential targets (HB-pC-pT) network

(4) Potential targets and the biology process they partici-pate in were used to construct the pT-F network

(5) Compounds and targets through molecule dockingvalidating were used to build a compound-target (C-T) network

All networks were generated and analyzed by Cytoscape 340[52] an open source of bioinformatic package for biologicalnetwork analysis and visualization Two topological param-eters including degree and betweenness were calculated forthe obtained networks which disclose the significance ofa node

27 Gene Ontology (GO) and Pathway Enrichment Analy-sis The functional enrichment tool DAVID [53] (DAVIDhttpsdavidncifcrfgov) ver 68) was used to calculateboth the KEGG pathway and GO biological processes (BP)enrichment

28 Statistical Analysis All data were expressed as mean plusmnstandard deviation (SD) The molecule descriptors data wereanalyzed by one-way ANOVA The criterion for statisticalsignificance was p lt 005 Statistical analyses were conductedusing the SPSS 240

3 Results

TCM an experience-based medicine has been widely usedfor thousands of years It has accumulated abundant clinicalexperience forming a comprehensive and unique medicalsystem [35] The complexity of the phytochemical compo-nents makes it extremely difficult to illustrate the actionmechanisms of XFZYD from a molecule or system levelAs a chief mean of treating diseases clinically generallyTCM doctors prescribe formula based on the principle ofldquoJun-Chen-Zuo-Shirdquo ldquoJunrdquo (monarch) treats the main causeor primary symptoms of the disease ldquoChenrdquo (minister)enhances the actions of ldquoJunrdquo or treats the accompanyingsymptoms ldquoZuordquo (adjuvant) not only reduces or eliminatesthe possible toxic effects of the Jun or Chen but also treatsthe accompanying symptoms ldquoShirdquo (guide) helps to deliveror guide the other herbs to the target organs [18] Accordingto the unique feature of TCM ourwork tried to perform ldquoJun-Chen-Zuo-Shirdquo based system study to clarify the multiplemechanisms of XFZYD in the treatment of TBI

31 Herbal Ingredient Comparison and Target Predictionof XFZYD We obtained 162 components originated fromXFZYD Of these compounds 160 chemicals that were inaccord with standard requirements were searched from theTCMSP database The other 2 components amygdalin andhydroxysafflor yellow A were taken into consideration fortheir obvious pharmacological action as well The detailedinformation of these compounds is showed in Table S1Persicae Semen (Tao ren) and Carthami Flos (Hong hua)the Jun (monarch) herbs of XFZYD contained 36 bioactivecomponents which accounted for 22 of the 162 chemicalsRadix Paeoniae Rubra (Chi shao) Chuanxiong Rhizoma(Chuan xiong) andAchyranthis Bidentatae Radix (Niu xi) theChen (minister) herbs contained 31 bioactive componentswhich accounted for 19 of the 162 chemicals AngelicaeSinensis Radix (Dang gui) Rehmannia glutinosa Libosch(Sheng di huang) Platycodon Grandiforus (Jie geng) AurantiiFructus (zhi ke) Radix Bupleuri (chai hu) and licorice (Gancao) the Zuo-Shi (adjuvant and guide) herbs of XFZYDcontained 109 bioactive components which accounted for67 of the 162 chemicals Ingredients from these herbswere compared based on the 6 important drug-associateddescriptors including molecular weight (MW) number ofhydrogen-bond donors (nHdon) number of hydrogen-bondacceptors (nHacc) partition coefficient between octanol andwater (AlogP) oral bioavailability (OB) and drug-likeness(DL)The distributions of the 6 descriptors of the ingredientsfrom the three groups are shown in Table 1 and Figure 2 Wefoundno significant differences in the values ofMW(p=016)nHdon (p=032) nHacc (p=061) and AlogP (p=082) amongthe 3 groups However the average OB value of compoundsfrom the march herbs is 5559plusmn2391 which was significantlydifferent from the Chen herbs (OB=4564plusmn1327 P=0004)and the Zuo-Shi herbs (OB=4877plusmn1505 P=0021) Thefollowing 2 groups had no significant difference in OBvalue (P=0272) As for DL the Chen herbs revealed thehighest DL index (053plusmn023) which displayed significantdifference from the Zuo-Shi herbs (044plusmn019 p=0012) while


Table 1 Comparison of molecular properties among the Jun Chen and Zuo-Shi herbs

INDEX MW nHdon nHacc AlogP OB DL(mean plusmn SD) (mean plusmn SD) (mean plusmn SD) (mean plusmn SD) (mean plusmn SD) (mean plusmn SD)

Jun herbs 38028 (9423) 265 (226) 511 (321) 337 (436) 5559 (2391) 049 (018)Chen herbs 38180 (9160) 218 (195) 55 (347) 314 (315) 4564 (1327) 053 (023)Zuo-shi herbs 35745 (8822) 261 (160) 56 (249) 344 (185) 4877 (1505) 044 (019)OB oral bioavailability MW molecular weight DL drug-likeness AlogP partition coefficient between octanol and water nHacc number of hydrogen-bondacceptors nHdon number of hydrogen-bond donors

Table 2 Top 10 candidate compounds according to 2 centrality indicators

Compounds Degree Compounds Betweennessquercetin 153 quercetin 035875838kaempferol 65 naringenin 008768253luteolin 48 kaempferol 007665228wogonin 46 luteolin 0057362047-Methoxy-2-methyl isoflavone 44 baicalein 005542898beta-sitosterol 41 beta-sitosterol 0041007baicalein 40 wogonin 003968963formononetin 39 Stigmasterol 003586788naringenin 39 nobiletin 003057461isorhamnetin 38 formononetin 003051437

showing nodifferencewith the Junherbs (049plusmn018 p=0333)Figure 3(a) indicated that 5 bioactive compounds wereshared by the Jun Chen and Zuo-Shi herbs One compoundoverlapped between the Jun andChen herbs while there were2 compounds shared by the Chen and Zuo-Shi herbs Onecompound overlapped between the Jun and Zuo-Shi herbs

32 Target Prediction of XFZYD A total of 285 potentialtargets from the 162 compounds were generated using thetarget prediction model The amounts of potential targets hitby the Jun Chen and Zuo-Shi drugs were 217 218 and 261respectively The detailed data of the targets is shown in TableS2 As depicted in Figure 3(b) there was a significant targetoverlap among the 3 groups (189 candidate targets) but lessoverlap between the Jun andChenherbs (9 candidate targets)The number of targets shared by the Jun and Zuo-Shi herbswas 14 while 10 targets were overlapped between the Chenand Zuo-Shi herbs

33 HB-cC-cT Network Construction and Analysis We nextestablished aHB-cC-cT network through network analysis toilluminate the relationship among the herbs candidate com-pounds and candidate targets (Figure 3(c)) This networkconsisted of 485 nodes (11 herbs 162 candidate compoundsand 285 candidate targets) and 2585 edges A herb (triangle)and cC (square) are connected if the compound is containedin this herb and the edges between cC and cT represent theinteraction The size of nodes is proportional to the valueof degree The larger size of the node means more phar-macologically important Two centrality indicators degreeand betweenness identify the important nodes within thenetwork Different centralities reflect different importanceof nodes in a network from different angles Interestingly

both of the two types of centrality indicators uniformlyconfirmed themost important 10 candidate compounds fromXFZYD and the top 10 targets anchored by XFZYD (Tables2 and 3) Figure 3(c) demonstrated that licorice possessedthe largest degree (88) compared with other herbs originatedfrom XFZYD This implicated that it contained the mostbioactive compounds (88) including quercetin (Mol 148degree=153) kaempferol (Mol 108 degree=65) 7-Methoxy-2-methyl isoflavone (Mol 33 degree=44) formononetin (Mol63 degree=39) naringenin (Mol 133 degree=39) isorham-netin (Mol 105 degree=38) medicarpin (Mol 131 degree=35)and licochalcone a (Mol 113 degree=33) followed byPersicae Semen (degree=19) Carthami Flos (degree=18)Achyranthis Bidentatae Radix (degree=17) Radix PaeoniaeRubra (degree=14) Radix Bupleuri (degree=12) ChuanxiongRhizoma (degree=6) Aurantii Fructus (degree=4) Platy-codon Grandiforus (degree=4) Rehmannia glutinosa Libosch(degree=3) andAngelicae Sinensis Radix (degree=2) PersicaeSemen (degree=19) and Carthami Flos (degree=18) the Junherbs from XFZYD possessed 29 specific compounds and5 unique target proteins including ALB CTNNB1 MMP10LYZ andNFKB1 Twenty-three Chen-specific potential com-pounds targeted 10 specific proteins including CD14 LBPNR3C1 BBC3 TEP1 PRKCD FN1 PDE10A GSTA1 andGSTA2 The Zuo-Shi herbs possessed the largest number ofspecific compounds (101) and 48 unique proteins such asHTR3A ADRA1D PYGM OLR1 CHRM5 RXRB STAT3MAPK10 OPRD1 and MAPK3 There were 189 proteinsanchored by the Jun Chen and Zuo-Shi drugs

Among the 162 candidate compounds quercetin hadthe largest value of degree (153) implicating its critical rolein XFZYD The four herbs namely Carthami Flos (Jun)Achyranthis Bidentatae Radix (Chen) and licorice and


50

40

30

20

10

0

50

40

40

30

20

20

10

0

0

10 30 50 70 90 110

60

60

60

01 02 03 04 05 06 07 08

225 275 325 375 425 475 525 575 625 minus6minus5minus4minus3minus2minus1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

minus2 minus1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

70

minus1 1 3 5 7 9 11 13 15 17

perc

entage

s (

)

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

perc

entage

s (

)

40

20

0

60

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

OB

MW

nHdon

DL

nHacc

Distribution

Distribution

Distribution

Distribution

Distribution

Distribution

AlogP

Jun herbsChen herbsZuo-Shi herbs






Figure 2 The profile distributions of six important molecular properties for all ingredients from the Jun Chen and Zuo-Shi herbs OBOral bioavailability MW molecular weight DL drug-likeness AlogP partition coefficient between octanol and water nHacc number ofhydrogen-bond acceptors nHdon number of hydrogen-bond donors


Jun herbs(29)

Zuo-

Shi h

erbs

(101

)

Chen herbs

(23)

1

2

15

(a)

Jun herbs(5)

Zuo-

Shi h

erbs

(48)

Chen herbs

(10)

9

10

14189

(b)

20Mol 1200000

MMMol 152Mol 15Mol 1521Mol 15Mol 15

Mol 8888

Mol 29Mol 2Mol 2Mol 2Mol 29

Mol 3Mol 3Mol 35Mol 3535

1Mol 121Mol 121Mol 122

Mol 124Mol 124Mol 1Mol 124Mol 124Mol 124

MMol 10Mol 1Mol 10M 00MMMM

MMol 73Mol 77333222

ABATABATA

MAPK3MAPKMAPK

UGT1A1GT1UGT1A1

GOT1GOTT1

SREBF1REBFSREBF1

RXRBRXRBRXRB

CYP19A1CYP19A1YP19A

PLB1PLBPLB1

FASLGFASLGASL

BCHEBCHHE

HSD3B1HSD3

MTTPMTT

CES1CES

TIMP1TIMP

ATP5BATP5

MAPK10MAPK 0

BADBAD

CHRM5CHRM5

EPHBEPHBPHB2

HSD3B2HSD3B2SD3B

SOAT2OATSOAT2

FASNFASNFASN

MT-ND6MT-N

HTR3AHTR3HTR3APLA2G4APLA2G4AA2G

PKIAAIA

ADH1AADHAD

AKR1C1KR1AKR1C1

CREB1CREBB1

HMGCRMGHMGCR

SOAT1OAT

ABCC1ABCC

OPRD1OPRDOPRD1

VCPVCP

LDLRLDLR

ADRA1DDRAA1D

NFATC1FATCFATCATCFATCA

EGLN1GLNGLNGLNGLN

FABP5ABP5ABPABPABPABP5

CYCSCYCSCYCSCYCSYCSFOSL1OSLOSLOSLOSL

ALOX12LOXLOXOXLOX

TDRD7DRDDDRDDRDDRDAPODAPODAPOPOAPOD

NNNNOXNOXNOXNOX5NOXX

Mol 40

NFKB1NFKBFKBFKBFKBLYZLYZLYZZLYZ CTNNB1TNNBTNNNNNN MMP10MMPMPMPMMP1ALBALBALBALBALB

3Mol 433MMol 28Mol 28Mol 2Mol 28

HSPA5SPASPASPA5HSPA5AERBB2ERBB2ERBBRBBB2ERBB2

HSPB1HSPBSPBSPBHSPB1HSPB1B

NQO1NQO1NQONQO1NQONQO1TOP1TOP1TOP1TOPTOPT

PORPPORPORPORPORR ACPPACPPACPPACPPCPP

SLC2ALC2A4LC2A4C2A4LC2A4LC2A4LC

SERPINE1SERPINE1PINRPINERPINPIN

JUNJUNNJUNNN

PTGER3PTGER3TGERTGERGERTGER

COL1A1OL1AOL1AOL1AA1CO

SSLPISLPSLPISLPISLPII

CCCALCCC MMMMMMSS

MMMMP1MMPMMPMMPTNFTNFTNFFTNF

CCND1CCNDCCNDCNDCNDCCND

SMDPSMDPSMDPSMD3PSMD3PSMDNFNFNFFFNF

ELK 1ELKELK LK ELK ELK CCL2CCL2CCLCCL2CCL2CCL2

MMol 14MMol 14Mol 1447

MMol 15MMol 1Mol 115Mol 15M

Mol 122Mol 122Mol 122MMol 12Mol 122222

MMol 24Mol 2Mol 2Mol 2444

Mol 78MMol 78Mol 7Mol 7Mol 788

Mol 38MMMMol 3Mol 3338

Mol 154Mol 154MMol 15ol 1ol 155M

Mol 67MMol 6Mol 6Mol Mol 67Mol 677766


Mol 48Mol 48MMMol 4Mol 4448M 4

PPPPARAPARPARPAR

PCOLCEPCOLCECOLCOLCCOLC

SPP1SPP1SPP1PP1SPPP1 AKR1C3AKR1C3KR1CKR1CKR1CKR

NNNOSNN 2222 DUOXDUOXDUOXDUOX2DUOXDUOX2

MCL1MCL1MCLMCLMCLMCL

PARP1ARP1ARPARPPARP1PEEMPOMPOMPOMPOM DDDUDUDUDDU

NGASYNGASYNGAP1NGAPNGAAP1RARAARARA

BAXXXXB X ESR1

GSTM2GSTM2GSTMSTMSTMGSTMSHSAAHSAAHSA1AHSA1AHSAHSAA GABRAGABRA2GABRA2GABRAGABRAGABRAMM2MMM2

CHRM2CHRM2CHRMHRMHRMCHRM2

VDRVDRVDRRVDRVDRARGABRA1GABRA1GABRAA11GABRA1G

IL888IL88

PPPPRSPRSPRSSSSSSSPPARDPARDPARPARDPARDPARDSELESELESELESELEEE

COL3A1COL3A1OL3AOL3AOL3AA1OL3ARB11111

CYP1A2222222 NCOANCOANCOANCOANCOANCOA22222211111 RRRRRR

Quercetin

Mol 9444444

Mol 99

Mol 63

Mol 75555

Mol 37Mol 37Mol 37Mol 37MolMol 33Mol 37MolM

Mol 158


Mol 49Mol 4Mol 4Mol 4Mol 44Mol 494Mol 4

Mol 6Mol 6666M 66

MMol 60Mol 60Mol 6MM



Mol 11MMol 1155Mol 11555M6060660

Mol 85Mol 85Mol 85MMol 88558554MMol 114Mol 114444M

Mol 116Mol 116Mol 116MMol 1ol 1Mol 11616M 1

Mol 9000

Mol 100Mol 1000Mol 106MMMol 106Mol 10Mol 1066Mol 322 Mol 30Mol 30Mol 30000MM

Mol 140MMol 14MMol 14Mol 1440Mol 14

PlatycodPlatycodatycodPlatycodP ononoGrandifondifoGrandGrand rususus

RadiRadixR diBupleurBupleuriBupleuriu

RehmanniRehmanniRehmanniiaaaglutinosglutinolutinoglutin aaaLiboschLiboschLiboschLLiLiLicoricececece

AngelicaAngelicaAngelican l eeSinensisSinenS nensisnensis

Radixadixdix

Mol 84

Mol 23 Mol 130Mol 13Mol 13Mol 11Mol 130Mol 13Mol 1MMol 13


0Mol 200000

Mol 34Mol 3Mol 3MolMol 3344Mol 3Mol 134

Mol 151

Mol 126Mol 126Mol 12666

Mol 8111AurantiiAurantAuranAurantiitFructusructusFructuructuFr


Mol 444


Mol 133

Mol 123MMol 12Mol 12ol 1Mol 121

Mol 142Mol 1422

Mol 36

0Mol 80Mol 88Mol 80M 80

Mol 277Mol 135Mol 13555M 555

Mol 141MMol 144Mol 14111

Mol 104Mol 104MMMol 10Mol 104044M

Mol 922222Mol 22 Mol 2Mol 2Mol 2Mol Mol 2Mol 22M 2

MMol 83333

Mol 110Mol 110

Mol 119MMol 11999999

Mol 88888 Mol 109Mol 10MMol 1Mol 100Mol 109M

Mol 5444

Mol 39999999

Mol 150MMol 155000M 0

Mol 611

21Mol 21MMol 221111

Mol 13

Mol 9Mol 91MMol 9911

Mol 118MMol 11Mol 1Mol 11Mol 1Mol 11ol

Mol 466

Mol 96Mol 96Mol 96Mol 996Mol 9696 Mol 53Mol 5Mol 5MolMol 5Mol 5Mol 535Mol 50Mol 50Mol 5Mol 5Mol 550Mol 5

Mol 107Mol 107MMol 10077Mol 1077

M l 149MMol 1449Mol 149Mol 149

Mol 14Mol 1444

Mol 89Mol 125MMol 1ol 1Mol 12MMMol 1MM

Mol 87

Mol 72MolMol 7Mol 7MolMol 72M 7M Mol 933Mol 112Mol 112Mol 112Mol 1122M

Mol 1Mol MMolMollMol 1Mol Mol 105

MAP2MAP2MAPMAPMAP

IL2I 2L22L22

SLC6A2LC6A2LC6A2LC6A2C6A2S

GABRA5ABRAABRGABRA5AABRCHRNA2CHRNA2HRNA2HRNHRNA2HRNA2

DRD1D1DRDDRDDRDDD1 MMAPKMAPK1MAMADRA1AADDDRADRA1ADRAADRA1A CASP3CASP3CASP3CASP3C

F2

Mol 17 Mol 7666Mol 33


Mol 161Mol 161Mol 161Mol 16Mol 16161MMo


Mol 97Mol 162MMol 16Mol 1Mol 1ol 111M 1

Mol 131

Mol 99Mol 9MMMolMol 9MMol 9Mol 99Mol 9ol

Mol 111

Mol 128Mol 128Mol 1ol 1Mol 121MolMol 199Mol 117Mol 117777

Mol 744444Mol 77

2Mol 52Mol 52Mol 5MM

MMMol 5Mol 5MMol 5Mol 5Mol 5M

MMol 58Mol 58Mol 58M 8

Mol 138MMol 1388M

Mol 102Mol 102Mol 10Mol 102MMol 10Mol 10

Mol 42MMMol 42M

MMMol 3Mol 3

Mol 137Mol 13Mol 13ol 13Mol 13Mol 13733

Mol 59Mol 59olMol 5Mol 59oMol 5Mol 559

Mol 129lMol 12ol 12ol 12Mol 129o 2ol 12o

Mol 62Mol 62Mol 6Mol 6Mol 6Mol 62Mol 6Mol 6ol

Mol 144Mol 144Mol 14Mol 14ol 14Mol 144ol 1

AchyraAchyraAchyranthisnthisnthisBidentBidentBidentataeataeatae

RadixRadixRadix

Mol 139Mool 13ol 13ol 139Mol 139Mool 13

ChuanxioChuanxioChuanxiongngngRhizomaRhizomaRhizoma

Mol 159Mol 159MoMol 15ol 15ol 15Mol 159o 5

Mol 136Mol 136ol 13ol 13ol 1ol 13ool 13

CXCL11CXCL11XCL1XCL1XCLXCL1p53p53p53p

Mol 47Mol 47Mol 4Mol 4Mol 4ol 47Mol 4o

MMol 156ol 15ol 15ol 1ol 15ooPRKCARKCRKCPRKCACARKC

PPP3CAPP3CAP3CAP3CAP3CAPPP3CAP

CDKN1BDKNDKNDKN1CDKN1BPTENPTENPTENPTENPTENPTENBBB

RadixRadixRadixPaeoniaePaeoniaePaeoniaePae

RubraRubraRubraNR1I3NR1I3NR1INR1INR1INR1I3

HERC5ERCERC5HERC5ERC5OODC1ODCODCODC1CERBB3RBBRBBERBB3RBBRBB3

CTSDCTSDCTSDCTSDCTSDCTSD Mol 18Mol 1Mol 1ol 18Mol 18MolMol 1

PLATPLATPLAPLATPLATL

DIOOO1OO1OEGFEGFEGEGFEGDIODDIODIO

BIL1BIL1BIL1BIL1BB

MMP 3MMP 3MMP 3MMPMMP 3M

THBDTHBDTHBTHBTHBTHBD

CYP1B1YP1BYP1BYP1BYP1BB1

PPPPPARPP GGGGGGPPP

KDR LLAACTACTACTLACTBLACTBACTTT

ESR2

CHEK1CHEK1CHEK1CHEK1CHEK1CHEK111CCHEK1C

CATCATCATCATTTCATCATT

CDK2

CCNA2CCNA2CCNA2CCNA2CCNA2CCNA2CCNA2CCCNA2CC

PIM1 GSK3B

MAPKKK1414MMAPKKKMM KMMM

IL10IL10IL10IL10IL10IL10

S2HAS2HAS2HAS22HAS2ADADDHDH1CADAD HAHAHHHHA

CDKN2ACDKN2CDKNCDKNDKN2ACDKN

Mol 155Mol 155Mol 15Mol 15Mol 15ol 1ol 15ol 15Mol 15MMo

Mol 153Mol 15Mol 15ol 15Mol 153ol 15Mol 15Mol 15

CHEKCHEKCHEKHEK2HEK2HEK

MMP2MMP2MMPMMPMMPMMP2

MGAMMGAMMGAMGAAM

KCNH2222

CXCL2CXCL2CXXCLXCLXCL

GJA1GJA1GJAGJA1GJA1GJA1KK222K2

IKBKBIKBKBIKBKBIKCNH2KCNH2

IFNGIFNGIFNGIFNGIFNGIFNGFNEIF666F6IGHG1IGHG1GHGIGHG1IGGHG

SSStigSStiggmmmaS gg steeerolerol

PPTPNPTPN1PTPN1P 1SCN5ASCN5AASCN5ASCN5A BetaBetaaaa-sata istosssststerolerolllroNR3C1R3CGSTA2STA BBC3BBC3LBPLBP TTEP1TEP1 RKCDPRKCD PDE10ADE10GSTA1STA FN1FN1CD14CD14

