Systems Pharmacological Approach to the Effect of Bulsu ...downloads.hindawi.com/journals/ecam/2017/7236436.pdf · Evidence-BasedComplementaryandAlternativeMedicine 5 Table1:Continued

Research ArticleSystems Pharmacological Approach to the Effect ofBulsu-san Promoting Parturition

Su Yeon Suh andWon G An

Department of Pharmacology School of Korean Medicine Pusan National University Yangsan Gyeongnam 50612 Republic of Korea

Correspondence should be addressed to Won G An wganpusanackr

Received 28 July 2017 Accepted 25 September 2017 Published 29 October 2017

Academic Editor Gihyun Lee

Copyright copy 2017 Su Yeon Suh and Won G AnThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited

Bulsu-san (BSS) has been commonly used in orientalmedicine for pregnant women in East AsiaThe purpose of this researchwas toelucidate the effect of BSS on ease of parturition using a systems-level in silico analytic approach Research results show that BSS ishighly connected to the parturition related pathways biological processes and organs There were numerous interactions betweenmost compounds of BSS and multiple target genes and this was confirmed using herb-compound-target network target-pathwaynetwork and gene ontology analysis Furthermore the mRNA expression of relevant target genes of BSS was elevated significantlyin related organ tissues such as those of the uterus placenta fetus hypothalamus and pituitary gland This study used a networkanalytical approach to demonstrate that Bulsu-san (BSS) is closely related to the parturition related pathways biological processesand organs It is meaningful that this systems-level network analysis result strengthens the basis of clinical applications of BSS onease of parturition

1 Introduction

The name of Bulsu-san (BSS) originated from its therapeuticeffects that help to promote easy labor as if being touchedby merciful Buddharsquos hand [1] BSS is composed of AngelicaeSinensisRadix (Danggui DG) andCnidium officinaleMakino(Cheongung CG) which is one of the most commonlyused herb pairs in Traditional Medicine of East Asia andthe usual component ratio is 2 3 (CG DG) or 1 1 [2]BSS is widely used in womenrsquos medicine in East Asia itsrecognized therapeutic effects are as follows removal ofimpure blood blood making easy parturition accelerationof labor elimination of dead fetus or placenta amelioration ofpain nourishing blood and promoting blood circulation [3]

What is more recent experimental research on the CG-DG herb pair indicated that they affect the nourishment ofblood [4] activate blood circulation and prevent blood stasis[5] In addition the CG-DG herb pair showed significantinhibitory effects on the proliferation and protein synthesis ofvascular smooth muscle cells [6] It was suggested BSS couldaffect the activities of Akt kinase and eNOS by increasingintracellular Ca2+ and reducing ROS levels [7] and regulatemenstruation and provide relief from pain by enabling the

management of uterine smooth muscle contractions [8]Although BSS has therapeutic effects on various pathologicalsymptoms in pregnant or childbearing aged women thisresearch focused on the molecular mechanisms and impactof BSS on easing parturition and the acceleration of labor

In terms of parturition onset numerous studies havedescribed the complex hormone interactions between estro-gen progesterone oxytocin corticosteroid and prostaglan-din Among these corticotrophin releasing hormone (CRH)is regarded as a trigger that initiates the labor [9]Theplacentareleases substantial amounts of CRH which stimulates thepituitary glands of both mother and fetus to secrete adreno-corticotropin hormone [10] This in turn induces the releaseof estrogen precursor which is converted into estrogen bythe placenta that induces smooth muscle contraction [10]Additionally dilatation of cervical connective tissue andsmooth muscle is induced by the following changes a shiftfrom progesterone to estrogen dominance increased respon-siveness to oxytocin via the upregulation of myometrial oxy-tocin receptor increased prostaglandins synthesis in uterusincreased myometrial gap junction formation decreasednitric oxide activity and increased influx of calcium intomyocyte [11]

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2017 Article ID 7236436 15 pageshttpsdoiorg10115520177236436

2 Evidence-Based Complementary and Alternative Medicine

ADME Screening

Active Compound

Target Fishing

Potential Target

H-C-T Network

T-P Network

GO Analysis

Target organ location map

Angelicae Sinensis Radix Cnidium ocinale Makino

-aminobutyric acid receptor subunit -1-aminobutyric-acid receptor -2 subunit-aminobutyric-acid receptor -3 subunit-aminobutyric-acid receptor subunit -6