BACE1ACEBACE1 SLC6A1LC6AACD163CD16 GSRGSRR ADIPOQDIPOQSTAT3TATOPRM1OPRM1OPRMOPRMOPRMO ADRA1BADRA1BAADRA1BBBB

SLC6A4LC6ALC6ASLC6A44SLCYCYP1A1YP1A1YP1A1CYP1AYP1A1

SLC6A3SLC6A3SLC6ASLC6A3SLC6A3

PDE3APDE3AA

CHRNA7CHRNA7HRNAHRNAHRNAA

PPPTGPP S1S1S1S1SS111NKX3-1NKX3-1NKX3KX3NKX3NKX3-

BIRCBIRC5BIRCBIRCBIRC55

IL6666

HK2HK2HK2HK2HK2HK2

RUNX2UNXUNXUNXRUNX2UNXHSF1HSF1HSF1HSF1HSF1HSF1

IGFBP3GFBPGFBPFBPIGFBP3

STAT1T1TAT1TATSTAT1TATT

NCF1NCFNCFNCF1NCFN

PRSS3RSSSIRT1SIRTGATMGAT OLR1OLRAPOBAPOPYGMPYGM

TGFB1GFBGFBGFBGFBTGFB1F10 MMP9MMPMMPMMPP9PNFE2L2FE2LFE2LFE2LNFE2L2FE2L2L

Mol 160Mol 44Mol 44ol 4Mol 444Mol 444ol 4ol 4ol 44

Mol 55MoMol 5Mol 5Mol 555Mol 55Mol 5Mol 5MoMol 5

MMMol 132

MMMol 57

CRPCRPCRPCRPPHH

RUNX1T1UNX1NX1NX1NX1T1R

BCGABCGABCG2BCGA

CXCL10CXCL10XCXCLCXCLCXCL IGG

CLDN4LDN4LDN4LDN4ABABABAAB RRAHRAHRBBBIB

RARRAF1RAF1RAF11KKKKKKaemKKKKK pffefeferereerf referololol

CASP9CCASPCASP9PMDM2MDMMMDMMDMMDM2MDMMDM

BMAOBMAOBMAOBMAOBMAOBINSRINSRINSRINSRINSRRRNCOA1NCOA11NCOA1

HTR2AHTR2HTR2HTR222A

CHRMCHRMCHRM3MM3BCL2LCL2CL2L1LCL2BCL2L1111 CHCCHCCCCH

BCL2222BCL2CASP8CASP8CASP8CASP8CASP

RELARELARELAAAR

BaicalBaicalBaBaicalcacacalicaBB calcaac ininininininninninnCHUCHUKHUKCHUKHUKUKH AAAAAA

EGFREGFRGFREGFREGFR

NFKBIAFKBIFKBFKBNFKBIAFKBI

E2F2E2F2E2F2E2F2E

APPAPAPPAPPPAPPAPPA

CASP7CASPCASPASPCASPCASPPP IL4IL444L4L44

NUF2NUFNUFNUFNUFNUFNUFNUFN

CDK4CDKCDKCDKCDKCDKCD

XIAPXIAPXIAXIAXIAXIAX MEMEMETMETMETMEETMMME

ADCY2ADCYDCYDCDCYDCD

Mol 127

NNR3C2NR3C2NR3CNR3C2N

DPP4

DCAF5DCACAFDCAF55DCAFAKR1B1AKR1BKKR1BKR1BKR1BCTRB1CTRBTRBCTRBCTRB

LTA4HLTA4LTA4TA4LTA4LTA4H4

XDHXDHXDHHHXDH

PTGS2

Mol 51Mol 51Mol 5MMolMolMol 5Mol 5MMol 5

Mol 145Mol 14Mol 14ol 1ol 1ol 1Mol 1Mo

Mol 146MMMMool 1ol 11461

Mol 143Mol 14Mol 14Mool 1ol 11Mol 1411

Mol 70MMMolMol 7Mol 77Mol 70Mol 7Mol 7

Mol 71Mol 7Mol Mol 777Mol 71Mol 7Mol

Mol 25Mol 25MMMol Mol 22Mol 2

Mol 79Mol 7Mol 7Mol Mol 7Mol 779MM 7

Mol 26Mol 26MMol 2Mol Mol 22Mol 2M 22

CA22222222ADH1BADHADHDHADH1ADH1DH KCNMA1CNMCNMCNMCNMKCNMAKCNMCGABRA6GABRAABRAABRAABRAGABRAGA A6GA RAGRIA2GRIAGRIAGRIAGRIAAAA2GRIA

RASSFRASSF1ASSFASSFASSF

Mol 31MMol 3Mol 3Mol 3311M 3Mol 98Mol 98Mol 98MMol 9Mol 999Mol 98MM

GSTP1GSTP1GSTPGSTPGSTPGSTPF33333

Mol 69Mol 6MMol 6Mol 6Mol 66Mol 69Mol 69M 66

VCAM1VCAMCAMCAMVCAM1C

MAPK8MAPK8MAPKMAPMAPKM

CYP3A4CYP3A4YP3AYP3AYP3AY

Mol 68Mol 68MMol 6Mol 6Mol 66MMol 68Mol 6MMol 16Mol 16Mol 1Mol 1Mol Mol 1Mol 16

MMMMol 6MMol 66Mol 666Mo

CCartCarta hamihamimiiiiiFlosFlosFlosossoss

Mol 9566Mol 65Mol 6Mol 6MMol MolMol 6M 666M

PersPersPerserrr icaeicaeicaesemesemesemeemememeem nnn

ICAM1CAMCAMM1CAMI

E2F1E2FE2F1E2F1E2F1ENPEPPSPEPPSPEPPSEPPSPEPPSNPEPP

IGF2IGF2IGF2IGF2F

FOSFOSFOSFOSSFOSFOSSSS

CCNB1CCNBCNBCNBCCNB1CCNB1CDK1CDK1CDKCDKCDKCC

PRKCBPRKCBRKCRKCRKCR CB

CHRM1CHRM11CHRM11

HHHHSP9HHHH 0ABABAB2B2B2B2PPPPPPPPPPPPTOP2A ACACACACACACACACAACACAACACA

PRKACA

TOP2TOP2

My c FF7FFIRF1IRF1IRF1IRF1IRF1IR

CAV1CCAVCAVCAV1V1CAV1

ACHE

ADRB1ADRBRBADRBADR

ADRADRADRA2A2AA2A

SOD1SSODSOD1D11

NOS33

PLAUPLAUPLAAUUPLAUPRXRA

PGR

HHMOX11MOXMOXHMOX

GSTM1GSTM1GSTMGSTMSTMAAA

HIF1AHIF1HIF1HIF11AHIF1A

FOSL2OSLOSLOSL22FO

ALOX5ALOXALOXALOXALOX5

VEGFAVEGFAVEGFAVEGFAV FFA

PON1PONPONPONN1PON

PIK3CGPIK3CGGG

SULT1E1SULT1E1ULT1ELT1LT1GAGAABRAGABRA3AGG

AKT1AKTT1AKT11A

CHRMCHRMCHRMCHRM4CHRM4RMM

MAOAMAOAMAOAMAOMAOCD40LGCD40LGCD40LGD40LGCD40LGCD40LBRA3RAAABRA3CHRCHHHCHR

ADRB2

(c)

Figure 3 HB-cC-cT network of XFZYD (a) and (b) The distribution of different candidate compounds and targets in the network (red theJun herbs-specific cC (a) and cT (b) aqua the Chen herbs-specific cC (a) and cT (b) periwinkle the Zuo-Shi herbs-specific cC (a) and cT(b) claybank common cC (a) and cT (b) between the Jun and Chen herbs blue common cC (a) and cT (b) between the Jun and Zuo-Shiherbs green common cC (a) and cT (b) between the Chen and Zuo-Shi herbs purple common cC (a) and cT (b) among the 3 group ofherbs (c) The triangles with circle backgrounds represent the herbs (HB) the squares and circles represent the candidate compounds (cC)and candidate targets (cT) The red triangles squares and circles represent corresponding HB cC and cT in the Jun herbs the same is toaqua representing the Chen herbs and periwinkle representing the Zuo-Shi herbs The claybank squares and circles represent correspondingcC and cT overlap between the Jun and Chen herbs the same is to blue representing the overlap between the Jun and Zuo-Shi herbs and thegreen representing the overlap between the Chen and Zuo-Shi herbs The purple squares and circles represent the corresponding cC and cTshared by the 3 group of herbs The size of the node is proportional to the value of degree

Radix Bupleuri (Zuo-Shi) contained quercetin It targeted149 bioactive proteins PTGS2 (degree=126) HSP90AB2P(degree=85) AR (degree=81) NCOA2 (degree=75) PRSS1(degree=68) PTGS1 (degree=67) PPARG (degree=66)and F10 (degree=60) were predicted as the major candidatetargets of quercetin followed by kaempferol (degree=65)which was contained by Carthami Flos (Jun) AchyranthisBidentatae Radix (Chen) and Radix Bupleuri licorice(Zuo-Shi) It targeted 61 bioactive proteins includingPTGS2 (degree=126) HSP90AB2P (degree=85) CALM(degree=81) AR (degree=81) NOS2 (degree=76) andNCOA2 (degree=75) Quercetin stigmasterol kaempferol

baicalin and beta-sitosterol existed in 3 the Jun Chenand Zuo-Shi drugs demonstrating crucial roles of thesecomponents The 5 ingredients in the Jun Chen and Zuo-Shiherbs targeted 186 bioactive proteins which accounted for65 targets of XFZYD Baicalein existed in the Jun andChen herbs Luteolin existed in the Jun and Zuo-Shi herbsSpinasterol and sitosterol existed in the Chen and Zuo-Shiherbs 126 bioactive compounds targeted PTGS2 followedby ESR1 (88) HSP90AB2P (85) AR (81) CALM (81) NOS2(76) NCOA2 (75) PRSS1 (68) PTGS1 (67) and PPARG(66) As depicted in Figure 3(c) these target proteins wereanchored by ingredients in the 3 group drugs


Table 3 Top 10 target proteins of XFZYD according to 2 centrality indicators

Proteins Degree Proteins BetweennessPTGS2 126 PTGS2 0128936ESR1 88 NCOA2 0060806HSP90AB2P 85 HSP90AB2P 0049647AR 81 PRKACA 0046484CALM 81 PTGS1 004365NOS2 76 AR 0030252NCOA2 75 PRSS1 0025575PRSS1 68 ESR1 0022212PTGS1 67 PPARG 0021403PPARG 66 PGR 0020685Note the centrality indicators identify the important nodes within the network Higher degree centrality and betweenness centrality indicate greaterimportance

The analysis of the network revealed that quercetin (Mol148) kaempferol (Mol 108) luteolin (Mol 127) wogonin (Mol160) 7-Methoxy-2-methyl (Mol 33) and beta-sitosterol (Mol41) were predicted as the major active compounds of XFZYDTheproteins including F2 NOS2 PTGS1 PTGS2 and CALMwere predicted as essential pharmacological proteins for thetherapeutic effects of XFZYD

34 Analyses on TBI Based Specific Protein Interaction Net-work Network biology integrated with different kinds ofdata including physical or functional networks and diseasegene sets is used to interpret humandiseases Protein-proteininteraction networks (PPI) are fundamental to understandthe cellular organizations biological processes and proteinfunctions [54] From the systematic perspective the analysisof TBI-related PPI will improve the understanding of thecomplicated molecular pathways and the dynamic processesunderlying TBI We screened the TBI-specific genes andprotein targets using Online Mendelian Inheritance in Mandatabase (OMIM) and Therapeutic Target Database (TTD)Figure 4 indicated that 21 TBI-specific genesproteins wereacquired Further these hub-proteins were submitted toHPRD and STRING to establish the TBI-specific proteininteraction network The detailed information of the TBI-specific proteins is shown in Table S3 The results suggestedthat the network consisted of 489 nodes and 5738 edges(Figure 4(a)) We obtained top 10 TBI-related proteinsaccording to 2 centrality indicators generated and summa-rized in Table 4 Interestingly we found that the node withhigher betweenness tends to possess larger degree (Fig-ure 5) Network topology analysis showed that protoonco-gene tyrosine-protein kinase Src (SRC degree=164 between-ness=0059) RAC-alpha serinethreonine-protein kinase(AKT1 degree=157 betweenness=0045) Serum albumin(ALB degree=153 betweenness=0069) Epidermal growthfactor receptor (EGFR degree=139 betweenness=0053)and Amyloid beta A4 protein (APP degree=134 between-ness=0072) contributed to the essential role in the patho-physiology of TBI All of these indicated that the top mutualtarget proteins performed various beneficial functions to treatTBI at the molecular level For example SRC is activatedfollowing engagement of many different classes of cellular

receptors It participates in signal pathways that controla diverse spectrum of biological activities including genetranscription immune response cell adhesion cell cycleprogression apoptosis migration and transformation [55]SRC can result in blood-brain barrier (BBB) disruptionand brain edema at the acute stage the inhibition of SRCfamily kinases can protect hippocampal neurons and improvecognitive function after TBI [56] AKT1 regulates manyprocesses including metabolism proliferation cell survivalgrowth and angiogenesis [57] The PI3KAKTPTEN path-way has been shown to play a pivotal role in neuroprotectionenhancing cell survival by stimulating cell proliferation andinhibiting apoptosis after TBI [58] ALB is the main proteinof plasma and can be a biomarker to predict outcome ofTBI [59] Its main function is the regulation of the colloidalosmotic pressure of blood We found that it may participatein pathological process of TBI

KEGG pathway analysis was also used to determine thefunctions of proteins Table 5 describes the top 10 significantlyenriched KEGG pathways These pathways play crucial rolesin pathophysiology process which have also been widelydiscussed in existing literature For instanceMAPK signalingpathway can promote pathological axonal death throughtriggering a local energy deficit [60] Neurotrophin signalingthrough Trk receptors regulates cell survival proliferationthe fate of neural precursors axon and dendrite growth andpatterning and the expression and activity of functionallyimportant proteins such as ion channels and neurotransmit-ter receptors [61] Engagement of cells with the extracellularmatrix (ECM) proteins is crucial for various biological pro-cesses including cell adhesion differentiation and apoptosiscontributing to maintenance of tissue integrity and woundhealing [62]The 47 TBI-specific proteins targeted byXFZYD(yellow and green) were further discussed below

35 HB-pC-pT Network pT-F Network Construction andMolecule Docking Analyses of XFZYD for the Treatment ofTBI To investigate the therapeutic mechanisms of XFZYDfor the treatment of TBI a HB-pC-pT network of XFZYDfor treating TBI was built (Figure 6) 47 TBI-specific targetproteins (circles) were targeted by 119 potential compounds(squares) from XFZYD (Figure 6) Detailed information


BLMH

GPRASP2

GJC2

CAMK2N1

OBSL1

ZNF292

RLFAMPD3

NANOS1CAMTA1HYPKCCS

DLGAP4PF4V1

TRIM2

CHKB

F8A1

TIAM1

BMX

RAPGEF1

APBB1

KCNMA1

XRCC6

TTR

TGM2MAP2

PRNP

RASGRF1 PPP3CADMD SPTAN1

ACE

TGFB2

AP2M1GRAP2

SCN5A

MYH9

PKN1

ACHE

SLC25A13

PHKG1

SPAST

UMOD

PRPF40B

BBC3

TUBA4A TTPALRYR2

STUB1KRT6A

AKAP8L

GFI1BTHRAP3

ZNF232

SOD1

CRKL

CDH2

MBP MAP2K2

DCN

MAP3K5NGFR

PIK3CA

ITGA2

DNM1

RAP1A

GRIN2B

PTPN11

PRKCA

LDLRAP1

DNAJA3INA

SP3

CACNA2D3

CSF1

CNTF

TNFRSF1B

BCL10

KLC1

DCTN1

IDE

SERPINA3

HSPA1A

HSPG2

FN1

LRP2

TUBB

GRIN2A

YWHAB

CAMK2D

HTRA2

PRKCE

CRYAB

APC

GIT1

PIAS4

HPX

TRIP10

PDE4B

MARK4

PLAT

UBE2K

APOC2

LIN7B BGN

MAP3K10MAPK8IP2

CBS

SH3GL3

STAU1

CASP6

PPP5C

KRT16

DAB1

CASP1SHC2

CTSD

UCHL1

HP

SNCACAMK2G

TGFB1

GNB1

PTPN1PIN1

TJP1

CASP8PLCG1

NPHS1

PPP2R2A

DNAJB1

ADRBK1

INADL

NCSTN

MATK

NEDD4L

KAT5IFNGTBP

FRS2

CSNK1A1

CALRKNG1

SGOL2

KRT6B

TRAF3 DLG3

SACS

BDKRB2PRKCB

CAV1

MAPK3F2 SMAD3

APOEAKAP9 RANBP2

CLTC

TSC22D1GAB2PSEN2

MLF1CROT

KRT9

ADRA1B

EPB41

COL4A1

SHC3

ARHGAP32

ATM

PPP2R5A

CAMK2A

NTRK1

KRT18

TNFAPOA2

LAT

GRIN2D

COL4A6

KLK3

VLDLR

COL4A5

COL4A2

NEFH

OR8D2

MTSS1

PDZRN4

PTPN4

OR3A2

OR2T6

DGKG

CASP3

IGF1R

CASK

DRD2

TRAF2

EPHB2

PPM1A

PRKCG

CACNB3

HNRNPUSIN3A

DLG1

CLU

RAP2A

ERBB4CANX

BACE1 GABBR1

KARS

CNOT1

UNG

AGA CDCP1

UTP14A PLAG1

EXOC6

HRAS

CTNNB1

SP1

NOS3 SUMO1

PSEN1

HSPA8

HSP90AA1

BCL2

GNAO1

RPS6KB1

PARK2

DLG4

PTK2B

GSN

NAE1 TLN2LRFN2

PLTP

NUMBLSTX1A

DERL1

NEFM

HMOX2

AATF

PPIAMTRNR2L2AP1M1

OGT

DDB1

AP4M1

MED31

RGS3

TDP2

KRT5

ADAM9

REST

PACSIN1

SHB

CTSL1

LAMA1

SH2B1

PLA2G4F

SMURF2

SLC9A8

KRT14

CIT

TGFB1I1

PPP2R1APIK3R1

NUMB

ADAM17

DLG2

LRP1

APOA4

LTA

IRS1

GSK3B

EGFR

CTSB

TRAF6

SHC1

PPP2CB

NGF

HTT

PPIDLDB3

APOC1HIP1

ZDHHC17COL25A1MAGI3

ITGB5

ACTB

GNA11

ACTN2CAMK2B

CDK1

LIN7C

S100B

PDLIM5

DLGAP1

LIN7A

TPR

SYNGAP1

CFD

GRIN3A

F12

SLC1A3

GRK5

CACNA2D2

TANC1

DUSP4

EXOC4

AHSG

GRIN3B

UCP2

TTN

GPC1

NSF

FGA

DYNLL1

MAPK8IP1

PICALM

PPBP

ITM2B

NID1

STXBP1

CTBP1

SGK1

TRAF1

SQSTM1

TNFRSF1A

ACTN1

OPTN

UBE2D2

AP2A2

FUS

APOA1

DICER1

CACNA1B

CST3

NCOA3

SCARB1

APOC3

SLC6A3

KIAA1551 KRT13

DCD

KIAA0232

ENSG00000258818

SPATA31A7

CTAGE5

CEP44

SH2B2

EPHB4

CAPN1

F7

APBA2

COL4A3

LDLR

GIPC1

GFAP

SERPING1

SRC

MAPK12APP

GAPDH

CDK5

CREBBP

NOS1

YWHAZCALM1

YWHAG

YWHAQGRIN1

RPS6KA3

COL1A2

TCERG1

A2M

CASP7

LRP8

PDK2

AGTR1

FYN

ALBGRB2

MAPK1AKT1

STAT1

MAPT

GSK3A

UBB

PPP2CA

SMAD4

PRKCD

RGS12

SPTB

SH3BP5

CACNA1I

IL16

SLA2

PFN2

NLRC4

TNFRSF14

PRTN3

SNCB

FBLN1

BACE2

SETX

FANCD2

SAP30

RANBP3

PALB2

SLC1A5RASA1

HAP1

LRRC7

CFB

ADRBK2

CDC45

CLSTN3

PCED1B

SCAF1KIAA1377

FAM71E2

FEZ1 ACSBG2

PCDH1

TRAPPC11QTRTD1

KRT1

LRP1B

HADHB

TP53BP2

DRD1

ST13

PRPF40A

TRAIP

KIDINS220

GRK6

MMP17

LTBR

EIF6

PGAM1

CHD3

PRSS3

APBB3

CHRNA7

KRT10

RIMS1

CRMP1

PDIK1L

SORBS3

SYMPK

GCN1L1

RNF19A

HOMER3

GRK4

JARID2

MYLK3

EFS

CRB1

HSD17B10

TST

HOMER2

PHC3

TM2D1 FICD

PEG3

CABLES1

LGALS2

ITIH1

HOXB2

TAF4FLOT1

BABAM1

CFH

HIP1R

LTBMYL4

NCOR1

CASP4

NF1

AP4E1

CLCA2

IGDCC4

NECAB3

CXorf27

SH3GLB1

CTCF

PLCG2

(a)

STAT1

EGFR

FN1

PLAT

SOD1

PRKCA CDK1

GSK3B

ALB APP

PPP3CA

IFNG

BBC3

SCN5A

KCNMA1

MAP2

ACHE

MAPK3F2

PTPN1

NOS3 BCL2

CAV1

CTNNB1

PRKCB

TGFB1CASP8

TNF

AKT1

F7

MAPK1LDLR

PRKCD

SLC6A3

DRD1

CASP3

CHRNA7

PRSS3

TP53BP2

CASP7

EPHB2

SYNGAP1

CALM1

CTSD

BACE1

ADRA1B

(b)

Figure 4 TBI-related protein interaction network (a) 21 hub proteins (red and green) were identified through the analysis of TherapeuticTargetDatabase (TTD) aswell asOnlineMendelian Inheritance inMan (OMIM) 4 overlapped protein targets (green)were obtained between21 hub proteins in TBI and candidate targets of XFZYD Periwinkle proteins fromHPRD and STRING analyses were not targeted by XFZYD(b) 47 candidate protein targets of XFZYD were screened for treating TBI Yellow candidate protein targets of XFZYD The size of nodes isproportional to the value of degree


Table 4 Top 10 proteins of TBI specific proteins according to 2 centrality indicators

Proteins Degree Proteins BetweennessSRC 164 APP 0071814AKT1 157 ALB 0069343ALB 153 SRC 0058568EGFR 139 EGFR 0052938APP 134 AKT1 0045466GAPDH 131 HTT 0037164HSP90AA1 108 GAPDH 0034549BCL2 106 HSP90AA1 0027596MAPK1 105 CTNNB1 0021759HRAS 105 GNB1 0019492Note the centrality indicators identify the important nodes within the network Higher degree centrality and betweenness centrality indicate greaterimportance

Table 5 Top 10 significantly enriched KEGG pathways in TBI-specific proteins

Pathway ID Pathway description Gene count FDR4010 MAPK signaling pathway 44 299E-235200 Pathways in cancer 43 113E-184722 Neurotrophin signaling pathway 41 101E-344151 PI3K-Akt signaling pathway 40 111E-154510 Focal adhesion 39 292E-225205 Proteoglycans in cancer 39 410E-215010 Alzheimer s disease 34 124E-204015 Rap1 signaling pathway 33 769E-174014 Ras signaling pathway 33 646E-164020 Calcium signaling pathway 31 505E-17

0

001

002

003

004

005

006

007

008

0 20 40 60 80 100 120 140 160 180

Betw

eenn

ess

Degree

APP

ALB SRCEGFR

AKT1HTT

Figure 5 Relationship between degree and betweenness centralityin the TBI-specific protein interaction network

for the 119 potential compounds is shown in Table S4Similarly 5 pharmacologically active ingredients in the JunChen and Zuo-Shi groups including quercetin stigmasterolkaempferol baicalin and beta-sitosterol anchored 33 TBI-specific proteins such as CALM SCN5A F2 ACHE F7ADRA1B NOS3 BCL2 CASP3 and AKT1 11 Jun-specificcompounds targeted 2 specific targets (ALB CTNNB1) while12 Chen-specific compounds anchored 3 unique proteins(PRKCD FN1 and BC3) The Zuo-Shi herbs possessed thelargest number of active compounds (89) and targeted 5

unique proteins including EPHB2 BACE1 LDLR MAPK3and PRSS3 GSK3Bwas the common target between theChenandZuo-Shi drugs KCNMA1 CASP7 andAPPwere targetedby the Jun and Zuo-Shi drugs

The top 10 candidate compounds and targets to treat TBIwere showed in Tables 6 and 7 Formost of active compoundsfrom XFZYD each component hit more than one targetTable 6 demonstrated that quercetin had the highest numberof targets (degree =76) followed by kaempferol (degree=43) beta-sitosterol (degree =35) stigmasterol (degree =19)luteolin (degree=18) baicalein (degree=15) 7-Methoxy-2-methyl isoflavone (degree=12) wogonin (degree=12)nobiletin (degree=11) and naringenin (degree=9) Forinstance quercetin (3310158404101584057-pentahydroxyflavone) is anaturally occurring flavonoid commonly found in fruits andvegetables It regulates multiple biological pathways elicitinginduction of apoptosis as well as inhibiting angiogenesisand proliferation [63 64] Quercetin can attenuate neuronalautophagy and apoptosis in rat traumatic brain injury modelvia activation of PI3KAkt signaling pathway [65] It has alsobeen reported to have a protective ability against oxidativestress and mutagenesis in normal cells [66 67] Kaempferol(3 41015840 5 7 tetrahydroxy flavone) is a yellow-colored flavonoidthat is widely distributed in many botanical families[68] It has been shown to possess a variety of biologicalcharacteristics including effects of anti-inflammatory[69] antioxidative [70] tumor growth inhibition [71] and


Mol 22Mol 33

Mol 29Mol 32 Mol 23Mol 20

Mol 97Mol 106

Mol 104Mol 100Mol 94

Mol 63Mol 90

Mol 87

Mol 91Mol 61

Mol 19

Mol 109

Mol 161

Mol 118

Mol 111

Mol 158

Mol 114

Mol 149

Mol 141

Mol 152

Mol 14

CASP3

BCL2

NOS3

SCN5A

F7

ADRA1B

ACHE

F2

Mol 4

Mol 49

Mol 127

APP CASP7

Mol 92

Mol 54

Mol 6

Mol 36

KCNMA1

Mol 27


Mol 17

Mol 39

Mol 2

Mol 21

Mol 12

Mol 142

Mol 126

Mol 135

Mol 121

Mol 119

Mol 124

Mol 120

Mol 117

Mol 133

Mol 131

Mol 134

PlatycodonGrandiforus

Aurantii Fructus

Licorice

Radix Bupleuri

RehmanniaglutinosaLibosch

AngelicaeSinensis Radix

Mol 8

Mol 73

Mol 75

Mol 77

Mol 80

Mol 7

Mol 82

Mol 76

Mol 74

Mol 60

Mol 46

Mol 150

Mol 151

Mol 112

Mol 115

Mol 11

Mol 116

Mol 113

Mol 110

Mol 1


Mol 103Mol 89 Mol 107

Mol 96PRSS3 LDLRMAPK3 BACE1 EPHB2

Mol 35Mol 81

Mol 86

Mol 85

Mol 84

Mol 88

Mol 83Mol 30

Mol 137

ChuanxiongRhizoma

Mol 3

Mol 57

Mol 139

Achyranthis

Bidentatae

RadixMol 102

CASP8

IGHG1AKT1p53

CHRNA7

Mol 40

SLC6A3 PTPN1

SOD1MAPK1

Mol 38

Mol 95

Carthami Flos

Mol 24

Mol 78 Persicae Semen

Mol 122

Mol 25

Mol 98

TGFB1

GSK3B

PRKCA

Radix Paeoniae Rubra

Mol 52

Mol 42

Mol 62

Mol 138

EGFR

STAT1 PPP3CAPLAT

Stigmasterol

MAP2

Beta-sistosterol Quercetin

Kaempferol

SYNGAP1

CALM

Baicalin

PRKCB

CAV1

CTSD

TNF

DRD1

CDK1

IFNG

FN1BBC3 PRKCD

Mol 132

Mol 160

Mol 58

Mol 67

Mol 69 Mol 43ALB

Mol 64CTNNB1

xiongixioChuanxC nxnxioaamaRhihihizoma

Achyranthisiistntnt

aeeaeBidenBidennntatae

RadixadixR diR di

oniae nianiaiaonRadix PaeoPaePRadix P eeoeonRRRRubra dondonddoodPlatycolatycPlatyycPl ycoyccoPlatPlatycoPlatyccocod

rususrusususruGranG anGranGranGranGrGGranndndiforu

ructusuctuc sructusuctusructusruAurantiirA ntaA ntiitiirantAurantintiurantAur iiii Fru

cecececececececeecLiLLiLLiLiLLLLLLLLiLiLiLLiLLLiLicoric

leuririeuuurieurileurleurieurieurieurieurileRadix BBRadRad Bdix Bdixx R i Bdi BBBadix Radix BBuple

RehmanniaRe mRe m nnRehmanniamReRehmhmannnniamanniaRehmehmanniRR nosasasasaosaosglutilutglutgluulutiglgl titinos

LiboschLibLLibo hschib chLiboschboscLLib chschLibos

icaecaecacaeicaeicAngelAnAngeAngelAnAng lAAngeelielicdix dix dixdixdSinensinensSS nennensSinSSiSinensSinensSine sissis Rad

FloslololFlhamaCartharthhaamami Fl

menmennnnmicae Scae SSem

Figure 6 HB-pC-pT network of XFZYD for treating TBI The triangles with circle backgrounds represent the herbs (HB) the squares andcircles represent the potential compounds (pC) and targets (pT)The red triangles squares and circles represent corresponding HB pC andpT in the Junherbs the same is to aqua representing theChen herbs and periwinkle representing the Zuo-Shi herbsThe claybank squares andcircles represent corresponding pC and pT shared by the Chen and Zuo-Shi herbs the same is to blue representing the overlap between theJun and Zuo-Shi herbs and the green representing the overlap between the Chen and Zuo-Shi herbsThe purple squares and circles representthe corresponding pC and pT shared by the 3 groups of herbs

alleviating insulin resistance in type 2 diabetic rats [72]Beta-sitosterol (BS) is a vegetable-derived compound foundin various plants and is suggested to modulate the immunefunction inflammation and pain levels by controlling theproduction of inflammatory cytokines [73]

For targets analysis CALM possesses the largest degree(degree =84) followed by GSK3B (degree =61) SCN5A(degree = 59) F2 (degree = 43) ACHE (degree=28)F7 (degree=28) ADRA1B (degree=28) NOS3 (degree=20)BCL2 (degree=18) and CASP3 (degree=18) which demon-strated their crucial therapeutic effects for treating TBI Forinstance CALM possess an essential position in calciumsignaling pathway and is related to morphological changesmigration proliferation and secretion of cytokines andreactive oxygen species ofMicroglial cells [74]The activationof CaMKII120572 major isoform of Ca2+calmodulin-dependentprotein kinase (CaMK) in brain is directly associated withthe production of proinflammatory cytokines such as TNF-120572and IL-1120573 [75] GSK-3120573 is a serinethreonine-protein kinasewhich is abundant in the central nervous system (CNS)particularly in neurons [76] It can control gene transcrip-tion axonal transport and cytoskeletal dynamics in growthcones [77] The inhibition of GSK-3120573 attenuates apoptotic

signals and prevents neuronal death [78] There is increasingevidence that prothrombin (F2) and its active derivativethrombin are expressed locally in the central nervous systemBeside the central role in the coagulation cascade the gener-ation of thrombin leads to receptor mediated inflammatoryresponses cell proliferationmodulation cell protection andapoptosis [79 80] The role in brain injury depends upon itsconcentration as higher amounts cause neuroinflammationand apoptosis while lower concentrations might even becytoprotective [81]

Direct tissue damage aswell as hypoxic-ischemic increas-ing anaerobic glycolysis of the brain tissue results in theATP-stores depletion and failure of energy-dependent mem-brane ion pumps especially for voltage-dependent Ca2+ andNa+-channels Accumulated Ca2+ activates lipid peroxidasesproteases and phospholipases and caspases at the sametime increasing the intracellular concentration of free fattyacids and free radicals leading to necrosis or apoptosis ofneurocyte [82] At the same time the activation of residentglial cells microglia and astrocytes and the infiltration ofblood leukocytes secrete various immune mediators elicitedinflammatory responses which subsequently intersect withadjacent pathological cascades including oxidative stress


Table 6 Top 10 potential candidate compounds of XFZYD for treating TBI according to 2 centrality indicators

Compound Degree Compound Betweennessquercetin 76 quercetin 01682179kaempferol 43 kaempferol 005501511beta-sitosterol 35 wogonin 005141376Stigmasterol 19 beta-sitosterol 004451294luteolin 18 naringenin 003251738baicalein 15 beta-carotene 002977217-Methoxy-2-methyl isoflavone 12 nobiletin 002787992wogonin 12 7-Methoxy-2-methyl isoflavone 002096439nobiletin 11 luteolin 002090223naringenin 9 baicalein 001453488

Table 7 Top 10 potential targets of XFZYD for treating TBI according to 2 centrality indicators

Targets Degree Targets BetweennessCALM 84 CALM 021452046GSK3B 61 SCN5A 011441591SCN5A 59 GSK3B 009553896F2 43 F2 00689171ACHE 28 BCL2 002651903F7 28 CASP3 002372836ADRA1B 28 F7 002032647NOS3 20 ACHE 001845996BCL2 18 ADRA1B 001704505CASP3 18 NOS3 00166699

excitotoxicity or reparative events including angiogenesisscarring and neurogenesis [83] Function analysis of the 47target proteins regulated by XFZYD was mainly associatedwith core pathophysiology process of TBI (Figure 7) 47 targetproteins were connected with 16 key process related to TBIMost of the targets have one or more links to other biolog-ical process such as apoptosis cell proliferation superoxideanion generation nitric oxide biosynthetic process responseto calcium ion I-kappaB kinaseNF-kappaB signaling andregulation of inflammation The above analysis implied themultifunction character of these target proteins regulated byXFZYD Of these target proteins 25 proteins (53 of the 47)such as TGFB1 EGFR CAV1 MAPK1 PRKCB and AKT1were responsible for regulating the apoptosis process 17 forblood coagulation 14 for cell proliferation and axon genesisand 12 for hypoxia andMAPK cascade We found that TGFB1was the crucial protein because it participated in 9 biologicalprocesses related to TBI such as apoptosis blood coagulationcell proliferation and MAPK cascade followed by EGFR (8)CAV1 (7) MAPK1 (6) PRKCB (6) and AKT1 (6)

Overall these observations strongly support the evidencethat the generated HB-pCminuspT network and pT-F networkhave important roles in treating TBI further validating thedrug targeting approach

Molecule docking was used to further validate the bind-ing mode between candidate compounds and their targetproteins We found that 18 TBI-specific target proteins inter-acted with 91 candidate compounds from XFZYD (Figure 8)

Other 29 target proteins were not discussed for the lackof proper protein crystal structure The detailed moleculedocking results are shown in Table S5The 6 essential proteinsincluding GSK3B AKT1 CDK1 F2 NOS3 and ACHEwere used to elucidate the exact binding mode (Figure 9)Quercetin was located within the binding cavity of AKT1 andCDK1 (Figures 9(a) and 9(b) and S1A B) Four conventionalhydrogen bonds were formed between quercetin and AKT1by interacting with the key amino acids including ILE-290 THR-211 and SER 205 Additionally 120587-120587 interactionsbetween quercetin and TRP-90 were found in the activesite which helped the stabilization of the compound at thebinding site (Figure 9(a) S1A) Figure 9(b) and S1B suggestedthat five conventional hydrogen bonds (LEU-83 ASP-146and LYS-33) and 120587-120587 interaction (PHE-80) were formedbetween quercetin and CDK1 The GSK3B-FA complexes(Figure 9(c) S1C) were stabilized by 6 hydrogen-bondinginteractions between FA and LYS-85 GLU-97 TYR-134 andARG-141 Glyasperin Bmainly bonds to F2 through hydrogenbonds by interacting with the key amino acids includingGLY-193 SER-195 and GLY-219 (Figure 9(d) S1D) andan edge-to-face 120587 minus 120587 interaction was also observed withTYR-228 The GLN-247 GLU-351 and GLY-355 from theactive site pocket of NOS3 participated in the hydrogen-bondformationwith 1-Methoxyphaseollidin (Figure 9(e) S1E)The(-)-Medicocarpin formed a total of 6 hydrogen bonds withSER-293 PHE-295 ARG-296 and TRY-341 in the active siteof ACHE (Figure 9(f) S1F) Besides an edge-to-face 120587 minus 120587


KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A

I-kappaB kinase NF-kappaB signaling

Regulation of inflammation

Response to calcium ion

TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia

Superoxide anion generation

Nitric oxide biosynthetic process

Astrocyte activation

Amyloid-beta regulation

Microglial cell activation

LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3

Figure 7 pT-F network of XFZYD for treating TBI 16 biological processes (red square) the 47 target proteins (periwinkle circle) of XFZYDparticipate in for treating TBI

interactionwas also observedwith TYR-337 From the resultshydrogen-bonding and edge-to-face 120587 minus 120587 interactions playkey roles in the proteinminusligand recognition and stabilitywhich may be helpful in determining the inhibitor activitiesAnd the C-T network confirmed the potential therapeuticeffects of the candidate compounds from XFZYD to treatTBI through interacting with the relevant proteins The com-putational analysis further elucidated the accurate moleculemechanisms between active compounds and targets

4 Discussion

Traumatic brain injury (TBI) is a growing public healthproblem worldwide and is a leading cause of death anddisability [84] Although major progress has been made in

understanding the pathophysiology of this injury this hasnot yet led to substantial improvements in outcome by alack of treatments which have proven successful during phaseIII trials for modern medicine [85 86] TCM rooted inthousands of years of history may offer an alternative or acomplementary strategy for the treatment of TBI XFZYDa representative formula in TCM has been used for yearsto treat TBI in China and has been demonstrated to beeffective in clinical practice However its ldquomulticomponentsrdquoand ldquomultitargetsrdquo features make it much difficult to decipherthemolecular mechanisms of XFZYD in the treatment of TBIfrom a systematic perspective if employing routine methods

In the present study a network pharmacology-basedmethod was employed to elucidate the pharmacologicalmechanisms of XFZYD to treat TBI according to the drug


Figure 8 C-T network through molecule docking validating 119 potential compounds (green triangles) interacting with 18 potential targets(yellow circles) of XFZYDThe size of the nodes is proportional to the value of degree

combination principle of TCM We first proposed a newmodeling system combining OB and DL screening multipledrug targets prediction and validation network constructionand molecule docking to probe the efficiency of a typicalTCM formula XFZYD for the treatment of TBI The 11herbs from XFZYD possessed 162 bioactive compounds andtargeted 285 proteins There were 5 compounds and 189

target proteins overlapped among the Jun Chen and Zuo-Shigroup Furthermore 47 TBI-specific proteins were targetedby 119 (73) bioactive compounds from XFZYD Similarly 5common compounds and 33 (70) common target proteinsamong the 3 groups of drugs were observed Most of thebioactive ingredients targeted more than one protein The 47target proteins regulated several essential pathophysiological


(a) (b) (c)

(d) (e) (f)

Figure 9 Hydrogen-bonding networks within the binding site of the compoundminustarget complexes obtained from molecule docking(a) AKT1-quercetin (b) CDK1-quercetin (c) GSK3B-FA (d) F2-glyasperin B (e) NOS3-1-Methoxyphaseollidin and (f) ACHE-(-)-Medicocarpin The molecules are presented as ball and stick models Active site amino acid residues are represented as lines Dotted bluelines in these pictures represent hydrogen bonds with distance unit of A Other O and N atoms are colored as red and blue respectively

processes of TBI that referred to apoptosis inflammationcell proliferation superoxide anion generation nitric oxidebiosynthetic process response to calcium ion etc The aboveanalysis reveals that the synergistic action mechanisms ofXFZYDmay be (1) bioactive compounds overlapping amongthe different group of herbs (2) specific bioactive com-pounds from different groups of herbs targeting the sameproteins (3) specific bioactive compounds from differentgroups of herbs targeting different proteins which participatein the same pathophysiological process of the disease Toa certain degree the 5 compounds including quercetinstigmasterol kaempferol baicalin and beta-sitosterol playedessential role in XFZYD for TBI treatment MAPK3MAPK1AKT1 PRKCA TNF PRKCB EGFR BCL2 GSK3B CASP3PPP3CA and NOS3 were the main target proteins regulatedby XFZYD in the treatment of TBI

Interestingly Beta-carotene (Mol 43) from Carthami Flos(the Jun herb) specifically regulated 120573-Catenin (CTNNB1)and played critical role for curing TBI The 120573-Catenin is acritical downstream component of the Wnt pathway whichplays essential role in the regulation of mammalian neuraldevelopment [87] In vitro and in vivo studies demonstrate

that the Wnt120573-catenin pathway regulates the proliferationand differentiation of neural progenitor cells [88] Neuronaldifferentiation is induced by overexpression of 120573-cateninor the pharmacological inhibition of GSK3120573 (the phospho-rylating enzyme of 120573-catenin) [89 90] This pathway alsopromotes blood vessel formation during vascular develop-ment as well as the vascular repair process after TBI [91]In addition wogonin (Mol 160) from Achyranthis BidentataeRadix (the Chen herb) specifically targeted fibronectin (FN1)Bcl-2-binding component 3 (BBC3) and Protein KinaseC delta type (PRKCD) FN1 an important component ofthe extracellular matrix (ECM) environment promotes cellmigration neurite outgrowth and synapse formation dur-ing neural development [92] It aggregates in the injuredbrain and plays a neuroprotection role through antiapoptosisand anti-inflammation ways following TBI [93 94] BBC3namely p53 upregulated modulator of apoptosis (PUMA) iscritical for the p53-dependent apoptosis pathway which playsan important role in hippocampal neuronal loss and associ-ated cognitive deficits [95] PRKCD one of PKC isoformsactivates signal transduction pathways involved in neuronalregeneration [96] synaptic transmissionplasticity [97] and


activation of apoptosis processes [98] as well as higher brainfunctions such as learning andmemory [99]The activators ofPKCare effective for the treatment of TBI [100] FurthermoreMitogen-activated protein kinase 3 (MAPK3) Beta-secretase1 (BACE1) Ephrin type-B receptor 2 (EphB) and low-densitylipoprotein receptor (LDLR) were specifically targeted bythe ingredients in the Zuo-Shi herbs Naringenin (Mol133) targeted LDLR MAPK3 while euchrenone (Mol 60)anchored BACE1 and nobiletin (Mol 134) targeted EphB2MAPK3 is an essential component of the MAP kinase signaltransduction pathway It has been appreciated recently thatthe ERK12 cascade plays a fundamental role in synapticplasticity and memory [101] BACE1 is responsible for pro-duction of A120573 from amyloid precursor protein (APP) A120573can cause cell death activate inflammatory pathways [102]and prime proapoptotic pathways for activation by otherinsults [103] The blocking of BACE1 can ameliorate motorand cognitive deficits and reduce cell loss after experimentalTBI in mice [104] EphB is localized to synaptic sites inhippocampal neurons [105] The interaction between EphBand NMDA receptors regulates excitatory synapse formation[106] LDLR acts as an important receptor that facilitatesbrain A120573 clearance and inhibits amyloid deposition [107]and then ameliorates Alzheimerrsquos disease neuropathologyafter TBI [108] The analysis above indicates the ldquoJunrdquoldquoChenrdquo and ldquoZuo-Shirdquo herbs from XFZYD trigger theirspecific targets regulation respectively for the therapeuticeffects

XFZYD is a very famous traditional Chinese formula inpromoting qi circulation and removing blood stasis accord-ing to TCM theory However several limited researches havedemonstrated its efficacy for treating TBI such as anti-inflammatory and synaptic regulation [30 31] which arein accord with our study However previous studies merelypartially deciphered the molecule mechanism of XFZYD fortreating TBI This study reports 119 bioactive compounds inXFZYD that target 47 TBI-specific proteins such as MAPK3MAPK1 AKT1 PRKCA TNF PRKCB and EGFR Theseproteins regulate several crucial pathophysiological processesof TBI such as apoptosis inflammation blood coagulationand axon genesis Our study demonstrates that the therapeu-tic actions of XFZYD refer to ldquomulticompoundsrdquo ldquomultitar-getsrdquo features rather than only the improvement of bloodcirculation With the help of molecule docking methodwe further validate the interactions between bioactive com-pounds and potential targets of XFZYD The hydrogen-bonding and edge-to-face 120587 minus120587 interactions play key roles inthe proteinminusligand recognition and stability This provides avaluable reference for further experimental investigations ofbioactive ingredients and therapeutic targets of XFZYD fortreating TBI

5 Conclusion

Our work successfully illuminates the efficiency of XFZYDfor the treatment of TBI as well as herb combination ruleof TCM formula Network pharmacology with moleculedocking method confirms the ldquomulticompounds multitar-getsrdquo therapeutic actions of XFZYD in the treatment of TBI

The present work may provide valuable evidence for furtherclinical application of XFZYD for treating TBI

Abbreviations

TBI Traumatic brain injuryXFZYD Xuefu Zhuyu decoctionTCM Traditional Chines medicineDL Drug-likenessOB Oral bioavailabilityHB-cC-cT Herb-candidate compound-candidate

targetHB-pC-pT Herb-potential compound-potential targetCALM CalmodulinGSK3B Glycogen synthase kinase-3 betaSCN5A Sodium channel protein type 5 subunit

alphaF2 ProthrombinACHE AcetylcholinesteraseGO Gene OntologyKEGG Kyoto Encyclopedia of Genes and