Glucocorticoid receptorGlutamate receptor 2

GABRA1GABRA2GABRA3GABRA6NR3C1GRIA2

Glycogen synthase kinase-3 Heat shock protein HSP 90

Ig -1 chain C regionLeukotriene A-4 hydrolase

GSK3BHSP90AB1

IGHG1LTA4H

transcription DNA-templated

positive regulation of transcription from RNA polymerase II promoter

negative regulation of transcription from RNA polymerase II promoter

chloride transport

gamma-aminobutyric acid signaling pathway

peptidyl-serine phosphorylation

protein autophosphorylation

regulation of cell proliferation

synaptic transmission cholinergic

adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signaling pathway

phospholipase C-activating G-protein coupled acetylcholine receptor signaling pathway

positive regulation of MAPK cascade

positive regulation of sequence-specic DNA binding transcription factor activity

regulation of blood pressure

regulation of smooth muscle contraction

adenylate cyclase-activating adrenergic receptor signaling pathway

cyclooxygenase pathway

Figure 1 The workflow the network pharmacological approach of Bulsu-san (BSS) namely active compounds screening target fishingnetwork analysis and relevant organ location mapping was performed in this study

The hypothesis of this study was that BSS may promotethe positive-feedback of hormone loops as well as a seriesof myometrial and cervical changes to ease parturition andsafely accelerate labor A network based in silico approachwas used to identify the effect of BSS on parturition relatedsystems and the aim of this study was to elucidate the effect ofBSS on the parturition by system-level analysisTheworkflowof the network pharmacological study is summarized inFigure 1

2 Material and Methods

21 Identification of Active Compounds Compounds in CGand DG were identified using a phytochemical databasethat is the Traditional Chinese Medicine Systems Phar-macology (TCMSP httpibtshkbueduhkLSPtcmspphp)We applied parameters related to absorption distributionmetabolism and excretion (ADME) namely human drug-likeness (DL) [12] oral bioavailability (OB) [13] and Caco-2 permeability (Caco-2) to screen the Potential active com-pounds in BSS [14]

211 Drug-Likeness Evaluation DL helps filter ldquodrug-likerdquocompounds in oriental herbs as DL represents a qualitativeconcept for valuations based on how ldquodrug-likerdquo a prospec-tive compound is [15] Accordingly a high DL may lead toa greater possibility of therapeutic success and compoundswith a higher DL value are more likely to possess certainbiological properties [16] The calculations of DL in TCMSP

database were based on Tanimoto coefficient formula [17] asfollows

119865 (119860 119861) =119860 times 119861

1198602 + 1198612 minus 119860 times 119861 (1)

where 119860 represents the molecular parameters of herbal com-pounds and119861 is the averagemolecular parameters of all com-pounds in theDrugbank database (httpwwwdrugbankca)[18] In the present study we excluded compounds with a DLof lt008 Other previous researches of herbal formulas set ahigher threshold in the range of 01 to 018However we foundout that most compounds of DG have low DL In detail only36 compounds of 125 in DG show higher or equal DL valuethan 008 For this reason this study sets a lower threshold ofDL than other previous researches to see the most potentialtargets of BSS

212 Oral Bioavailability (OB) Prediction OB is defined asthe ratio of active compoundsrsquo absorption into the systemiccirculation which represents the convergence of the ADMEprocess [13] OB values are dependent on drug dissolution inthe gastrointestinal (GI) tract and hepatic and intestinal first-pass metabolism as well as on intestinal membrane perme-ation whichmakes it a major pharmacokinetic parameter fordrug evaluations [16] In this study the OB threshold was setas ge15

213 Caco-2 Permeability Screening Caco-2 permeability isused to predict the absorption of an orally administered

Evidence-Based Complementary and Alternative Medicine 3

drug [14] Surface absorptivity of the small intestine ismaximized with the presence of villi and microvilli for thisreason most orally administered drug absorption occurs inthe small intestine [19] Moreover the movement of orallyadministered drugs across the intestinal epithelial barrierdetermines the rate and extent of human absorption andultimately affects drug bioavailability [20] In the presentstudy compounds with OB DL and Caco-2 values of greaterthan 15 008 and gtminus04 respectively were regarded asactive compounds and subjected to further analysis