Genomes

Data Availability

The data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

The authors declare that they have no conflicts of interest

Authorsrsquo Contributions

YangWang and Zebing Huang participated in the conceptionand design of the study YuanyuanZhong YangWang ZebingHuang Jiekun Luo Tao Tang and Pengfei Li acquired andanalyzed the data Yuanyuan Zhong Tao Liu and HanjinCui drafted and revised the manuscript The correspondingauthor and all of the authors have read and approved the finalsubmitted manuscript

Acknowledgments

This work was supported by the National Natural ScienceFoundation of China (Nos 81673719 81874409 81603670and 81803948) Project funded byChina Postdoctoral ScienceFoundation (Nos 2016M600639 and 2017T100614)

Supplementary Materials

Table S1 162 bioactive compounds in XFZYD Table S2 targetproteins of XFZYD Table S3 TBI-specific proteins Table S4119 potential compounds of XFZYD for treating TBI TableS5 docking result of 18 target proteins with 91 potential com-pounds Fig S1 the exact bindingmode between active ingre-dients and protein targets obtained from molecule docking(A) AKT1-quercetin (B) CDK1-quercetin (C) GSK3B-FA


(D) F2-glyasperin B (E) NOS3-1-Methoxyphaseollidin and(F)ACHE-(-)-Medicocarpin (Supplementary Materials)

References

[1] L Yang Y Chu D Tweedie et al ldquoPost-trauma administrationof the pifithrin-120572 oxygen analog improves histological andfunctional outcomes after experimental traumatic brain injuryrdquoExperimental Neurology vol 269 pp 56ndash66 2015

[2] J A Langlois W Rutland-Brown and M M Wald ldquoTheepidemiology and impact of traumatic brain injury a briefoverviewrdquo The Journal of Head Trauma Rehabilitation vol 21no 5 pp 375ndash378 2006

[3] H A Alsulaim B J Smart A O Asemota et al ldquoConsciousstatus predictsmortality among patientswith isolated traumaticbrain injury in administrative datardquo The American Journal ofSurgery vol 214 no 2 pp 207ndash210 2017

[4] M Majdan D Plancikova A Maas et al ldquoYears of life lost dueto traumatic brain injury in Europe A cross-sectional analysisof 16 countriesrdquo PLoS Medicine vol 14 no 7 p e1002331 2017

[5] P Cheng P Yin P Ning et al ldquoTrends in traumatic braininjury mortality in China 2006ndash2013 A population-basedlongitudinal studyrdquo PLoS Medicine vol 14 no 7 Article IDe1002332 2017

[6] M V Russo and D B McGavern ldquoInflammatory neuroprotec-tion following traumatic brain injuryrdquo Science vol 353 no 6301pp 783ndash785 2016

[7] WWang H Li J Yu et al ldquoProtective Effects of ChineseHerbalMedicine Rhizoma drynariae in Rats After Traumatic BrainInjury and Identification of Active Compoundrdquo MolecularNeurobiology vol 53 no 7 pp 4809ndash4820 2016

[8] M Das S Mohapatra and S S Mohapatra ldquoNew perspectiveson central and peripheral immune responses to acute traumaticbrain injuryrdquo Journal of Neuroinflammation vol 9 p 236 2012

[9] J W Finnie ldquoNeuroinflammation Beneficial and detrimentaleffects after traumatic brain injuryrdquo Inflammopharmacologyvol 21 no 4 pp 309ndash320 2013

[10] T Cheng W Wang Q Li et al ldquoCerebroprotection of flavanol(minus)-epicatechin after traumatic brain injury viaNrf2-dependentand -independent pathwaysrdquo Free Radical Biology amp Medicinevol 92 pp 15ndash28 2016

[11] W Young ldquoRole of calcium in central nervous system injuriesrdquoJournal of Neurotrauma vol 9 Suppl 1 pp S9ndashS25 1992

[12] R Bullock A Zauner J S Myseros et al ldquoEvidence forProlonged Release of Excitatory Amino Acids in Severe HumanHead Trauma Relationship to Clinical Eventsrdquo Annals of theNew York Academy of Sciences vol 765 no 1 pp 290ndash297 1995

[13] A T Mazzeo A Beat A Singh and M R Bullock ldquoTherole of mitochondrial transition pore and its modulation intraumatic brain injury and delayed neurodegeneration afterTBIrdquo Experimental Neurology vol 218 no 2 pp 363ndash370 2009

[14] S Gennai A Monsel Q Hao et al ldquoCell-Based therapy fortraumatic brain injuryrdquo British Journal of Anaesthesia vol 115no 2 pp 203ndash212 2015

[15] J Ghajar ldquoTraumatic brain injuryrdquo The Lancet vol 356 no9233 pp 923ndash929 2000

[16] D J Loane and A I Faden ldquoNeuroprotection for traumaticbrain injury translational challenges and emerging therapeuticstrategiesrdquoTrends in Pharmacological Sciences vol 31 no 12 pp596ndash604 2010

[17] Y Wang X Fan T Tang et al ldquoRhein and rhubarb simi-larly protect the blood-brain barrier after experimental trau-matic brain injury via gp91phox subunit of NADPH oxidaseROSERKMMP-9 signaling pathwayrdquo Scientific Reports vol 6p 37098 2016

[18] D-X Kong X-J Li and H-Y Zhang ldquoWhere is the hopefor drug discovery Let history tell the futurerdquo Drug DiscoveryTherapy vol 14 no 3-4 pp 115ndash119 2009

[19] F Cheung ldquoTCM made in Chinardquo Nature vol 480 no 7378pp S82ndashS83 2011

[20] C Fu Z Xia Y Liu et al ldquoQualitative analysis of majorconstituents from Xue Fu Zhu Yu Decoction using ultra highperformance liquid chromatographywith hybrid ion trap time-of-flight mass spectrometryrdquo Journal of Separation Science vol39 no 17 pp 3457ndash3468 2016

[21] H-J Zhang and Y-Y Cheng ldquoAn HPLCMS method for iden-tifying major constituents in the hypocholesterolemic extractsof Chinese medicine formula lsquoXue-Fu-Zhu-Yu decoctionrsquordquoBiomedical Chromatography vol 20 no 8 pp 821ndash826 2006

[22] L Zhang L Zhu YWang et al ldquoCharacterization and quantifi-cation of major constituents of Xue Fu Zhu Yu by UPLC-DAD-MSMSrdquo Journal of Pharmaceutical and Biomedical Analysisvol 62 pp 203ndash209 2012

[23] X Yang X Xiong G Yang and J Wang ldquoChinese patentmedicine Xuefu Zhuyu capsule for the treatment of unstableangina pectoris a systematic review of randomized controlledtrialsrdquo Complementary Therapies in Medicine vol 22 no 2 pp391ndash399 2014

[24] J Wang X Yang F Chu et al ldquoThe effects of Xuefu Zhuyuand Shengmai on the evolution of syndromes and inflammatorymarkers in patients with unstable angina pectoris after percuta-neous coronary intervention a randomised controlled clinicaltrialrdquoEvidence-BasedComplementary andAlternativeMedicinevol 2013 Article ID 896467 9 pages 2013

[25] Q Zhang H Yu J Qi et al ldquoNatural formulas and the natureof formulas Exploring potential therapeutic targets based ontraditional Chinese herbal formulasrdquo PLoS ONE vol 12 no 2p e0171628 2017

[26] J LeeWHsu T Yen et al ldquoTraditional ChinesemedicineXue-Fu-Zhu-Yu decoction potentiates tissue plasminogen activatoragainst thromboembolic stroke in ratsrdquo Journal of Ethnophar-macology vol 134 no 3 pp 824ndash830 2011

[27] Y-C Shen C-K Lu K-T Liou et al ldquoCommon and uniquemechanisms of Chinese herbal remedies on ischemic strokemice revealed by transcriptome analysesrdquo Journal of Ethnophar-macology vol 173 pp 370ndash382 2015

[28] F Xue-hai G Yan and L Jian-tao ldquoTherapeutic effect of XiefuZhuyu decoction joint brain protein hydrolysat injection intraumatic brain injury and its effect on cerebrospinal fluid ofET-1rdquo Chinese Journal of Biochemical Pharmaceutics no 02 pp55ndash58 2017

[29] L Shuxiang W Jingchun C Jie et al ldquoEffect of Xuefu Zhuyudecoction on the neural functional recovery and living abilityin patients with craniocerebral injuryrdquo Modern Journal ofIntegrated Traditional Chinese andWesternMedicine no 04 pp350ndash352 2015

[30] L Zhong W Ning and W Dong-pi ldquoModel Study of theTherapy of Replenishing Qi and Activating Blood Circulationon Protecting the Brain Impairment Caused by Hypoxic -ischemic Encephalopathy in SD Ratsrdquo Journal of TraditionalChinese Medicine vol 07 pp 1552ndash1555 2011


[31] M Sun X-P Zhan C-Y Jin J-Z Shan S Xu and Y-LWang ldquoclinical observation on treatment of post-craniocerebraltraumatic mental disorder by integrative medicinerdquo ChineseJournal of Integrative Medicine vol 14 no 2 pp 137ndash141 2008

[32] Z Xing Z Xia W Peng et al ldquoXuefu Zhuyu decoction atraditional Chinese medicine provides neuroprotection in arat model of traumatic brain injury via an anti-inflammatorypathwayrdquo Scientific Reports vol 6 Article ID 20040 2016

[33] J Zhou T Liu H Cui et al ldquoXuefu zhuyu decoction improvescognitive impairment in experimental traumatic brain injuryvia synaptic regulationrdquo Oncotarget vol 8 no 42 2017

[34] S Li ldquoExploring traditional chinese medicine by a novel thera-peutic concept of network targetrdquo Chinese Journal of IntegrativeMedicine vol 22 no 9 pp 647ndash652 2016

[35] S Li and B Zhang ldquoTraditional Chinese medicine networkpharmacology theory methodology and applicationrdquo ChineseJournal of Natural Medicines vol 11 no 2 pp 110ndash120 2013

[36] A L Hopkins ldquoNetwork pharmacology the next paradigm indrug discoveryrdquoNature Chemical Biology vol 4 no 11 pp 682ndash690 2008

[37] Y Li C Han J Wang et al ldquoInvestigation into the mechanismof Eucommia ulmoides Oliv based on a systems pharmacologyapproachrdquo Journal of Ethnopharmacology vol 151 no 1 pp452ndash460 2014

[38] Y Yao X Zhang Z Wang et al ldquoDeciphering the combinationprinciples of Traditional Chinese Medicine from a systemspharmacology perspective based on Ma-huang DecoctionrdquoJournal of Ethnopharmacology vol 150 no 2 pp 619ndash638 2013

[39] Bo Zhang Xu Wang and Shao Li ldquoAn Integrative Platform ofTCM Network Pharmacology and Its Application on a HerbalFormula Qing-Luo-Yinrdquo Evidence-Based Complementary andAlternativeMedicine vol 2013 Article ID 456747 12 pages 2013

[40] J Ru P Li J Wang et al ldquoTCMSP a database of systemspharmacology for drug discovery from herbal medicinesrdquoJournal of Cheminformatics vol 6 no 1 p 13 2014

[41] J V Turner D J Maddalena and S Agatonovic-KustrinldquoBioavailability Prediction Based on Molecular Structure for aDiverse Series of Drugsrdquo Pharmaceutical Research vol 21 no 1pp 68ndash82 2004

[42] X XuW Zhang CHuang et al ldquoAnovel chemometricmethodfor the prediction of human oral bioavailabilityrdquo InternationalJournal of Molecular Sciences vol 13 no 6 pp 6964ndash6982 2012

[43] A Zhang W Pan J Lv and H Wu ldquoProtective Effect ofAmygdalin on LPS-Induced Acute Lung Injury by InhibitingNF-120581B and NLRP3 Signaling Pathwaysrdquo Inflammation vol 40no 3 pp 745ndash751 2017

[44] X Wei H Liu X Sun et al ldquoHydroxysafflor yellow A protectsrat brains against ischemia-reperfusion injury by antioxidantactionrdquo Neuroscience Letters vol 386 no 1 pp 58ndash62 2005

[45] W PWalters andM A Murcko ldquoPrediction of lsquodrug-likenessrsquordquoAdvanced Drug Delivery Reviews vol 54 no 3 pp 255ndash2712002

[46] Y Yamanishi M Kotera M Kanehisa and S Goto ldquoDrug-target interactionprediction from chemical genomic and phar-macological data in an integrated frameworkrdquo Bioinformaticsvol 26 no 12 pp i246ndashi254 2010

[47] H Yu J Chen X Xu et al ldquoA systematic prediction ofmultiple drug-target interactions from chemical genomic andpharmacological datardquo PLoS ONE vol 7 no 5 Article IDe37608 2012

[48] X Chen Z L Ji and Y Z Chen ldquoTTD therapeutic targetdatabaserdquo Nucleic Acids Research vol 30 no 1 pp 412ndash4152002

[49] A Hamosh A F Scott J S Amberger C A Bocchini andV AMcKusick ldquoOnline Mendelian Inheritance in Man (OMIM) aknowledgebase of human genes and genetic disordersrdquo NucleicAcids Research vol 33 pp D514ndashD517 2005

[50] T S Keshava Prasad RGoel K Kandasamy et al ldquoHuman pro-tein reference databasemdash2009 updaterdquo Nucleic Acids Researchvol 37 no 1 pp D767ndashD772 2009

[51] A Franceschini D Szklarczyk S Frankild et al ldquoSTRING v91protein-protein interaction networks with increased coverageand integrationrdquoNucleic Acids Research vol 41 no 1 pp D808ndashD815 2013

[52] P Shannon A Markiel O Ozier et al ldquoCytoscape a softwareEnvironment for integratedmodels of biomolecular interactionnetworksrdquo Genome Research vol 13 no 11 pp 2498ndash25042003

[53] G Dennis Jr B T Sherman D A Hosack et al ldquoDAVIDDatabase for Annotation Visualization and IntegratedDiscov-eryrdquo Genome Biology vol 4 no 5 p P3 2003

[54] L Yang X Zhao and X Tang ldquoPredicting disease-related pro-teins based on clique backbone in protein-protein interactionnetworkrdquo International Journal of Biological Sciences vol 10 no7 pp 677ndash688 2014

[55] S MThomas and J S Brugge ldquoCellular functions regulated bySRC family kinasesrdquo Annual Review of Cell and DevelopmentalBiology vol 13 pp 513ndash609 1997

[56] D Z Liu F R Sharp K C Van et al ldquoInhibition of Src familykinases protects hippocampal neurons and improves cognitivefunction after traumatic brain injuryrdquo Journal of Neurotraumavol 31 no 14 pp 1268ndash1276 2014

[57] B D Manning and A Toker ldquoAKTPKB Signaling Navigatingthe Networkrdquo Cell vol 169 no 3 pp 381ndash405 2017

[58] Y Kitagishi and S Matsuda ldquoDiets involved in PPAR andPI3KAKTPTEN pathway may contribute to neuroprotectionin a traumatic brain injuryrdquoAlzheimerrsquos ResearchampTherapy vol5 no 5 p 42 2013

[59] D Chen L Bao S-Q Lu and F Xu ldquoSerum albumin andprealbuminpredict the poor outcomeof traumatic brain injuryrdquoPLoS ONE vol 9 no 3 Article ID e93167 2014

[60] J Yang Z Wu N Renier et al ldquoPathological axonal deaththrough aMapk cascade that triggers a local energy deficitrdquoCellvol 160 no 1-2 pp 161ndash176 2015

[61] E J Huang and L F Reichardt ldquoTrk receptors roles in neuronalsignal transductionrdquoAnnual Review of Biochemistry vol 72 pp609ndash642 2003

[62] J W Lee and R Juliano ldquoMitogenic signal transductionby integrin- and growth factor receptor-mediated pathwaysrdquoMolecules and Cells vol 17 no 2 pp 188ndash202 2004

[63] C S Yang J M Landau M T Huang and H L NewmarkldquoInhibition of carcinogenesis by dietary polyphenolic com-poundsrdquo Annual Review of Nutrition vol 21 pp 381ndash406 2001

[64] A Murakami H Ashida and J Terao ldquoMultitargeted cancerprevention by quercetinrdquoCancer Letters vol 269 no 2 pp 315ndash325 2008

[65] G Du Z Zhao Y Chen et al ldquoQuercetin attenuates neuronalautophagy and apoptosis in rat traumatic brain injury modelvia activation of PI3KAkt signaling pathwayrdquo NeurologicalResearch vol 38 no 11 pp 1ndash8 2016


[66] Q Cai R O Rahn and R Zhang ldquoDietary flavonoidsquercetin luteolin andgenistein reduce oxidativeDNAdamageand lipid peroxidation and quench free radicalsrdquoCancer Lettersvol 119 no 1 pp 99ndash107 1997

[67] G A Bongiovanni E A Soria and A R Eynard ldquoEffectsof the plant flavonoids silymarin and quercetin on arsenite-induced oxidative stress in CHO-K1 cellsrdquo Food and ChemicalToxicology vol 45 no 6 pp 971ndash976 2007

[68] H Li L Yang Y Zhang et al ldquoKaempferol inhibits fibroblastcollagen synthesis proliferation and activation in hypertrophicscar via targeting TGF-beta receptor type Irdquo Biomedicine ampPharmacotherapy = Biomedecine amp Pharmacotherapie vol 83pp 967ndash974 2016

[69] K P Devi D S Malar S F Nabavi et al ldquoKaempferol andinflammation From chemistry to medicinerdquo PharmacologicalResearch vol 99 pp 1ndash10 2015

[70] M Zhou H Ren J Han W Wang Q Zheng and DWang ldquoProtective effects of kaempferol against myocardialischemiareperfusion injury in isolated rat heart via antioxidantactivity and inhibition of glycogen synthase kinase-3120573rdquo Oxida-tive Medicine and Cellular Longevity vol 2015 p 481405 2015

[71] C-F Lee J-S Yang F-J Tsai et al ldquoKaempferol inducesATMp53-mediated death receptor and mitochondrial apop-tosis in human umbilical vein endothelial cellsrdquo InternationalJournal of Oncology vol 48 no 5 pp 2007ndash2014 2016

[72] C Luo H Yang C Tang et al ldquoKaempferol alleviates insulinresistance via hepatic IKKNF-120581B signal in type 2 diabetic ratsrdquoInternational Immunopharmacology vol 28 no 1 pp 744ndash7502015

[73] A B Awad and C S Fink ldquoPhytosterols as anticancer dietarycomponents evidence and mechanism of actionrdquo Journal ofNutrition vol 130 no 9 pp 2127ndash2130 2000

[74] K Farber and H Kettenmann ldquoFunctional role of calciumsignals for microglial functionrdquoGlia vol 54 no 7 pp 656ndash6652006

[75] Y Lu Y Gu X Ding et al ldquoIntracellular Ca2+ homeostasisand JAK1STAT3 pathway are involved in the protective effectof propofol on BV2 microglia against hypoxia-induced inflam-mation and apoptosisrdquo PLoS ONE vol 12 no 5 p e01780982017

[76] K Leroy and J-P Brion ldquoDevelopmental expression and local-ization of glycogen synthase kinase-3120573 in rat brainrdquo Journal ofChemical Neuroanatomy vol 16 no 4 pp 279ndash293 1999

[77] C-M Liu E-M Hur and F-Q Zhou ldquoCoordinating geneexpression and axon assembly to control axon growth Potentialrole ofGSK3 signalingrdquo Frontiers inMolecularNeuroscience vol3 p 3 2012

[78] D A E Cross A A Culbert K A Chalmers L Facci S DSkaper and A D Reith ldquoSelective small-molecule inhibitors ofglycogen synthase kinase-3 activity protect primary neuronesfrom deathrdquo Journal of Neurochemistry vol 77 no 1 pp 94ndash102 2001

[79] V S Ossovskaya and NW Bunnett ldquoProtease-activated recep-tors contribution to physiology and diseaserdquo PhysiologicalReviews vol 84 no 2 pp 579ndash621 2004

[80] M Steinhoff J Buddenkotte V Shpacovitch et al ldquoProteinase-activated receptors transducers of proteinase-mediated signal-ing in inflammation and immune responserdquoEndocrine Reviewsvol 26 no 1 pp 1ndash43 2005

[81] H Krenzlin V Lorenz S Danckwardt O Kempski and BAlessandri ldquoThe importance of thrombin in cerebral injury and

diseaserdquo International Journal of Molecular Sciences vol 17 no1 2016

[82] M J McGinn and J T Povlishock ldquoPathophysiology of Trau-matic Brain InjuryrdquoNeurosurgery Clinics of North America vol27 no 4 pp 397ndash407 2016

[83] T Woodcock and M C Morganti-Kossmann ldquoThe role ofmarkers of inflammation in traumatic brain injuryrdquo Frontiersin Neurology vol 4 article 18 2013

[84] F Tanriverdi H J Schneider G Aimaretti B E Masel F FCasanueva and F Kelestimur ldquoPituitary dysfunction after trau-matic brain injury A clinical and pathophysiological approachrdquoEndocrine Reviews vol 36 no 3 pp 305ndash342 2015

[85] J V Rosenfeld A I Maas P Bragge M C Morganti-Kossmann G T Manley and R L Gruen ldquoEarly managementof severe traumatic brain injuryrdquoThe Lancet vol 380 no 9847pp 1088ndash1098 2012

[86] B M Aertker S Bedi and C S Cox ldquoStrategies for CNS repairfollowing TBIrdquo Experimental Neurology vol 275 no 3 pp 411ndash426 2016

[87] K Adachi Z Mirzadeh M Sakaguchi et al ldquo120573-catenin signal-ing promotes proliferation of progenitor cells in the adultmousesubventricular zonerdquo Stem Cells vol 25 no 11 pp 2827ndash28362007

[88] Y Hirabayashi and Y Gotoh ldquoStage-dependent fate determina-tion of neural precursor cells in mouse forebrainrdquo NeuroscienceResearch vol 51 no 4 pp 331ndash336 2005

[89] S Ding T Y H Wu A Brinker et al ldquoSynthetic smallmolecules that control stem cell faterdquo Proceedings of theNationalAcadamy of Sciences of the United States of America vol 100 no13 pp 7632ndash7637 2003

[90] N Israsena M Hu W Fu L Kan and J A Kessler ldquoThepresence of FGF2 signaling determines whether 120573-cateninexerts effects on proliferation or neuronal differentiation ofneural stem cellsrdquo Developmental Biology vol 268 no 1 pp220ndash231 2004

[91] A Salehi A Jullienne M Baghchechi et al ldquoUp-regulation ofWnt120573-catenin expression is accompanied with vascular repairafter traumatic brain injuryrdquo Journal of Cerebral Blood Flow ampMetabolism vol 38 no 2 pp 274ndash289 2017

[92] L F Reichardt and K J Tomaselli ldquoExtracellular matrixmolecules and their receptors Functions in neural develop-mentrdquoAnnual Review of Neuroscience vol 14 pp 531ndash570 1991

[93] R M Gibson S E Craig L Heenan C Tournier and M JHumphries ldquoActivation of integrin 12057251205731 delays apoptosis ofNtera2 neuronal cellsrdquoMolecularandCellularNeuroscience vol28 no 3 pp 588ndash598 2005

[94] C C Tate A J Garcıa andMC LaPlaca ldquoPlasma fibronectin isneuroprotective following traumatic brain injuryrdquoExperimentalNeurology vol 207 no 1 pp 13ndash22 2007

[95] C Culmsee and M P Mattson ldquop53 in neuronal apoptosisrdquoBiochemical and Biophysical Research Communications vol 331no 3 pp 761ndash777 2005

[96] M S Geddis and V Rehder ldquoThe phosphorylation state ofneuronal processes determines growth cone formation afterneuronal injuryrdquo Journal of Neuroscience Research vol 74 no2 pp 210ndash220 2003

[97] M L Craske M Fivaz N N Batada and T Meyer ldquoSpines andneurite branches function as geometric attractors that enhanceprotein kinase C actionrdquoThe Journal of Cell Biology vol 170 no7 pp 1147ndash1158 2005


[98] A Muscella C Vetrugno L G Cossa et al ldquoApoptosis by[Pt(OOrsquo-acac)(gamma-acac)(DMS)] requires PKC-deltamedi-ated p53 activation in malignant pleural mesotheliomardquo PloSone vol 12 no 7 Article ID e0181114 2017

[99] J S Bonini W C Da Silva L R M Bevilaqua J H MedinaI Izquierdo and M Cammarota ldquoOn the participation ofhippocampal PKC in acquisition consolidation and reconsol-idation of spatial memoryrdquo Neuroscience vol 147 no 1 pp 37ndash45 2007

[100] O Zohar R Lavy X Zi et al ldquoPKC activator therapeutic formild traumatic brain injury in micerdquo Neurobiology of Diseasevol 41 no 2 pp 329ndash337 2011

[101] J David Sweatt ldquoTheneuronalMAPkinase cascade a biochem-ical signal integration system subserving synaptic plasticity andmemoryrdquo Journal ofNeurochemistry vol 76 no 1 pp 1ndash10 2001

[102] Y Matsuoka M Picciano B Maleste et al ldquoInflammatoryresponses to amyloidosis in a transgenic mouse model ofAlzheimerrsquos diseaserdquo The American Journal of Pathology vol158 no 4 pp 1345ndash1354 2001

[103] L Esposito L Gan G-Q Yu C Essrich and L MuckeldquoIntracellularly generated amyloid-120573 peptide counteracts theantiapoptotic function of its precursor protein and primesproapoptotic pathways for activation by other insults in neu-roblastoma cellsrdquo Journal of Neurochemistry vol 91 no 6 pp1260ndash1274 2004

[104] D J Loane A Pocivavsek C E-H Moussa et al ldquoAmyloidprecursor protein secretases as therapeutic targets for traumaticbrain injuryrdquo Nature Medicine vol 15 no 4 pp 377ndash379 2009

[105] R Torres B L Firestein H Dong et al ldquoPDZ proteins bindcluster and synaptically colocalize with Eph receptors and theirephrin ligandsrdquo Neuron vol 21 no 6 pp 1453ndash1463 1998

[106] M B Dalva M A Takasu M Z Lin et al ldquoEphB receptorsinteract with NMDA receptors and regulate excitatory synapseformationrdquo Cell vol 103 no 6 pp 945ndash956 2000

[107] J M Basak P B Verghese H Yoon J Kim and D MHoltzman ldquoLow-density lipoprotein receptor represents anapolipoprotein E-independent pathway of A120573 uptake anddegradation by astrocytesrdquoThe Journal of Biological Chemistryvol 287 no 17 pp 13959ndash13971 2012

[108] L Yao X Gu Q Song et al ldquoNanoformulated alpha-mangostinameliorates Alzheimerrsquos disease neuropathology by elevatingLDLR expression and accelerating amyloid-beta clearancerdquoJournal of Controlled Release vol 226 pp 1ndash14 2016

Stem Cells International

Hindawiwwwhindawicom Volume 2018


MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine


Behavioural Neurology

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom


(ie intracranial pressure) and the preventive measures toreduce morbidity and mortality [14] Despite the fact thatdetailed medicines contain free-radical scavengers antago-nists of N-methyl-D-aspartate and calcium channel blockers[15] the results of the controlled clinical trials of these drugsare disappointing [16] Neuroscientists and doctors tend tosearch for potential novel drugs from traditional Chinesemedicine (TCM) library to treat TBI [17]

TCM is a comprehensive medicinal system that has beenused in clinical practice for thousands of years and playsan important role in the health maintenance for people allover the world [18 19] The validated curative effects of TCMmake it a feasible alternative therapeutic agent for diseasetreatment Xuefu Zhuyu decoction (XFZYD) a representa-tive TCM formula was first recorded in Correction of Errorsin Medical Works by Qing-ren Wang XFZYD consists of11 crude herbs Persicae Semen (Tao ren) Carthami Flos(Hong hua) Radix Paeoniae Rubra (Chi shao) ChuanxiongRhizoma (Chuan xiong) Achyranthis Bidentatae Radix (Niuxi) Angelicae Sinensis Radix (Dang gui) Rehmannia glutinosaLibosch (Sheng di huang) Platycodon Grandiforus (Jie geng)Aurantii Fructus (zhi qiao) Radix Bupleuri (chai hu) andlicorice (Gan cao)Themain chemicals from XFZYD includeflavonoids organic acids terpenoids and steroidal saponins[20ndash22] The formula has been proven reliable and effectivefor curing various diseases including unstable angina pectoris[23 24] coronary artery disease [25] thromboembolic stroke[26] ischemic stroke [27] and TBI The therapeutic agent ofXFZYD is to promote blood circulation and remove bloodstasis according to the TCM theory Several randomizedcontrolled clinical trials and animal experiments have showeddefinite therapeutic effects of XFZYD for the treatment ofTBI [28ndash31] Recent researches demonstrate that XFZYDprovides neuroprotection via anti-inflammatory pathway andcognitive improvement through synaptic regulation [32 33]However merely these evidences to explain the multipletherapeutic mechanisms of TCM for TBI treatment areunavailable Because the effects of TCM are always contro-versial in terms of their abstract theory unclear basis com-plex interactions between various ingredients and complexinteractive biological systems [25] it is essential to developan advanced technique to deeply uncover the synthesizedpharmacological effects of XFZYD in the treatment of TBI

With the development of TCM modernization networkpharmacology has become a novel method to elucidate themulti-druggable targets effects of TCM [34] TCM networkpharmacology first proposed by Shao Li [35] makes itfeasible to understand the effective constituents and targetsof the herbs from TCM formula This analytical methodintegrates bioinformatics systems biology and polypharma-cology and further utilizes network analysis to imply themultiple actions of drugs across multiple scales ranging frommolecularcellular to tissueorganism levels [36 37] Coin-ciding with the holistic and systemic characteristics of TCMnetwork pharmacology is expected to bridge the gap betweenTCM and modern medicine [25] Previous researches haveclarified the scientific basis and systematic features of herbalmedicine to treat diseases through network pharmacologysuch asQing-Luo-Yin andMa-HuangDecoction etc [38 39]

In the present work we explored the pharmacologicalmechanisms of XFZYD acting on TBI via a network pharma-cology approach Network analyses and molecular dockingmethod were used to reveal candidate drug targets relatedto TBI Target analysis suggested that XFZYD regulatedseveral key biological processes of TBI development suchas apoptosis inflammation blood coagulation and axongenesis These processes contributed to the clarifying of themolecular mechanisms of XFZYD for TBI treatment Thiswill help to improve the effectiveness and specificity of TCMclinical usage (Figure 1 depicts a flowchart of the entireresearch procedure)

2 Methods

21 Database Construction The chemical ingredients of11 herbs in XFZYD were screened from Traditional Chi-nese Medicine Systems Pharmacology database (TCMSPhttplspnwueducntcmspphp) [40] As a chemically ori-ented herbal encyclopedia TCMSP can provide comprehen-sive information about herb ingredients including chemicalstructural data oral bioavailability drug targets and theirrelationships with diseases as well as the biological or physio-logical consequences of drug actions involving drug-likenessintestinal epithelial permeability and aqueous solubility [40]The structures of these compoundswere saved asmol2 formatfor further analysis Discovery studio 25 was employed tooptimize these molecules with a Merck molecular force field(MMFF) All detailed information about these ingredients isprovided in Table S1

22 Pharmacokinetic Prediction Due to the disadvantagesof biological experiments as being time-consuming and ofhigh cost identification of ADME (absorption distributionmetabolism and excretion) properties by in silico toolshas now become a necessary paradigm in pharmaceuticalresearch In this study 2 ADME-related models includingthe evaluation of oral bioavailability (OB) and drug-likeness(DL) were employed to identify the potential bioactivecompounds of XFZYD

Oral bioavailability (OB) one of the most importantpharmacokinetic parameters represents the speed of a drugof becoming available to the body and the eventuallyabsorbed extent of the oral dose [41] which is particularly sig-nificant in drug discovery of TCM formost oral Chinese herbformulas Poor OB is indeed the main reason responsible forthe unsuccessful development of compounds into therapeuticdrugs in drug screening cascades Here a reliable in silicomodel OBioavail 11 [42] which integrates the metabolism(P450 3A4) and transport (P-glycoprotein) information wasemployed to calculate the OB values of herbal ingredientsIn this study OBge30 (a suggested criterion by TCMSPdatabase) was regarded as one threshold for screening pos-sible candidate drugs presently while 2 compounds withOB le 30 were also taken into consideration due to theirtherapeutic effects according to literatures such as amygdalinand hydroxysafflor yellow A [43 44]

Drug-likeness (DL) is a qualitative profile used in drugdesign to evaluate whether a compound is chemically suitable






HB-cC-cT network



OB DL

STRING


Cytoscape 340

TTD amp OMIM



pathway analysis







119879 (119883119884) =119883 sdot 119884

1198832 + 1198842 minus 119883 sdot 119884(1)

















3 Results















50

40

30

20

10

0

50

40

40

30

20

20

10

0

0

10 30 50 70 90 110

60

60

60

01 02 03 04 05 06 07 08


minus2 minus1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

70

minus1 1 3 5 7 9 11 13 15 17

perc

entage

s (

)

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

perc

entage

s (

)

40

20

0

60

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

OB

MW

nHdon

DL

nHacc

Distribution

Distribution

Distribution

Distribution

Distribution

Distribution

AlogP









Jun herbs(29)

Zuo-

Shi h

erbs

(101

)

Chen herbs

(23)

1

2

15

(a)

Jun herbs(5)

Zuo-

Shi h

erbs

(48)

Chen herbs

(10)

9

10

14189

(b)

20Mol 1200000


Mol 8888






MMol 73Mol 77333222

ABATABATA

MAPK3MAPKMAPK

UGT1A1GT1UGT1A1

GOT1GOTT1

SREBF1REBFSREBF1

RXRBRXRBRXRB

CYP19A1CYP19A1YP19A

PLB1PLBPLB1

FASLGFASLGASL

BCHEBCHHE

HSD3B1HSD3

MTTPMTT

CES1CES

TIMP1TIMP

ATP5BATP5

MAPK10MAPK 0

BADBAD

CHRM5CHRM5

EPHBEPHBPHB2

HSD3B2HSD3B2SD3B

SOAT2OATSOAT2

FASNFASNFASN

MT-ND6MT-N


PKIAAIA

ADH1AADHAD

AKR1C1KR1AKR1C1

CREB1CREBB1

HMGCRMGHMGCR

SOAT1OAT

ABCC1ABCC

OPRD1OPRDOPRD1

VCPVCP

LDLRLDLR

ADRA1DDRAA1D


EGLN1GLNGLNGLNGLN



ALOX12LOXLOXOXLOX



Mol 40









JUNJUNNJUNNN




CCCALCCC MMMMMMSS















PPPPARAPARPARPAR







BAXXXXB X ESR1




IL888IL88




Quercetin

Mol 9444444

Mol 99

Mol 63

Mol 75555


Mol 158



Mol 6Mol 6666M 66




Mol 11MMol 1155Mol 11555M6060660



Mol 9000







Radixadixdix

Mol 84



0Mol 200000


Mol 151

Mol 126Mol 126Mol 12666



Mol 444


Mol 133


Mol 142Mol 1422

Mol 36


Mol 277Mol 135Mol 13555M 555




MMol 83333

Mol 110Mol 110

Mol 119MMol 11999999


Mol 5444

Mol 39999999

Mol 150MMol 155000M 0

Mol 611

21Mol 21MMol 221111

Mol 13



Mol 466




Mol 14Mol 1444


Mol 87



MAP2MAP2MAPMAPMAP

IL2I 2L22L22




F2






Mol 131


Mol 111


Mol 744444Mol 77




Mol 138MMol 1388M


Mol 42MMMol 42M

MMMol 3Mol 3







RadixRadixRadix
















BIL1BIL1BIL1BIL1BB




PPPPPARPP GGGGGGPPP


ESR2



CDK2


PIM1 GSK3B









MGAMMGAMMGAMGAAM

KCNH2222










PDE3APDE3AA




IL6666

HK2HK2HK2HK2HK2HK2




NCF1NCFNCFNCF1NCFN





MMMol 132

MMMol 57

CRPCRPCRPCRPPHH


BCGABCGABCG2BCGA









RELARELARELAAAR


EGFREGFRGFREGFREGFR


E2F2E2F2E2F2E2F2E

APPAPAPPAPPPAPPAPPA






Mol 127


DPP4



XDHXDHXDHHHXDH

PTGS2























ICAM1CAMCAMM1CAMI


IGF2IGF2IGF2IGF2F




CHRM1CHRM11CHRM11


PRKACA

TOP2TOP2



ACHE

ADRB1ADRBRBADRBADR

ADRADRADRA2A2AA2A

SOD1SSODSOD1D11

NOS33


PGR

HHMOX11MOXMOXHMOX



FOSL2OSLOSLOSL22FO



PON1PONPONPONN1PON

PIK3CGPIK3CGGG


AKT1AKTT1AKT11A



ADRB2

(c)













BLMH

GPRASP2

GJC2

CAMK2N1

OBSL1

ZNF292

RLFAMPD3

NANOS1CAMTA1HYPKCCS

DLGAP4PF4V1

TRIM2

CHKB

F8A1

TIAM1

BMX

RAPGEF1

APBB1

KCNMA1

XRCC6

TTR

TGM2MAP2

PRNP


ACE

TGFB2

AP2M1GRAP2

SCN5A

MYH9

PKN1

ACHE

SLC25A13

PHKG1

SPAST

UMOD

PRPF40B

BBC3

TUBA4A TTPALRYR2

STUB1KRT6A

AKAP8L

GFI1BTHRAP3

ZNF232

SOD1

CRKL

CDH2

MBP MAP2K2

DCN

MAP3K5NGFR

PIK3CA

ITGA2

DNM1

RAP1A

GRIN2B

PTPN11

PRKCA

LDLRAP1

DNAJA3INA

SP3

CACNA2D3

CSF1

CNTF

TNFRSF1B

BCL10

KLC1

DCTN1

IDE

SERPINA3

HSPA1A

HSPG2

FN1

LRP2

TUBB

GRIN2A

YWHAB

CAMK2D

HTRA2

PRKCE

CRYAB

APC

GIT1

PIAS4

HPX

TRIP10

PDE4B

MARK4

PLAT

UBE2K

APOC2

LIN7B BGN

MAP3K10MAPK8IP2

CBS

SH3GL3

STAU1

CASP6

PPP5C

KRT16

DAB1

CASP1SHC2

CTSD

UCHL1

HP

SNCACAMK2G

TGFB1

GNB1

PTPN1PIN1

TJP1

CASP8PLCG1

NPHS1

PPP2R2A

DNAJB1

ADRBK1

INADL

NCSTN

MATK

NEDD4L

KAT5IFNGTBP

FRS2

CSNK1A1

CALRKNG1

SGOL2

KRT6B

TRAF3 DLG3

SACS

BDKRB2PRKCB

CAV1

MAPK3F2 SMAD3

APOEAKAP9 RANBP2

CLTC

TSC22D1GAB2PSEN2

MLF1CROT

KRT9

ADRA1B

EPB41

COL4A1

SHC3

ARHGAP32

ATM

PPP2R5A

CAMK2A

NTRK1

KRT18

TNFAPOA2

LAT

GRIN2D

COL4A6

KLK3

VLDLR

COL4A5

COL4A2

NEFH

OR8D2

MTSS1

PDZRN4

PTPN4

OR3A2

OR2T6

DGKG

CASP3

IGF1R

CASK

DRD2

TRAF2

EPHB2

PPM1A

PRKCG

CACNB3

HNRNPUSIN3A

DLG1

CLU

RAP2A

ERBB4CANX

BACE1 GABBR1

KARS

CNOT1

UNG

AGA CDCP1

UTP14A PLAG1

EXOC6

HRAS

CTNNB1

SP1

NOS3 SUMO1

PSEN1

HSPA8

HSP90AA1

BCL2

GNAO1

RPS6KB1

PARK2

DLG4

PTK2B

GSN

NAE1 TLN2LRFN2

PLTP

NUMBLSTX1A

DERL1

NEFM

HMOX2

AATF

PPIAMTRNR2L2AP1M1

OGT

DDB1

AP4M1

MED31

RGS3

TDP2

KRT5

ADAM9

REST

PACSIN1

SHB

CTSL1

LAMA1

SH2B1

PLA2G4F

SMURF2

SLC9A8

KRT14

CIT

TGFB1I1

PPP2R1APIK3R1

NUMB

ADAM17

DLG2

LRP1

APOA4

LTA

IRS1

GSK3B

EGFR

CTSB

TRAF6

SHC1

PPP2CB

NGF

HTT

PPIDLDB3

APOC1HIP1

ZDHHC17COL25A1MAGI3

ITGB5

ACTB

GNA11

ACTN2CAMK2B

CDK1

LIN7C

S100B

PDLIM5

DLGAP1

LIN7A

TPR

SYNGAP1

CFD

GRIN3A

F12

SLC1A3

GRK5

CACNA2D2

TANC1

DUSP4

EXOC4

AHSG

GRIN3B

UCP2

TTN

GPC1

NSF

FGA

DYNLL1

MAPK8IP1

PICALM

PPBP

ITM2B

NID1

STXBP1

CTBP1

SGK1

TRAF1

SQSTM1

TNFRSF1A

ACTN1

OPTN

UBE2D2

AP2A2

FUS

APOA1

DICER1

CACNA1B

CST3

NCOA3

SCARB1

APOC3

SLC6A3

KIAA1551 KRT13

DCD

KIAA0232

ENSG00000258818

SPATA31A7

CTAGE5

CEP44

SH2B2

EPHB4

CAPN1

F7

APBA2

COL4A3

LDLR

GIPC1

GFAP

SERPING1

SRC

MAPK12APP

GAPDH

CDK5

CREBBP

NOS1

YWHAZCALM1

YWHAG

YWHAQGRIN1

RPS6KA3

COL1A2

TCERG1

A2M

CASP7

LRP8

PDK2

AGTR1

FYN

ALBGRB2

MAPK1AKT1

STAT1

MAPT

GSK3A

UBB

PPP2CA

SMAD4

PRKCD

RGS12

SPTB

SH3BP5

CACNA1I

IL16

SLA2

PFN2

NLRC4

TNFRSF14

PRTN3

SNCB

FBLN1

BACE2

SETX

FANCD2

SAP30

RANBP3

PALB2

SLC1A5RASA1

HAP1

LRRC7

CFB

ADRBK2

CDC45

CLSTN3

PCED1B

SCAF1KIAA1377

FAM71E2

FEZ1 ACSBG2

PCDH1

TRAPPC11QTRTD1

KRT1

LRP1B

HADHB

TP53BP2

DRD1

ST13

PRPF40A

TRAIP

KIDINS220

GRK6

MMP17

LTBR

EIF6

PGAM1

CHD3

PRSS3

APBB3

CHRNA7

KRT10

RIMS1

CRMP1

PDIK1L

SORBS3

SYMPK

GCN1L1

RNF19A

HOMER3

GRK4

JARID2

MYLK3

EFS

CRB1

HSD17B10

TST

HOMER2

PHC3

TM2D1 FICD

PEG3

CABLES1

LGALS2

ITIH1

HOXB2

TAF4FLOT1

BABAM1

CFH

HIP1R

LTBMYL4

NCOR1

CASP4

NF1

AP4E1

CLCA2

IGDCC4

NECAB3

CXorf27

SH3GLB1

CTCF

PLCG2

(a)

STAT1

EGFR

FN1

PLAT

SOD1

PRKCA CDK1

GSK3B

ALB APP

PPP3CA

IFNG

BBC3

SCN5A

KCNMA1

MAP2

ACHE

MAPK3F2

PTPN1

NOS3 BCL2

CAV1

CTNNB1

PRKCB

TGFB1CASP8

TNF

AKT1

F7

MAPK1LDLR

PRKCD

SLC6A3

DRD1

CASP3

CHRNA7

PRSS3

TP53BP2

CASP7

EPHB2

SYNGAP1

CALM1

CTSD

BACE1

ADRA1B

(b)







0

001

002

003

004

005

006

007

008

0 20 40 60 80 100 120 140 160 180

Betw

eenn

ess

Degree

APP

ALB SRCEGFR

AKT1HTT






Mol 22Mol 33


Mol 97Mol 106


Mol 63Mol 90

Mol 87

Mol 91Mol 61

Mol 19

Mol 109

Mol 161

Mol 118

Mol 111

Mol 158

Mol 114

Mol 149

Mol 141

Mol 152

Mol 14

CASP3

BCL2

NOS3

SCN5A

F7

ADRA1B

ACHE

F2

Mol 4

Mol 49

Mol 127

APP CASP7

Mol 92

Mol 54

Mol 6

Mol 36

KCNMA1

Mol 27


Mol 17

Mol 39

Mol 2

Mol 21

Mol 12

Mol 142

Mol 126

Mol 135

Mol 121

Mol 119

Mol 124

Mol 120

Mol 117

Mol 133

Mol 131

Mol 134


Aurantii Fructus

Licorice

Radix Bupleuri



Mol 8

Mol 73

Mol 75

Mol 77

Mol 80

Mol 7

Mol 82

Mol 76

Mol 74

Mol 60

Mol 46

Mol 150

Mol 151

Mol 112

Mol 115

Mol 11

Mol 116

Mol 113

Mol 110

Mol 1




Mol 35Mol 81

Mol 86

Mol 85

Mol 84

Mol 88

Mol 83Mol 30

Mol 137

ChuanxiongRhizoma

Mol 3

Mol 57

Mol 139

Achyranthis

Bidentatae

RadixMol 102

CASP8

IGHG1AKT1p53

CHRNA7

Mol 40

SLC6A3 PTPN1

SOD1MAPK1

Mol 38

Mol 95

Carthami Flos

Mol 24


Mol 122

Mol 25

Mol 98

TGFB1

GSK3B

PRKCA


Mol 52

Mol 42

Mol 62

Mol 138

EGFR

STAT1 PPP3CAPLAT

Stigmasterol

MAP2


Kaempferol

SYNGAP1

CALM

Baicalin

PRKCB

CAV1

CTSD

TNF

DRD1

CDK1

IFNG

FN1BBC3 PRKCD

Mol 132

Mol 160

Mol 58

Mol 67

Mol 69 Mol 43ALB

Mol 64CTNNB1


Achyranthisiistntnt


RadixadixR diR di


























KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A




TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia






LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3



4 Discussion









(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
























HB-cC-cT network



OB DL

STRING


Cytoscape 340

TTD amp OMIM



pathway analysis







119879 (119883119884) =119883 sdot 119884

1198832 + 1198842 minus 119883 sdot 119884(1)

















3 Results















50

40

30

20

10

0

50

40

40

30

20

20

10

0

0

10 30 50 70 90 110

60

60

60

01 02 03 04 05 06 07 08


minus2 minus1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

70

minus1 1 3 5 7 9 11 13 15 17

perc

entage

s (

)

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

perc

entage

s (

)

40

20

0

60

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

OB

MW

nHdon

DL

nHacc

Distribution

Distribution

Distribution

Distribution

Distribution

Distribution

AlogP









Jun herbs(29)

Zuo-

Shi h

erbs

(101

)

Chen herbs

(23)

1

2

15

(a)

Jun herbs(5)

Zuo-

Shi h

erbs

(48)

Chen herbs

(10)

9

10

14189

(b)

20Mol 1200000


Mol 8888






MMol 73Mol 77333222

ABATABATA

MAPK3MAPKMAPK

UGT1A1GT1UGT1A1

GOT1GOTT1

SREBF1REBFSREBF1

RXRBRXRBRXRB

CYP19A1CYP19A1YP19A

PLB1PLBPLB1

FASLGFASLGASL

BCHEBCHHE

HSD3B1HSD3

MTTPMTT

CES1CES

TIMP1TIMP

ATP5BATP5

MAPK10MAPK 0

BADBAD

CHRM5CHRM5

EPHBEPHBPHB2

HSD3B2HSD3B2SD3B

SOAT2OATSOAT2

FASNFASNFASN

MT-ND6MT-N


PKIAAIA

ADH1AADHAD

AKR1C1KR1AKR1C1

CREB1CREBB1

HMGCRMGHMGCR

SOAT1OAT

ABCC1ABCC

OPRD1OPRDOPRD1

VCPVCP

LDLRLDLR

ADRA1DDRAA1D


EGLN1GLNGLNGLNGLN



ALOX12LOXLOXOXLOX



Mol 40









JUNJUNNJUNNN




CCCALCCC MMMMMMSS















PPPPARAPARPARPAR







BAXXXXB X ESR1




IL888IL88




Quercetin

Mol 9444444

Mol 99

Mol 63

Mol 75555


Mol 158



Mol 6Mol 6666M 66




Mol 11MMol 1155Mol 11555M6060660



Mol 9000







Radixadixdix

Mol 84



0Mol 200000


Mol 151

Mol 126Mol 126Mol 12666



Mol 444


Mol 133


Mol 142Mol 1422

Mol 36


Mol 277Mol 135Mol 13555M 555




MMol 83333

Mol 110Mol 110

Mol 119MMol 11999999


Mol 5444

Mol 39999999

Mol 150MMol 155000M 0

Mol 611

21Mol 21MMol 221111

Mol 13



Mol 466




Mol 14Mol 1444


Mol 87



MAP2MAP2MAPMAPMAP

IL2I 2L22L22




F2






Mol 131


Mol 111


Mol 744444Mol 77




Mol 138MMol 1388M


Mol 42MMMol 42M

MMMol 3Mol 3







RadixRadixRadix
















BIL1BIL1BIL1BIL1BB




PPPPPARPP GGGGGGPPP


ESR2



CDK2


PIM1 GSK3B









MGAMMGAMMGAMGAAM

KCNH2222










PDE3APDE3AA




IL6666

HK2HK2HK2HK2HK2HK2




NCF1NCFNCFNCF1NCFN





MMMol 132

MMMol 57

CRPCRPCRPCRPPHH


BCGABCGABCG2BCGA









RELARELARELAAAR


EGFREGFRGFREGFREGFR


E2F2E2F2E2F2E2F2E

APPAPAPPAPPPAPPAPPA






Mol 127


DPP4



XDHXDHXDHHHXDH

PTGS2























ICAM1CAMCAMM1CAMI


IGF2IGF2IGF2IGF2F




CHRM1CHRM11CHRM11


PRKACA

TOP2TOP2



ACHE

ADRB1ADRBRBADRBADR

ADRADRADRA2A2AA2A

SOD1SSODSOD1D11

NOS33


PGR

HHMOX11MOXMOXHMOX



FOSL2OSLOSLOSL22FO



PON1PONPONPONN1PON

PIK3CGPIK3CGGG


AKT1AKTT1AKT11A



ADRB2

(c)













BLMH

GPRASP2

GJC2

CAMK2N1

OBSL1

ZNF292

RLFAMPD3

NANOS1CAMTA1HYPKCCS

DLGAP4PF4V1

TRIM2

CHKB

F8A1

TIAM1

BMX

RAPGEF1

APBB1

KCNMA1

XRCC6

TTR

TGM2MAP2

PRNP


ACE

TGFB2

AP2M1GRAP2

SCN5A

MYH9

PKN1

ACHE

SLC25A13

PHKG1

SPAST

UMOD

PRPF40B

BBC3

TUBA4A TTPALRYR2

STUB1KRT6A

AKAP8L

GFI1BTHRAP3

ZNF232

SOD1

CRKL

CDH2

MBP MAP2K2

DCN

MAP3K5NGFR

PIK3CA

ITGA2

DNM1

RAP1A

GRIN2B

PTPN11

PRKCA

LDLRAP1

DNAJA3INA

SP3

CACNA2D3

CSF1

CNTF

TNFRSF1B

BCL10

KLC1

DCTN1

IDE

SERPINA3

HSPA1A

HSPG2

FN1

LRP2

TUBB

GRIN2A

YWHAB

CAMK2D

HTRA2

PRKCE

CRYAB

APC

GIT1

PIAS4

HPX

TRIP10

PDE4B

MARK4

PLAT

UBE2K

APOC2

LIN7B BGN

MAP3K10MAPK8IP2

CBS

SH3GL3

STAU1

CASP6

PPP5C

KRT16

DAB1

CASP1SHC2

CTSD

UCHL1

HP

SNCACAMK2G

TGFB1

GNB1

PTPN1PIN1

TJP1

CASP8PLCG1

NPHS1

PPP2R2A

DNAJB1

ADRBK1

INADL

NCSTN

MATK

NEDD4L

KAT5IFNGTBP

FRS2

CSNK1A1

CALRKNG1

SGOL2

KRT6B

TRAF3 DLG3

SACS

BDKRB2PRKCB

CAV1

MAPK3F2 SMAD3

APOEAKAP9 RANBP2

CLTC

TSC22D1GAB2PSEN2

MLF1CROT

KRT9

ADRA1B

EPB41

COL4A1

SHC3

ARHGAP32

ATM

PPP2R5A

CAMK2A

NTRK1

KRT18

TNFAPOA2

LAT

GRIN2D

COL4A6

KLK3

VLDLR

COL4A5

COL4A2

NEFH

OR8D2

MTSS1

PDZRN4

PTPN4

OR3A2

OR2T6

DGKG

CASP3

IGF1R

CASK

DRD2

TRAF2

EPHB2

PPM1A

PRKCG

CACNB3

HNRNPUSIN3A

DLG1

CLU

RAP2A

ERBB4CANX

BACE1 GABBR1

KARS

CNOT1

UNG

AGA CDCP1

UTP14A PLAG1

EXOC6

HRAS

CTNNB1

SP1

NOS3 SUMO1

PSEN1

HSPA8

HSP90AA1

BCL2

GNAO1

RPS6KB1

PARK2

DLG4

PTK2B

GSN

NAE1 TLN2LRFN2

PLTP

NUMBLSTX1A

DERL1

NEFM

HMOX2

AATF

PPIAMTRNR2L2AP1M1

OGT

DDB1

AP4M1

MED31

RGS3

TDP2

KRT5

ADAM9

REST

PACSIN1

SHB

CTSL1

LAMA1

SH2B1

PLA2G4F

SMURF2

SLC9A8

KRT14

CIT

TGFB1I1

PPP2R1APIK3R1

NUMB

ADAM17

DLG2

LRP1

APOA4

LTA

IRS1

GSK3B

EGFR

CTSB

TRAF6

SHC1

PPP2CB

NGF

HTT

PPIDLDB3

APOC1HIP1

ZDHHC17COL25A1MAGI3

ITGB5

ACTB

GNA11

ACTN2CAMK2B

CDK1

LIN7C

S100B

PDLIM5

DLGAP1

LIN7A

TPR

SYNGAP1

CFD

GRIN3A

F12

SLC1A3

GRK5

CACNA2D2

TANC1

DUSP4

EXOC4

AHSG

GRIN3B

UCP2

TTN

GPC1

NSF

FGA

DYNLL1

MAPK8IP1

PICALM

PPBP

ITM2B

NID1

STXBP1

CTBP1

SGK1

TRAF1

SQSTM1

TNFRSF1A

ACTN1

OPTN

UBE2D2

AP2A2

FUS

APOA1

DICER1

CACNA1B

CST3

NCOA3

SCARB1

APOC3

SLC6A3

KIAA1551 KRT13

DCD

KIAA0232

ENSG00000258818

SPATA31A7

CTAGE5

CEP44

SH2B2

EPHB4

CAPN1

F7

APBA2

COL4A3

LDLR

GIPC1

GFAP

SERPING1

SRC

MAPK12APP

GAPDH

CDK5

CREBBP

NOS1

YWHAZCALM1

YWHAG

YWHAQGRIN1

RPS6KA3

COL1A2

TCERG1

A2M

CASP7

LRP8

PDK2

AGTR1

FYN

ALBGRB2

MAPK1AKT1

STAT1

MAPT

GSK3A

UBB

PPP2CA

SMAD4

PRKCD

RGS12

SPTB

SH3BP5

CACNA1I

IL16

SLA2

PFN2

NLRC4

TNFRSF14

PRTN3

SNCB

FBLN1

BACE2

SETX

FANCD2

SAP30

RANBP3

PALB2

SLC1A5RASA1

HAP1

LRRC7

CFB

ADRBK2

CDC45

CLSTN3

PCED1B

SCAF1KIAA1377

FAM71E2

FEZ1 ACSBG2

PCDH1

TRAPPC11QTRTD1

KRT1

LRP1B

HADHB

TP53BP2

DRD1

ST13

PRPF40A

TRAIP

KIDINS220

GRK6

MMP17

LTBR

EIF6

PGAM1

CHD3

PRSS3

APBB3

CHRNA7

KRT10

RIMS1

CRMP1

PDIK1L

SORBS3

SYMPK

GCN1L1

RNF19A

HOMER3

GRK4

JARID2

MYLK3

EFS

CRB1

HSD17B10

TST

HOMER2

PHC3

TM2D1 FICD

PEG3

CABLES1

LGALS2

ITIH1

HOXB2

TAF4FLOT1

BABAM1

CFH

HIP1R

LTBMYL4

NCOR1

CASP4

NF1

AP4E1

CLCA2

IGDCC4

NECAB3

CXorf27

SH3GLB1

CTCF

PLCG2

(a)

STAT1

EGFR

FN1

PLAT

SOD1

PRKCA CDK1

GSK3B

ALB APP

PPP3CA

IFNG

BBC3

SCN5A

KCNMA1

MAP2

ACHE

MAPK3F2

PTPN1

NOS3 BCL2

CAV1

CTNNB1

PRKCB

TGFB1CASP8

TNF

AKT1

F7

MAPK1LDLR

PRKCD

SLC6A3

DRD1

CASP3

CHRNA7

PRSS3

TP53BP2

CASP7

EPHB2

SYNGAP1

CALM1

CTSD

BACE1

ADRA1B

(b)







0

001

002

003

004

005

006

007

008

0 20 40 60 80 100 120 140 160 180

Betw

eenn

ess

Degree

APP

ALB SRCEGFR

AKT1HTT






Mol 22Mol 33


Mol 97Mol 106


Mol 63Mol 90

Mol 87

Mol 91Mol 61

Mol 19

Mol 109

Mol 161

Mol 118

Mol 111

Mol 158

Mol 114

Mol 149

Mol 141

Mol 152

Mol 14

CASP3

BCL2

NOS3

SCN5A

F7

ADRA1B

ACHE

F2

Mol 4

Mol 49

Mol 127

APP CASP7

Mol 92

Mol 54

Mol 6

Mol 36

KCNMA1

Mol 27


Mol 17

Mol 39

Mol 2

Mol 21

Mol 12

Mol 142

Mol 126

Mol 135

Mol 121

Mol 119

Mol 124

Mol 120

Mol 117

Mol 133

Mol 131

Mol 134


Aurantii Fructus

Licorice

Radix Bupleuri



Mol 8

Mol 73

Mol 75

Mol 77

Mol 80

Mol 7

Mol 82

Mol 76

Mol 74

Mol 60

Mol 46

Mol 150

Mol 151

Mol 112

Mol 115

Mol 11

Mol 116

Mol 113

Mol 110

Mol 1




Mol 35Mol 81

Mol 86

Mol 85

Mol 84

Mol 88

Mol 83Mol 30

Mol 137

ChuanxiongRhizoma

Mol 3

Mol 57

Mol 139

Achyranthis

Bidentatae

RadixMol 102

CASP8

IGHG1AKT1p53

CHRNA7

Mol 40

SLC6A3 PTPN1

SOD1MAPK1

Mol 38

Mol 95

Carthami Flos

Mol 24


Mol 122

Mol 25

Mol 98

TGFB1

GSK3B

PRKCA


Mol 52

Mol 42

Mol 62

Mol 138

EGFR

STAT1 PPP3CAPLAT

Stigmasterol

MAP2


Kaempferol

SYNGAP1

CALM

Baicalin

PRKCB

CAV1

CTSD

TNF

DRD1

CDK1

IFNG

FN1BBC3 PRKCD

Mol 132

Mol 160

Mol 58

Mol 67

Mol 69 Mol 43ALB

Mol 64CTNNB1


Achyranthisiistntnt


RadixadixR diR di


























KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A




TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia






LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3



4 Discussion









(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






























3 Results















50

40

30

20

10

0

50

40

40

30

20

20

10

0

0

10 30 50 70 90 110

60

60

60

01 02 03 04 05 06 07 08


minus2 minus1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

70

minus1 1 3 5 7 9 11 13 15 17

perc

entage

s (

)

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

perc

entage

s (

)

40

20

0

60

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

OB

MW

nHdon

DL

nHacc

Distribution

Distribution

Distribution

Distribution

Distribution

Distribution

AlogP









Jun herbs(29)

Zuo-

Shi h

erbs

(101

)

Chen herbs

(23)

1

2

15

(a)

Jun herbs(5)

Zuo-

Shi h

erbs

(48)

Chen herbs

(10)

9

10

14189

(b)

20Mol 1200000


Mol 8888






MMol 73Mol 77333222

ABATABATA

MAPK3MAPKMAPK

UGT1A1GT1UGT1A1

GOT1GOTT1

SREBF1REBFSREBF1

RXRBRXRBRXRB

CYP19A1CYP19A1YP19A

PLB1PLBPLB1

FASLGFASLGASL

BCHEBCHHE

HSD3B1HSD3

MTTPMTT

CES1CES

TIMP1TIMP

ATP5BATP5

MAPK10MAPK 0

BADBAD

CHRM5CHRM5

EPHBEPHBPHB2

HSD3B2HSD3B2SD3B

SOAT2OATSOAT2

FASNFASNFASN

MT-ND6MT-N


PKIAAIA

ADH1AADHAD

AKR1C1KR1AKR1C1

CREB1CREBB1

HMGCRMGHMGCR

SOAT1OAT

ABCC1ABCC

OPRD1OPRDOPRD1

VCPVCP

LDLRLDLR

ADRA1DDRAA1D


EGLN1GLNGLNGLNGLN



ALOX12LOXLOXOXLOX



Mol 40









JUNJUNNJUNNN




CCCALCCC MMMMMMSS















PPPPARAPARPARPAR







BAXXXXB X ESR1




IL888IL88




Quercetin

Mol 9444444

Mol 99

Mol 63

Mol 75555


Mol 158



Mol 6Mol 6666M 66




Mol 11MMol 1155Mol 11555M6060660



Mol 9000







Radixadixdix

Mol 84



0Mol 200000


Mol 151

Mol 126Mol 126Mol 12666



Mol 444


Mol 133


Mol 142Mol 1422

Mol 36


Mol 277Mol 135Mol 13555M 555




MMol 83333

Mol 110Mol 110

Mol 119MMol 11999999


Mol 5444

Mol 39999999

Mol 150MMol 155000M 0

Mol 611

21Mol 21MMol 221111

Mol 13



Mol 466




Mol 14Mol 1444


Mol 87



MAP2MAP2MAPMAPMAP

IL2I 2L22L22




F2






Mol 131


Mol 111


Mol 744444Mol 77




Mol 138MMol 1388M


Mol 42MMMol 42M

MMMol 3Mol 3







RadixRadixRadix
















BIL1BIL1BIL1BIL1BB




PPPPPARPP GGGGGGPPP


ESR2



CDK2


PIM1 GSK3B









MGAMMGAMMGAMGAAM

KCNH2222










PDE3APDE3AA




IL6666

HK2HK2HK2HK2HK2HK2




NCF1NCFNCFNCF1NCFN





MMMol 132

MMMol 57

CRPCRPCRPCRPPHH


BCGABCGABCG2BCGA









RELARELARELAAAR


EGFREGFRGFREGFREGFR


E2F2E2F2E2F2E2F2E

APPAPAPPAPPPAPPAPPA






Mol 127


DPP4



XDHXDHXDHHHXDH

PTGS2























ICAM1CAMCAMM1CAMI


IGF2IGF2IGF2IGF2F




CHRM1CHRM11CHRM11


PRKACA

TOP2TOP2



ACHE

ADRB1ADRBRBADRBADR

ADRADRADRA2A2AA2A

SOD1SSODSOD1D11

NOS33


PGR

HHMOX11MOXMOXHMOX



FOSL2OSLOSLOSL22FO



PON1PONPONPONN1PON

PIK3CGPIK3CGGG


AKT1AKTT1AKT11A



ADRB2

(c)













BLMH

GPRASP2

GJC2

CAMK2N1

OBSL1

ZNF292

RLFAMPD3

NANOS1CAMTA1HYPKCCS

DLGAP4PF4V1

TRIM2

CHKB

F8A1

TIAM1

BMX

RAPGEF1

APBB1

KCNMA1

XRCC6

TTR

TGM2MAP2

PRNP


ACE

TGFB2

AP2M1GRAP2

SCN5A

MYH9

PKN1

ACHE

SLC25A13

PHKG1

SPAST

UMOD

PRPF40B

BBC3

TUBA4A TTPALRYR2

STUB1KRT6A

AKAP8L

GFI1BTHRAP3

ZNF232

SOD1

CRKL

CDH2

MBP MAP2K2

DCN

MAP3K5NGFR

PIK3CA

ITGA2

DNM1

RAP1A

GRIN2B

PTPN11

PRKCA

LDLRAP1

DNAJA3INA

SP3

CACNA2D3

CSF1

CNTF

TNFRSF1B

BCL10

KLC1

DCTN1

IDE

SERPINA3

HSPA1A

HSPG2

FN1

LRP2

TUBB

GRIN2A

YWHAB

CAMK2D

HTRA2

PRKCE

CRYAB

APC

GIT1

PIAS4

HPX

TRIP10

PDE4B

MARK4

PLAT

UBE2K

APOC2

LIN7B BGN

MAP3K10MAPK8IP2

CBS

SH3GL3

STAU1

CASP6

PPP5C

KRT16

DAB1

CASP1SHC2

CTSD

UCHL1

HP

SNCACAMK2G

TGFB1

GNB1

PTPN1PIN1

TJP1

CASP8PLCG1

NPHS1

PPP2R2A

DNAJB1

ADRBK1

INADL

NCSTN

MATK

NEDD4L

KAT5IFNGTBP

FRS2

CSNK1A1

CALRKNG1

SGOL2

KRT6B

TRAF3 DLG3

SACS

BDKRB2PRKCB

CAV1

MAPK3F2 SMAD3

APOEAKAP9 RANBP2

CLTC

TSC22D1GAB2PSEN2

MLF1CROT

KRT9

ADRA1B

EPB41

COL4A1

SHC3

ARHGAP32

ATM

PPP2R5A

CAMK2A

NTRK1

KRT18

TNFAPOA2

LAT

GRIN2D

COL4A6

KLK3

VLDLR

COL4A5

COL4A2

NEFH

OR8D2

MTSS1

PDZRN4

PTPN4

OR3A2

OR2T6

DGKG

CASP3

IGF1R

CASK

DRD2

TRAF2

EPHB2

PPM1A

PRKCG

CACNB3

HNRNPUSIN3A

DLG1

CLU

RAP2A

ERBB4CANX

BACE1 GABBR1

KARS

CNOT1

UNG

AGA CDCP1

UTP14A PLAG1

EXOC6

HRAS

CTNNB1

SP1

NOS3 SUMO1

PSEN1

HSPA8

HSP90AA1

BCL2

GNAO1

RPS6KB1

PARK2

DLG4

PTK2B

GSN

NAE1 TLN2LRFN2

PLTP

NUMBLSTX1A

DERL1

NEFM

HMOX2

AATF

PPIAMTRNR2L2AP1M1

OGT

DDB1

AP4M1

MED31

RGS3

TDP2

KRT5

ADAM9

REST

PACSIN1

SHB

CTSL1

LAMA1

SH2B1

PLA2G4F

SMURF2

SLC9A8

KRT14

CIT

TGFB1I1

PPP2R1APIK3R1

NUMB

ADAM17

DLG2

LRP1

APOA4

LTA

IRS1

GSK3B

EGFR

CTSB

TRAF6

SHC1

PPP2CB

NGF

HTT

PPIDLDB3

APOC1HIP1

ZDHHC17COL25A1MAGI3

ITGB5

ACTB

GNA11

ACTN2CAMK2B

CDK1

LIN7C

S100B

PDLIM5

DLGAP1

LIN7A

TPR

SYNGAP1

CFD

GRIN3A

F12

SLC1A3

GRK5

CACNA2D2

TANC1

DUSP4

EXOC4

AHSG

GRIN3B

UCP2

TTN

GPC1

NSF

FGA

DYNLL1

MAPK8IP1

PICALM

PPBP

ITM2B

NID1

STXBP1

CTBP1

SGK1

TRAF1

SQSTM1

TNFRSF1A

ACTN1

OPTN

UBE2D2

AP2A2

FUS

APOA1

DICER1

CACNA1B

CST3

NCOA3

SCARB1

APOC3

SLC6A3

KIAA1551 KRT13

DCD

KIAA0232

ENSG00000258818

SPATA31A7

CTAGE5

CEP44

SH2B2

EPHB4

CAPN1

F7

APBA2

COL4A3

LDLR

GIPC1

GFAP

SERPING1

SRC

MAPK12APP

GAPDH

CDK5

CREBBP

NOS1

YWHAZCALM1

YWHAG

YWHAQGRIN1

RPS6KA3

COL1A2

TCERG1

A2M

CASP7

LRP8

PDK2

AGTR1

FYN

ALBGRB2

MAPK1AKT1

STAT1

MAPT

GSK3A

UBB

PPP2CA

SMAD4

PRKCD

RGS12

SPTB

SH3BP5

CACNA1I

IL16

SLA2

PFN2

NLRC4

TNFRSF14

PRTN3

SNCB

FBLN1

BACE2

SETX

FANCD2

SAP30

RANBP3

PALB2

SLC1A5RASA1

HAP1

LRRC7

CFB

ADRBK2

CDC45

CLSTN3

PCED1B

SCAF1KIAA1377

FAM71E2

FEZ1 ACSBG2

PCDH1

TRAPPC11QTRTD1

KRT1

LRP1B

HADHB

TP53BP2

DRD1

ST13

PRPF40A

TRAIP

KIDINS220

GRK6

MMP17

LTBR

EIF6

PGAM1

CHD3

PRSS3

APBB3

CHRNA7

KRT10

RIMS1

CRMP1

PDIK1L

SORBS3

SYMPK

GCN1L1

RNF19A

HOMER3

GRK4

JARID2

MYLK3

EFS

CRB1

HSD17B10

TST

HOMER2

PHC3

TM2D1 FICD

PEG3

CABLES1

LGALS2

ITIH1

HOXB2

TAF4FLOT1

BABAM1

CFH

HIP1R

LTBMYL4

NCOR1

CASP4

NF1

AP4E1

CLCA2

IGDCC4

NECAB3

CXorf27

SH3GLB1

CTCF

PLCG2

(a)

STAT1

EGFR

FN1

PLAT

SOD1

PRKCA CDK1

GSK3B

ALB APP

PPP3CA

IFNG

BBC3

SCN5A

KCNMA1

MAP2

ACHE

MAPK3F2

PTPN1

NOS3 BCL2

CAV1

CTNNB1

PRKCB

TGFB1CASP8

TNF

AKT1

F7

MAPK1LDLR

PRKCD

SLC6A3

DRD1

CASP3

CHRNA7

PRSS3

TP53BP2

CASP7

EPHB2

SYNGAP1

CALM1

CTSD

BACE1

ADRA1B

(b)







0

001

002

003

004

005

006

007

008

0 20 40 60 80 100 120 140 160 180

Betw

eenn

ess

Degree

APP

ALB SRCEGFR

AKT1HTT






Mol 22Mol 33


Mol 97Mol 106


Mol 63Mol 90

Mol 87

Mol 91Mol 61

Mol 19

Mol 109

Mol 161

Mol 118

Mol 111

Mol 158

Mol 114

Mol 149

Mol 141

Mol 152

Mol 14

CASP3

BCL2

NOS3

SCN5A

F7

ADRA1B

ACHE

F2

Mol 4

Mol 49

Mol 127

APP CASP7

Mol 92

Mol 54

Mol 6

Mol 36

KCNMA1

Mol 27


Mol 17

Mol 39

Mol 2

Mol 21

Mol 12

Mol 142

Mol 126

Mol 135

Mol 121

Mol 119

Mol 124

Mol 120

Mol 117

Mol 133

Mol 131

Mol 134


Aurantii Fructus

Licorice

Radix Bupleuri



Mol 8

Mol 73

Mol 75

Mol 77

Mol 80

Mol 7

Mol 82

Mol 76

Mol 74

Mol 60

Mol 46

Mol 150

Mol 151

Mol 112

Mol 115

Mol 11

Mol 116

Mol 113

Mol 110

Mol 1




Mol 35Mol 81

Mol 86

Mol 85

Mol 84

Mol 88

Mol 83Mol 30

Mol 137

ChuanxiongRhizoma

Mol 3

Mol 57

Mol 139

Achyranthis

Bidentatae

RadixMol 102

CASP8

IGHG1AKT1p53

CHRNA7

Mol 40

SLC6A3 PTPN1

SOD1MAPK1

Mol 38

Mol 95

Carthami Flos

Mol 24


Mol 122

Mol 25

Mol 98

TGFB1

GSK3B

PRKCA


Mol 52

Mol 42

Mol 62

Mol 138

EGFR

STAT1 PPP3CAPLAT

Stigmasterol

MAP2


Kaempferol

SYNGAP1

CALM

Baicalin

PRKCB

CAV1

CTSD

TNF

DRD1

CDK1

IFNG

FN1BBC3 PRKCD

Mol 132

Mol 160

Mol 58

Mol 67

Mol 69 Mol 43ALB

Mol 64CTNNB1


Achyranthisiistntnt


RadixadixR diR di


























KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A




TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia






LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3



4 Discussion









(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of































50

40

30

20

10

0

50

40

40

30

20

20

10

0

0

10 30 50 70 90 110

60

60

60

01 02 03 04 05 06 07 08


minus2 minus1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

70

minus1 1 3 5 7 9 11 13 15 17

perc

entage

s (

)

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

perc

entage

s (

)

40

20

0

60

perc

entage

s (

)50

40

30

20

10

0

perc

entage

s (

)

OB

MW

nHdon

DL

nHacc

Distribution

Distribution

Distribution

Distribution

Distribution

Distribution

AlogP









Jun herbs(29)

Zuo-

Shi h

erbs

(101

)

Chen herbs

(23)

1

2

15

(a)

Jun herbs(5)

Zuo-

Shi h

erbs

(48)

Chen herbs

(10)

9

10

14189

(b)

20Mol 1200000


Mol 8888






MMol 73Mol 77333222

ABATABATA

MAPK3MAPKMAPK

UGT1A1GT1UGT1A1

GOT1GOTT1

SREBF1REBFSREBF1

RXRBRXRBRXRB

CYP19A1CYP19A1YP19A

PLB1PLBPLB1

FASLGFASLGASL

BCHEBCHHE

HSD3B1HSD3

MTTPMTT

CES1CES

TIMP1TIMP

ATP5BATP5

MAPK10MAPK 0

BADBAD

CHRM5CHRM5

EPHBEPHBPHB2

HSD3B2HSD3B2SD3B

SOAT2OATSOAT2

FASNFASNFASN

MT-ND6MT-N


PKIAAIA

ADH1AADHAD

AKR1C1KR1AKR1C1

CREB1CREBB1

HMGCRMGHMGCR

SOAT1OAT

ABCC1ABCC

OPRD1OPRDOPRD1

VCPVCP

LDLRLDLR

ADRA1DDRAA1D


EGLN1GLNGLNGLNGLN



ALOX12LOXLOXOXLOX



Mol 40









JUNJUNNJUNNN




CCCALCCC MMMMMMSS















PPPPARAPARPARPAR







BAXXXXB X ESR1




IL888IL88




Quercetin

Mol 9444444

Mol 99

Mol 63

Mol 75555


Mol 158



Mol 6Mol 6666M 66




Mol 11MMol 1155Mol 11555M6060660



Mol 9000







Radixadixdix

Mol 84



0Mol 200000


Mol 151

Mol 126Mol 126Mol 12666



Mol 444


Mol 133


Mol 142Mol 1422

Mol 36


Mol 277Mol 135Mol 13555M 555




MMol 83333

Mol 110Mol 110

Mol 119MMol 11999999


Mol 5444

Mol 39999999

Mol 150MMol 155000M 0

Mol 611

21Mol 21MMol 221111

Mol 13



Mol 466




Mol 14Mol 1444


Mol 87



MAP2MAP2MAPMAPMAP

IL2I 2L22L22




F2






Mol 131


Mol 111


Mol 744444Mol 77




Mol 138MMol 1388M


Mol 42MMMol 42M

MMMol 3Mol 3







RadixRadixRadix
















BIL1BIL1BIL1BIL1BB




PPPPPARPP GGGGGGPPP


ESR2



CDK2


PIM1 GSK3B









MGAMMGAMMGAMGAAM

KCNH2222










PDE3APDE3AA




IL6666

HK2HK2HK2HK2HK2HK2




NCF1NCFNCFNCF1NCFN





MMMol 132

MMMol 57

CRPCRPCRPCRPPHH


BCGABCGABCG2BCGA









RELARELARELAAAR


EGFREGFRGFREGFREGFR


E2F2E2F2E2F2E2F2E

APPAPAPPAPPPAPPAPPA






Mol 127


DPP4



XDHXDHXDHHHXDH

PTGS2























ICAM1CAMCAMM1CAMI


IGF2IGF2IGF2IGF2F




CHRM1CHRM11CHRM11


PRKACA

TOP2TOP2



ACHE

ADRB1ADRBRBADRBADR

ADRADRADRA2A2AA2A

SOD1SSODSOD1D11

NOS33


PGR

HHMOX11MOXMOXHMOX



FOSL2OSLOSLOSL22FO



PON1PONPONPONN1PON

PIK3CGPIK3CGGG


AKT1AKTT1AKT11A



ADRB2

(c)













BLMH

GPRASP2

GJC2

CAMK2N1

OBSL1

ZNF292

RLFAMPD3

NANOS1CAMTA1HYPKCCS

DLGAP4PF4V1

TRIM2

CHKB

F8A1

TIAM1

BMX

RAPGEF1

APBB1

KCNMA1

XRCC6

TTR

TGM2MAP2

PRNP


ACE

TGFB2

AP2M1GRAP2

SCN5A

MYH9

PKN1

ACHE

SLC25A13

PHKG1

SPAST

UMOD

PRPF40B

BBC3

TUBA4A TTPALRYR2

STUB1KRT6A

AKAP8L

GFI1BTHRAP3

ZNF232

SOD1

CRKL

CDH2

MBP MAP2K2

DCN

MAP3K5NGFR

PIK3CA

ITGA2

DNM1

RAP1A

GRIN2B

PTPN11

PRKCA

LDLRAP1

DNAJA3INA

SP3

CACNA2D3

CSF1

CNTF

TNFRSF1B

BCL10

KLC1

DCTN1

IDE

SERPINA3

HSPA1A

HSPG2

FN1

LRP2

TUBB

GRIN2A

YWHAB

CAMK2D

HTRA2

PRKCE

CRYAB

APC

GIT1

PIAS4

HPX

TRIP10

PDE4B

MARK4

PLAT

UBE2K

APOC2

LIN7B BGN

MAP3K10MAPK8IP2

CBS

SH3GL3

STAU1

CASP6

PPP5C

KRT16

DAB1

CASP1SHC2

CTSD

UCHL1

HP

SNCACAMK2G

TGFB1

GNB1

PTPN1PIN1

TJP1

CASP8PLCG1

NPHS1

PPP2R2A

DNAJB1

ADRBK1

INADL

NCSTN

MATK

NEDD4L

KAT5IFNGTBP

FRS2

CSNK1A1

CALRKNG1

SGOL2

KRT6B

TRAF3 DLG3

SACS

BDKRB2PRKCB

CAV1

MAPK3F2 SMAD3

APOEAKAP9 RANBP2

CLTC

TSC22D1GAB2PSEN2

MLF1CROT

KRT9

ADRA1B

EPB41

COL4A1

SHC3

ARHGAP32

ATM

PPP2R5A

CAMK2A

NTRK1

KRT18

TNFAPOA2

LAT

GRIN2D

COL4A6

KLK3

VLDLR

COL4A5

COL4A2

NEFH

OR8D2

MTSS1

PDZRN4

PTPN4

OR3A2

OR2T6

DGKG

CASP3

IGF1R

CASK

DRD2

TRAF2

EPHB2

PPM1A

PRKCG

CACNB3

HNRNPUSIN3A

DLG1

CLU

RAP2A

ERBB4CANX

BACE1 GABBR1

KARS

CNOT1

UNG

AGA CDCP1

UTP14A PLAG1

EXOC6

HRAS

CTNNB1

SP1

NOS3 SUMO1

PSEN1

HSPA8

HSP90AA1

BCL2

GNAO1

RPS6KB1

PARK2

DLG4

PTK2B

GSN

NAE1 TLN2LRFN2

PLTP

NUMBLSTX1A

DERL1

NEFM

HMOX2

AATF

PPIAMTRNR2L2AP1M1

OGT

DDB1

AP4M1

MED31

RGS3

TDP2

KRT5

ADAM9

REST

PACSIN1

SHB

CTSL1

LAMA1

SH2B1

PLA2G4F

SMURF2

SLC9A8

KRT14

CIT

TGFB1I1

PPP2R1APIK3R1

NUMB

ADAM17

DLG2

LRP1

APOA4

LTA

IRS1

GSK3B

EGFR

CTSB

TRAF6

SHC1

PPP2CB

NGF

HTT

PPIDLDB3

APOC1HIP1

ZDHHC17COL25A1MAGI3

ITGB5

ACTB

GNA11

ACTN2CAMK2B

CDK1

LIN7C

S100B

PDLIM5

DLGAP1

LIN7A

TPR

SYNGAP1

CFD

GRIN3A

F12

SLC1A3

GRK5

CACNA2D2

TANC1

DUSP4

EXOC4

AHSG

GRIN3B

UCP2

TTN

GPC1

NSF

FGA

DYNLL1

MAPK8IP1

PICALM

PPBP

ITM2B

NID1

STXBP1

CTBP1

SGK1

TRAF1

SQSTM1

TNFRSF1A

ACTN1

OPTN

UBE2D2

AP2A2

FUS

APOA1

DICER1

CACNA1B

CST3

NCOA3

SCARB1

APOC3

SLC6A3

KIAA1551 KRT13

DCD

KIAA0232

ENSG00000258818

SPATA31A7

CTAGE5

CEP44

SH2B2

EPHB4

CAPN1

F7

APBA2

COL4A3

LDLR

GIPC1

GFAP

SERPING1

SRC

MAPK12APP

GAPDH

CDK5

CREBBP

NOS1

YWHAZCALM1

YWHAG

YWHAQGRIN1

RPS6KA3

COL1A2

TCERG1

A2M

CASP7

LRP8

PDK2

AGTR1

FYN

ALBGRB2

MAPK1AKT1

STAT1

MAPT

GSK3A

UBB

PPP2CA

SMAD4

PRKCD

RGS12

SPTB

SH3BP5

CACNA1I

IL16

SLA2

PFN2

NLRC4

TNFRSF14

PRTN3

SNCB

FBLN1

BACE2

SETX

FANCD2

SAP30

RANBP3

PALB2

SLC1A5RASA1

HAP1

LRRC7

CFB

ADRBK2

CDC45

CLSTN3

PCED1B

SCAF1KIAA1377

FAM71E2

FEZ1 ACSBG2

PCDH1

TRAPPC11QTRTD1

KRT1

LRP1B

HADHB

TP53BP2

DRD1

ST13

PRPF40A

TRAIP

KIDINS220

GRK6

MMP17

LTBR

EIF6

PGAM1

CHD3

PRSS3

APBB3

CHRNA7

KRT10

RIMS1

CRMP1

PDIK1L

SORBS3

SYMPK

GCN1L1

RNF19A

HOMER3

GRK4

JARID2

MYLK3

EFS

CRB1

HSD17B10

TST

HOMER2

PHC3

TM2D1 FICD

PEG3

CABLES1

LGALS2

ITIH1

HOXB2

TAF4FLOT1

BABAM1

CFH

HIP1R

LTBMYL4

NCOR1

CASP4

NF1

AP4E1

CLCA2

IGDCC4

NECAB3

CXorf27

SH3GLB1

CTCF

PLCG2

(a)

STAT1

EGFR

FN1

PLAT

SOD1

PRKCA CDK1

GSK3B

ALB APP

PPP3CA

IFNG

BBC3

SCN5A

KCNMA1

MAP2

ACHE

MAPK3F2

PTPN1

NOS3 BCL2

CAV1

CTNNB1

PRKCB

TGFB1CASP8

TNF

AKT1

F7

MAPK1LDLR

PRKCD

SLC6A3

DRD1

CASP3

CHRNA7

PRSS3

TP53BP2

CASP7

EPHB2

SYNGAP1

CALM1

CTSD

BACE1

ADRA1B

(b)







0

001

002

003

004

005

006

007

008

0 20 40 60 80 100 120 140 160 180

Betw

eenn

ess

Degree

APP

ALB SRCEGFR

AKT1HTT






Mol 22Mol 33


Mol 97Mol 106


Mol 63Mol 90

Mol 87

Mol 91Mol 61

Mol 19

Mol 109

Mol 161

Mol 118

Mol 111

Mol 158

Mol 114

Mol 149

Mol 141

Mol 152

Mol 14

CASP3

BCL2

NOS3

SCN5A

F7

ADRA1B

ACHE

F2

Mol 4

Mol 49

Mol 127

APP CASP7

Mol 92

Mol 54

Mol 6

Mol 36

KCNMA1

Mol 27


Mol 17

Mol 39

Mol 2

Mol 21

Mol 12

Mol 142

Mol 126

Mol 135

Mol 121

Mol 119

Mol 124

Mol 120

Mol 117

Mol 133

Mol 131

Mol 134


Aurantii Fructus

Licorice

Radix Bupleuri



Mol 8

Mol 73

Mol 75

Mol 77

Mol 80

Mol 7

Mol 82

Mol 76

Mol 74

Mol 60

Mol 46

Mol 150

Mol 151

Mol 112

Mol 115

Mol 11

Mol 116

Mol 113

Mol 110

Mol 1




Mol 35Mol 81

Mol 86

Mol 85

Mol 84

Mol 88

Mol 83Mol 30

Mol 137

ChuanxiongRhizoma

Mol 3

Mol 57

Mol 139

Achyranthis

Bidentatae

RadixMol 102

CASP8

IGHG1AKT1p53

CHRNA7

Mol 40

SLC6A3 PTPN1

SOD1MAPK1

Mol 38

Mol 95

Carthami Flos

Mol 24


Mol 122

Mol 25

Mol 98

TGFB1

GSK3B

PRKCA


Mol 52

Mol 42

Mol 62

Mol 138

EGFR

STAT1 PPP3CAPLAT

Stigmasterol

MAP2


Kaempferol

SYNGAP1

CALM

Baicalin

PRKCB

CAV1

CTSD

TNF

DRD1

CDK1

IFNG

FN1BBC3 PRKCD

Mol 132

Mol 160

Mol 58

Mol 67

Mol 69 Mol 43ALB

Mol 64CTNNB1


Achyranthisiistntnt


RadixadixR diR di


























KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A




TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia






LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3



4 Discussion









(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Jun herbs(29)

Zuo-

Shi h

erbs

(101

)

Chen herbs

(23)

1

2

15

(a)

Jun herbs(5)

Zuo-

Shi h

erbs

(48)

Chen herbs

(10)

9

10

14189

(b)

20Mol 1200000


Mol 8888






MMol 73Mol 77333222

ABATABATA

MAPK3MAPKMAPK

UGT1A1GT1UGT1A1

GOT1GOTT1

SREBF1REBFSREBF1

RXRBRXRBRXRB

CYP19A1CYP19A1YP19A

PLB1PLBPLB1

FASLGFASLGASL

BCHEBCHHE

HSD3B1HSD3

MTTPMTT

CES1CES

TIMP1TIMP

ATP5BATP5

MAPK10MAPK 0

BADBAD

CHRM5CHRM5

EPHBEPHBPHB2

HSD3B2HSD3B2SD3B

SOAT2OATSOAT2

FASNFASNFASN

MT-ND6MT-N


PKIAAIA

ADH1AADHAD

AKR1C1KR1AKR1C1

CREB1CREBB1

HMGCRMGHMGCR

SOAT1OAT

ABCC1ABCC

OPRD1OPRDOPRD1

VCPVCP

LDLRLDLR

ADRA1DDRAA1D


EGLN1GLNGLNGLNGLN



ALOX12LOXLOXOXLOX



Mol 40









JUNJUNNJUNNN




CCCALCCC MMMMMMSS















PPPPARAPARPARPAR







BAXXXXB X ESR1




IL888IL88




Quercetin

Mol 9444444

Mol 99

Mol 63

Mol 75555


Mol 158



Mol 6Mol 6666M 66




Mol 11MMol 1155Mol 11555M6060660



Mol 9000







Radixadixdix

Mol 84



0Mol 200000


Mol 151

Mol 126Mol 126Mol 12666



Mol 444


Mol 133


Mol 142Mol 1422

Mol 36


Mol 277Mol 135Mol 13555M 555




MMol 83333

Mol 110Mol 110

Mol 119MMol 11999999


Mol 5444

Mol 39999999

Mol 150MMol 155000M 0

Mol 611

21Mol 21MMol 221111

Mol 13



Mol 466




Mol 14Mol 1444


Mol 87



MAP2MAP2MAPMAPMAP

IL2I 2L22L22




F2






Mol 131


Mol 111


Mol 744444Mol 77




Mol 138MMol 1388M


Mol 42MMMol 42M

MMMol 3Mol 3







RadixRadixRadix
















BIL1BIL1BIL1BIL1BB




PPPPPARPP GGGGGGPPP


ESR2



CDK2


PIM1 GSK3B









MGAMMGAMMGAMGAAM

KCNH2222










PDE3APDE3AA




IL6666

HK2HK2HK2HK2HK2HK2




NCF1NCFNCFNCF1NCFN





MMMol 132

MMMol 57

CRPCRPCRPCRPPHH


BCGABCGABCG2BCGA









RELARELARELAAAR


EGFREGFRGFREGFREGFR


E2F2E2F2E2F2E2F2E

APPAPAPPAPPPAPPAPPA






Mol 127


DPP4



XDHXDHXDHHHXDH

PTGS2























ICAM1CAMCAMM1CAMI


IGF2IGF2IGF2IGF2F




CHRM1CHRM11CHRM11


PRKACA

TOP2TOP2



ACHE

ADRB1ADRBRBADRBADR

ADRADRADRA2A2AA2A

SOD1SSODSOD1D11

NOS33


PGR

HHMOX11MOXMOXHMOX



FOSL2OSLOSLOSL22FO



PON1PONPONPONN1PON

PIK3CGPIK3CGGG


AKT1AKTT1AKT11A



ADRB2

(c)













BLMH

GPRASP2

GJC2

CAMK2N1

OBSL1

ZNF292

RLFAMPD3

NANOS1CAMTA1HYPKCCS

DLGAP4PF4V1

TRIM2

CHKB

F8A1

TIAM1

BMX

RAPGEF1

APBB1

KCNMA1

XRCC6

TTR

TGM2MAP2

PRNP


ACE

TGFB2

AP2M1GRAP2

SCN5A

MYH9

PKN1

ACHE

SLC25A13

PHKG1

SPAST

UMOD

PRPF40B

BBC3

TUBA4A TTPALRYR2

STUB1KRT6A

AKAP8L

GFI1BTHRAP3

ZNF232

SOD1

CRKL

CDH2

MBP MAP2K2

DCN

MAP3K5NGFR

PIK3CA

ITGA2

DNM1

RAP1A

GRIN2B

PTPN11

PRKCA

LDLRAP1

DNAJA3INA

SP3

CACNA2D3

CSF1

CNTF

TNFRSF1B

BCL10

KLC1

DCTN1

IDE

SERPINA3

HSPA1A

HSPG2

FN1

LRP2

TUBB

GRIN2A

YWHAB

CAMK2D

HTRA2

PRKCE

CRYAB

APC

GIT1

PIAS4

HPX

TRIP10

PDE4B

MARK4

PLAT

UBE2K

APOC2

LIN7B BGN

MAP3K10MAPK8IP2

CBS

SH3GL3

STAU1

CASP6

PPP5C

KRT16

DAB1

CASP1SHC2

CTSD

UCHL1

HP

SNCACAMK2G

TGFB1

GNB1

PTPN1PIN1

TJP1

CASP8PLCG1

NPHS1

PPP2R2A

DNAJB1

ADRBK1

INADL

NCSTN

MATK

NEDD4L

KAT5IFNGTBP

FRS2

CSNK1A1

CALRKNG1

SGOL2

KRT6B

TRAF3 DLG3

SACS

BDKRB2PRKCB

CAV1

MAPK3F2 SMAD3

APOEAKAP9 RANBP2

CLTC

TSC22D1GAB2PSEN2

MLF1CROT

KRT9

ADRA1B

EPB41

COL4A1

SHC3

ARHGAP32

ATM

PPP2R5A

CAMK2A

NTRK1

KRT18

TNFAPOA2

LAT

GRIN2D

COL4A6

KLK3

VLDLR

COL4A5

COL4A2

NEFH

OR8D2

MTSS1

PDZRN4

PTPN4

OR3A2

OR2T6

DGKG

CASP3

IGF1R

CASK

DRD2

TRAF2

EPHB2

PPM1A

PRKCG

CACNB3

HNRNPUSIN3A

DLG1

CLU

RAP2A

ERBB4CANX

BACE1 GABBR1

KARS

CNOT1

UNG

AGA CDCP1

UTP14A PLAG1

EXOC6

HRAS

CTNNB1

SP1

NOS3 SUMO1

PSEN1

HSPA8

HSP90AA1

BCL2

GNAO1

RPS6KB1

PARK2

DLG4

PTK2B

GSN

NAE1 TLN2LRFN2

PLTP

NUMBLSTX1A

DERL1

NEFM

HMOX2

AATF

PPIAMTRNR2L2AP1M1

OGT

DDB1

AP4M1

MED31

RGS3

TDP2

KRT5

ADAM9

REST

PACSIN1

SHB

CTSL1

LAMA1

SH2B1

PLA2G4F

SMURF2

SLC9A8

KRT14

CIT

TGFB1I1

PPP2R1APIK3R1

NUMB

ADAM17

DLG2

LRP1

APOA4

LTA

IRS1

GSK3B

EGFR

CTSB

TRAF6

SHC1

PPP2CB

NGF

HTT

PPIDLDB3

APOC1HIP1

ZDHHC17COL25A1MAGI3

ITGB5

ACTB

GNA11

ACTN2CAMK2B

CDK1

LIN7C

S100B

PDLIM5

DLGAP1

LIN7A

TPR

SYNGAP1

CFD

GRIN3A

F12

SLC1A3

GRK5

CACNA2D2

TANC1

DUSP4

EXOC4

AHSG

GRIN3B

UCP2

TTN

GPC1

NSF

FGA

DYNLL1

MAPK8IP1

PICALM

PPBP

ITM2B

NID1

STXBP1

CTBP1

SGK1

TRAF1

SQSTM1

TNFRSF1A

ACTN1

OPTN

UBE2D2

AP2A2

FUS

APOA1

DICER1

CACNA1B

CST3

NCOA3

SCARB1

APOC3

SLC6A3

KIAA1551 KRT13

DCD

KIAA0232

ENSG00000258818

SPATA31A7

CTAGE5

CEP44

SH2B2

EPHB4

CAPN1

F7

APBA2

COL4A3

LDLR

GIPC1

GFAP

SERPING1

SRC

MAPK12APP

GAPDH

CDK5

CREBBP

NOS1

YWHAZCALM1

YWHAG

YWHAQGRIN1

RPS6KA3

COL1A2

TCERG1

A2M

CASP7

LRP8

PDK2

AGTR1

FYN

ALBGRB2

MAPK1AKT1

STAT1

MAPT

GSK3A

UBB

PPP2CA

SMAD4

PRKCD

RGS12

SPTB

SH3BP5

CACNA1I

IL16

SLA2

PFN2

NLRC4

TNFRSF14

PRTN3

SNCB

FBLN1

BACE2

SETX

FANCD2

SAP30

RANBP3

PALB2

SLC1A5RASA1

HAP1

LRRC7

CFB

ADRBK2

CDC45

CLSTN3

PCED1B

SCAF1KIAA1377

FAM71E2

FEZ1 ACSBG2

PCDH1

TRAPPC11QTRTD1

KRT1

LRP1B

HADHB

TP53BP2

DRD1

ST13

PRPF40A

TRAIP

KIDINS220

GRK6

MMP17

LTBR

EIF6

PGAM1

CHD3

PRSS3

APBB3

CHRNA7

KRT10

RIMS1

CRMP1

PDIK1L

SORBS3

SYMPK

GCN1L1

RNF19A

HOMER3

GRK4

JARID2

MYLK3

EFS

CRB1

HSD17B10

TST

HOMER2

PHC3

TM2D1 FICD

PEG3

CABLES1

LGALS2

ITIH1

HOXB2

TAF4FLOT1

BABAM1

CFH

HIP1R

LTBMYL4

NCOR1

CASP4

NF1

AP4E1

CLCA2

IGDCC4

NECAB3

CXorf27

SH3GLB1

CTCF

PLCG2

(a)

STAT1

EGFR

FN1

PLAT

SOD1

PRKCA CDK1

GSK3B

ALB APP

PPP3CA

IFNG

BBC3

SCN5A

KCNMA1

MAP2

ACHE

MAPK3F2

PTPN1

NOS3 BCL2

CAV1

CTNNB1

PRKCB

TGFB1CASP8

TNF

AKT1

F7

MAPK1LDLR

PRKCD

SLC6A3

DRD1

CASP3

CHRNA7

PRSS3

TP53BP2

CASP7

EPHB2

SYNGAP1

CALM1

CTSD

BACE1

ADRA1B

(b)







0

001

002

003

004

005

006

007

008

0 20 40 60 80 100 120 140 160 180

Betw

eenn

ess

Degree

APP

ALB SRCEGFR

AKT1HTT






Mol 22Mol 33


Mol 97Mol 106


Mol 63Mol 90

Mol 87

Mol 91Mol 61

Mol 19

Mol 109

Mol 161

Mol 118

Mol 111

Mol 158

Mol 114

Mol 149

Mol 141

Mol 152

Mol 14

CASP3

BCL2

NOS3

SCN5A

F7

ADRA1B

ACHE

F2

Mol 4

Mol 49

Mol 127

APP CASP7

Mol 92

Mol 54

Mol 6

Mol 36

KCNMA1

Mol 27


Mol 17

Mol 39

Mol 2

Mol 21

Mol 12

Mol 142

Mol 126

Mol 135

Mol 121

Mol 119

Mol 124

Mol 120

Mol 117

Mol 133

Mol 131

Mol 134


Aurantii Fructus

Licorice

Radix Bupleuri



Mol 8

Mol 73

Mol 75

Mol 77

Mol 80

Mol 7

Mol 82

Mol 76

Mol 74

Mol 60

Mol 46

Mol 150

Mol 151

Mol 112

Mol 115

Mol 11

Mol 116

Mol 113

Mol 110

Mol 1




Mol 35Mol 81

Mol 86

Mol 85

Mol 84

Mol 88

Mol 83Mol 30

Mol 137

ChuanxiongRhizoma

Mol 3

Mol 57

Mol 139

Achyranthis

Bidentatae

RadixMol 102

CASP8

IGHG1AKT1p53

CHRNA7

Mol 40

SLC6A3 PTPN1

SOD1MAPK1

Mol 38

Mol 95

Carthami Flos

Mol 24


Mol 122

Mol 25

Mol 98

TGFB1

GSK3B

PRKCA


Mol 52

Mol 42

Mol 62

Mol 138

EGFR

STAT1 PPP3CAPLAT

Stigmasterol

MAP2


Kaempferol

SYNGAP1

CALM

Baicalin

PRKCB

CAV1

CTSD

TNF

DRD1

CDK1

IFNG

FN1BBC3 PRKCD

Mol 132

Mol 160

Mol 58

Mol 67

Mol 69 Mol 43ALB

Mol 64CTNNB1


Achyranthisiistntnt


RadixadixR diR di


























KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A




TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia






LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3



4 Discussion









(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




























BLMH

GPRASP2

GJC2

CAMK2N1

OBSL1

ZNF292

RLFAMPD3

NANOS1CAMTA1HYPKCCS

DLGAP4PF4V1

TRIM2

CHKB

F8A1

TIAM1

BMX

RAPGEF1

APBB1

KCNMA1

XRCC6

TTR

TGM2MAP2

PRNP


ACE

TGFB2

AP2M1GRAP2

SCN5A

MYH9

PKN1

ACHE

SLC25A13

PHKG1

SPAST

UMOD

PRPF40B

BBC3

TUBA4A TTPALRYR2

STUB1KRT6A

AKAP8L

GFI1BTHRAP3

ZNF232

SOD1

CRKL

CDH2

MBP MAP2K2

DCN

MAP3K5NGFR

PIK3CA

ITGA2

DNM1

RAP1A

GRIN2B

PTPN11

PRKCA

LDLRAP1

DNAJA3INA

SP3

CACNA2D3

CSF1

CNTF

TNFRSF1B

BCL10

KLC1

DCTN1

IDE

SERPINA3

HSPA1A

HSPG2

FN1

LRP2

TUBB

GRIN2A

YWHAB

CAMK2D

HTRA2

PRKCE

CRYAB

APC

GIT1

PIAS4

HPX

TRIP10

PDE4B

MARK4

PLAT

UBE2K

APOC2

LIN7B BGN

MAP3K10MAPK8IP2

CBS

SH3GL3

STAU1

CASP6

PPP5C

KRT16

DAB1

CASP1SHC2

CTSD

UCHL1

HP

SNCACAMK2G

TGFB1

GNB1

PTPN1PIN1

TJP1

CASP8PLCG1

NPHS1

PPP2R2A

DNAJB1

ADRBK1

INADL

NCSTN

MATK

NEDD4L

KAT5IFNGTBP

FRS2

CSNK1A1

CALRKNG1

SGOL2

KRT6B

TRAF3 DLG3

SACS

BDKRB2PRKCB

CAV1

MAPK3F2 SMAD3

APOEAKAP9 RANBP2

CLTC

TSC22D1GAB2PSEN2

MLF1CROT

KRT9

ADRA1B

EPB41

COL4A1

SHC3

ARHGAP32

ATM

PPP2R5A

CAMK2A

NTRK1

KRT18

TNFAPOA2

LAT

GRIN2D

COL4A6

KLK3

VLDLR

COL4A5

COL4A2

NEFH

OR8D2

MTSS1

PDZRN4

PTPN4

OR3A2

OR2T6

DGKG

CASP3

IGF1R

CASK

DRD2

TRAF2

EPHB2

PPM1A

PRKCG

CACNB3

HNRNPUSIN3A

DLG1

CLU

RAP2A

ERBB4CANX

BACE1 GABBR1

KARS

CNOT1

UNG

AGA CDCP1

UTP14A PLAG1

EXOC6

HRAS

CTNNB1

SP1

NOS3 SUMO1

PSEN1

HSPA8

HSP90AA1

BCL2

GNAO1

RPS6KB1

PARK2

DLG4

PTK2B

GSN

NAE1 TLN2LRFN2

PLTP

NUMBLSTX1A

DERL1

NEFM

HMOX2

AATF

PPIAMTRNR2L2AP1M1

OGT

DDB1

AP4M1

MED31

RGS3

TDP2

KRT5

ADAM9

REST

PACSIN1

SHB

CTSL1

LAMA1

SH2B1

PLA2G4F

SMURF2

SLC9A8

KRT14

CIT

TGFB1I1

PPP2R1APIK3R1

NUMB

ADAM17

DLG2

LRP1

APOA4

LTA

IRS1

GSK3B

EGFR

CTSB

TRAF6

SHC1

PPP2CB

NGF

HTT

PPIDLDB3

APOC1HIP1

ZDHHC17COL25A1MAGI3

ITGB5

ACTB

GNA11

ACTN2CAMK2B

CDK1

LIN7C

S100B

PDLIM5

DLGAP1

LIN7A

TPR

SYNGAP1

CFD

GRIN3A

F12

SLC1A3

GRK5

CACNA2D2

TANC1

DUSP4

EXOC4

AHSG

GRIN3B

UCP2

TTN

GPC1

NSF

FGA

DYNLL1

MAPK8IP1

PICALM

PPBP

ITM2B

NID1

STXBP1

CTBP1

SGK1

TRAF1

SQSTM1

TNFRSF1A

ACTN1

OPTN

UBE2D2

AP2A2

FUS

APOA1

DICER1

CACNA1B

CST3

NCOA3

SCARB1

APOC3

SLC6A3

KIAA1551 KRT13

DCD

KIAA0232

ENSG00000258818

SPATA31A7

CTAGE5

CEP44

SH2B2

EPHB4

CAPN1

F7

APBA2

COL4A3

LDLR

GIPC1

GFAP

SERPING1

SRC

MAPK12APP

GAPDH

CDK5

CREBBP

NOS1

YWHAZCALM1

YWHAG

YWHAQGRIN1

RPS6KA3

COL1A2

TCERG1

A2M

CASP7

LRP8

PDK2

AGTR1

FYN

ALBGRB2

MAPK1AKT1

STAT1

MAPT

GSK3A

UBB

PPP2CA

SMAD4

PRKCD

RGS12

SPTB

SH3BP5

CACNA1I

IL16

SLA2

PFN2

NLRC4

TNFRSF14

PRTN3

SNCB

FBLN1

BACE2

SETX

FANCD2

SAP30

RANBP3

PALB2

SLC1A5RASA1

HAP1

LRRC7

CFB

ADRBK2

CDC45

CLSTN3

PCED1B

SCAF1KIAA1377

FAM71E2

FEZ1 ACSBG2

PCDH1

TRAPPC11QTRTD1

KRT1

LRP1B

HADHB

TP53BP2

DRD1

ST13

PRPF40A

TRAIP

KIDINS220

GRK6

MMP17

LTBR

EIF6

PGAM1

CHD3

PRSS3

APBB3

CHRNA7

KRT10

RIMS1

CRMP1

PDIK1L

SORBS3

SYMPK

GCN1L1

RNF19A

HOMER3

GRK4

JARID2

MYLK3

EFS

CRB1

HSD17B10

TST

HOMER2

PHC3

TM2D1 FICD

PEG3

CABLES1

LGALS2

ITIH1

HOXB2

TAF4FLOT1

BABAM1

CFH

HIP1R

LTBMYL4

NCOR1

CASP4

NF1

AP4E1

CLCA2

IGDCC4

NECAB3

CXorf27

SH3GLB1

CTCF

PLCG2

(a)

STAT1

EGFR

FN1

PLAT

SOD1

PRKCA CDK1

GSK3B

ALB APP

PPP3CA

IFNG

BBC3

SCN5A

KCNMA1

MAP2

ACHE

MAPK3F2

PTPN1

NOS3 BCL2

CAV1

CTNNB1

PRKCB

TGFB1CASP8

TNF

AKT1

F7

MAPK1LDLR

PRKCD

SLC6A3

DRD1

CASP3

CHRNA7

PRSS3

TP53BP2

CASP7

EPHB2

SYNGAP1

CALM1

CTSD

BACE1

ADRA1B

(b)







0

001

002

003

004

005

006

007

008

0 20 40 60 80 100 120 140 160 180

Betw

eenn

ess

Degree

APP

ALB SRCEGFR

AKT1HTT






Mol 22Mol 33


Mol 97Mol 106


Mol 63Mol 90

Mol 87

Mol 91Mol 61

Mol 19

Mol 109

Mol 161

Mol 118

Mol 111

Mol 158

Mol 114

Mol 149

Mol 141

Mol 152

Mol 14

CASP3

BCL2

NOS3

SCN5A

F7

ADRA1B

ACHE

F2

Mol 4

Mol 49

Mol 127

APP CASP7

Mol 92

Mol 54

Mol 6

Mol 36

KCNMA1

Mol 27


Mol 17

Mol 39

Mol 2

Mol 21

Mol 12

Mol 142

Mol 126

Mol 135

Mol 121

Mol 119

Mol 124

Mol 120

Mol 117

Mol 133

Mol 131

Mol 134


Aurantii Fructus

Licorice

Radix Bupleuri



Mol 8

Mol 73

Mol 75

Mol 77

Mol 80

Mol 7

Mol 82

Mol 76

Mol 74

Mol 60

Mol 46

Mol 150

Mol 151

Mol 112

Mol 115

Mol 11

Mol 116

Mol 113

Mol 110

Mol 1




Mol 35Mol 81

Mol 86

Mol 85

Mol 84

Mol 88

Mol 83Mol 30

Mol 137

ChuanxiongRhizoma

Mol 3

Mol 57

Mol 139

Achyranthis

Bidentatae

RadixMol 102

CASP8

IGHG1AKT1p53

CHRNA7

Mol 40

SLC6A3 PTPN1

SOD1MAPK1

Mol 38

Mol 95

Carthami Flos

Mol 24


Mol 122

Mol 25

Mol 98

TGFB1

GSK3B

PRKCA


Mol 52

Mol 42

Mol 62

Mol 138

EGFR

STAT1 PPP3CAPLAT

Stigmasterol

MAP2


Kaempferol

SYNGAP1

CALM

Baicalin

PRKCB

CAV1

CTSD

TNF

DRD1

CDK1

IFNG

FN1BBC3 PRKCD

Mol 132

Mol 160

Mol 58

Mol 67

Mol 69 Mol 43ALB

Mol 64CTNNB1


Achyranthisiistntnt


RadixadixR diR di


























KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A




TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia






LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3



4 Discussion









(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
























0

001

002

003

004

005

006

007

008

0 20 40 60 80 100 120 140 160 180

Betw

eenn

ess

Degree

APP

ALB SRCEGFR

AKT1HTT






Mol 22Mol 33


Mol 97Mol 106


Mol 63Mol 90

Mol 87

Mol 91Mol 61

Mol 19

Mol 109

Mol 161

Mol 118

Mol 111

Mol 158

Mol 114

Mol 149

Mol 141

Mol 152

Mol 14

CASP3

BCL2

NOS3

SCN5A

F7

ADRA1B

ACHE

F2

Mol 4

Mol 49

Mol 127

APP CASP7

Mol 92

Mol 54

Mol 6

Mol 36

KCNMA1

Mol 27


Mol 17

Mol 39

Mol 2

Mol 21

Mol 12

Mol 142

Mol 126

Mol 135

Mol 121

Mol 119

Mol 124

Mol 120

Mol 117

Mol 133

Mol 131

Mol 134


Aurantii Fructus

Licorice

Radix Bupleuri



Mol 8

Mol 73

Mol 75

Mol 77

Mol 80

Mol 7

Mol 82

Mol 76

Mol 74

Mol 60

Mol 46

Mol 150

Mol 151

Mol 112

Mol 115

Mol 11

Mol 116

Mol 113

Mol 110

Mol 1




Mol 35Mol 81

Mol 86

Mol 85

Mol 84

Mol 88

Mol 83Mol 30

Mol 137

ChuanxiongRhizoma

Mol 3

Mol 57

Mol 139

Achyranthis

Bidentatae

RadixMol 102

CASP8

IGHG1AKT1p53

CHRNA7

Mol 40

SLC6A3 PTPN1

SOD1MAPK1

Mol 38

Mol 95

Carthami Flos

Mol 24


Mol 122

Mol 25

Mol 98

TGFB1

GSK3B

PRKCA


Mol 52

Mol 42

Mol 62

Mol 138

EGFR

STAT1 PPP3CAPLAT

Stigmasterol

MAP2


Kaempferol

SYNGAP1

CALM

Baicalin

PRKCB

CAV1

CTSD

TNF

DRD1

CDK1

IFNG

FN1BBC3 PRKCD

Mol 132

Mol 160

Mol 58

Mol 67

Mol 69 Mol 43ALB

Mol 64CTNNB1


Achyranthisiistntnt


RadixadixR diR di


























KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A




TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia






LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3



4 Discussion









(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Mol 22Mol 33


Mol 97Mol 106


Mol 63Mol 90

Mol 87

Mol 91Mol 61

Mol 19

Mol 109

Mol 161

Mol 118

Mol 111

Mol 158

Mol 114

Mol 149

Mol 141

Mol 152

Mol 14

CASP3

BCL2

NOS3

SCN5A

F7

ADRA1B

ACHE

F2

Mol 4

Mol 49

Mol 127

APP CASP7

Mol 92

Mol 54

Mol 6

Mol 36

KCNMA1

Mol 27


Mol 17

Mol 39

Mol 2

Mol 21

Mol 12

Mol 142

Mol 126

Mol 135

Mol 121

Mol 119

Mol 124

Mol 120

Mol 117

Mol 133

Mol 131

Mol 134


Aurantii Fructus

Licorice

Radix Bupleuri



Mol 8

Mol 73

Mol 75

Mol 77

Mol 80

Mol 7

Mol 82

Mol 76

Mol 74

Mol 60

Mol 46

Mol 150

Mol 151

Mol 112

Mol 115

Mol 11

Mol 116

Mol 113

Mol 110

Mol 1




Mol 35Mol 81

Mol 86

Mol 85

Mol 84

Mol 88

Mol 83Mol 30

Mol 137

ChuanxiongRhizoma

Mol 3

Mol 57

Mol 139

Achyranthis

Bidentatae

RadixMol 102

CASP8

IGHG1AKT1p53

CHRNA7

Mol 40

SLC6A3 PTPN1

SOD1MAPK1

Mol 38

Mol 95

Carthami Flos

Mol 24


Mol 122

Mol 25

Mol 98

TGFB1

GSK3B

PRKCA


Mol 52

Mol 42

Mol 62

Mol 138

EGFR

STAT1 PPP3CAPLAT

Stigmasterol

MAP2


Kaempferol

SYNGAP1

CALM

Baicalin

PRKCB

CAV1

CTSD

TNF

DRD1

CDK1

IFNG

FN1BBC3 PRKCD

Mol 132

Mol 160

Mol 58

Mol 67

Mol 69 Mol 43ALB

Mol 64CTNNB1


Achyranthisiistntnt


RadixadixR diR di


























KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A




TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia






LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3



4 Discussion









(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of





























KCNMA1

P53

IFNG

PPP3CA

CASP8

SCN5A




TGFB1

TNF

PRKCA

CHRNA7

CAV1

STAT1

MAPK cascadeAKT1

BCL2

APP

EGFR

MAPK1

Angiogenesis

SYNGAP1

MAP2

PTPN1

Axonogenesis

GSK3B

EPHB2

CDK1

CASP7FN1

MAPK3

CTNNB1

F2

Autophagy

Cell proliferation

BACE1

SLC6A3

DRD1

ADRA1BACHE

CALMCASP3

PLAT

Apoptotic process

NOS3

PRKCB

Blood coagulation

Response to hypoxia






LDLR

PRSS3

F7

PRKCD

SOD1ALB

BBC3



4 Discussion









(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
























(a) (b) (c)

(d) (e) (f)








5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






















5 Conclusion



Abbreviations




Genomes

Data Availability






Acknowledgments






References





















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of





















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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