214 Lipinskirsquos Rule (LR) Screening In addition the screen-ing standard used was defined based on Lipinskirsquos rule (LR)which identifies druggable compounds as having molecularweight (MW)ofle500Da (MWle 500) chemical compositionwith le5 hydrogen-bond donors le10 hydrogen-bond accep-tors and an octanol-water partition coefficient AlogP of le5 [21] AlogP can be used to estimate local hydrophobicityto produce molecular hydrophobicity maps and to evaluatehydrophobic interactions in protein-ligand complexes [22]Hdon and Hacc are the number of possible hydrogen-bonddonors and acceptors and the hydrogen-bonding capacity ofa drug solute is recognized as a crucial determinant of perme-ability moreover high hydrogen-bonding potential is oftenrelated to lowpermeability and absorption [23] Eventually inthe present studywe selected active compounds satisfying thefollowing criteria OB ge 15 DL ge 008 Caco-2 ge minus04 MWle 500 H-bond donors le 5 H-bond acceptors le 10 AlogP le 5

22 Target Fishing Aside from filtering active compoundswe also sought to identify the molecular targets of theseactive compounds Compound-target interaction profileswere established based on a systematic prediction of mul-tiple drug-target interactions tool which employs randomforest (RF) and support vector machine (SVM) methodsand integrates chemical genomic and pharmacologicalinformation for drug targeting and discovery on a largescale [24] Compound-target interactions satisfying SVMscore ge 08 and RF score ge 07 were selected for furtherstudy Additionally filtered compound-target interactionprofile mapping was performed using the UniProt database(httpwwwuniprotorg) [25]

23 Gene Ontology (GO) Analysis Biological process (BP)of gene ontology (GO) analysis was employed to determinethe biological properties of target genes [26] GO annotationindicates the possibility of direct statistical analysis on genefunction information In this research GO BP terms with119875 values lt 001 were employed and the data was collectedusing the DAVID 68 Gene Functional Classification Tool(httpdavidabccncifcrfgov)

24 Network Construction and Analysis In order to under-stand the multiscale interactions between the active com-pounds of BSS and targets two types of networks werebuilt (1) the herb-compound-target network (H-C-T net-work) in which nodes represent either compounds tar-get genes or herbs and edges indicate herb-compound-target connections and (2) the target-pathway network (T-P

network) to extract the pathways from KEGG database(httpwwwgenomejpkegg) and the terms highly associ-ated with parturition with 119875 values lt 005 were selected asthe related pathways of targets in this work Related targetswere mapped onto relevant pathways which resulted in theT-P network Both networks were generated in Cytoscape351 an open-source biological network visualization anddata integration software package [27]

25 Target Organ Location Map Tissue-specific patterns ofmRNA expression can indicate important associations withbiological events or gene functions [28] To explore thebeneficial effects of BSS during parturition it is importantthat the tissue mRNA expression profiles of target genesat the organ level be known [29] The target organ loca-tion map was built according to the Dataset GeneAtlasU133A gcrma (httpbiogpsorg) BioGPS database providesexpression data acquired by direct measurements of geneexpression obtained by microarrays analysis [30] First themRNA expression patterns of each target gene in 176 partsof organ tissues were obtained Second average values werecalculated for each gene Third frequency of above averagemRNA expression tissue organs was inspected Forth basedon the result from the third step and parturition mechanismtheory mRNA expression data of relevant organ tissueswere extracted and categorized into 6 groups namely uterusandor uterus corpus fetus andor placenta hypothalamusandor pituitary smooth muscle and whole blood

3 Results

31 Identification of Active Compounds 314 compounds ofBSSwere identified including 189molecules in CG and 125 inDG (as shown in Supplementary Material Table S1 in Supple-mentary Material available online at httpsdoiorg10115520177236436) and active compounds met the criteria OBge 15 Caco-2 ge minus04 and DL ge 008 as well as thestandards of Lipinskirsquos rule (LR) (as shown in Table 1) Indetail 60 active compounds were initially chosen but 8 com-pounds were present in both herbs namely 3-butylidene-7-hydroxyphthalide adenine BdPh beta-selinene palmiticacid senkyunolide-C senkyunolide-D and senkyunolide-E and 14 had no target protein information and werethus excluded from the list of active compounds whereas27 compounds with lower ADME properties than abovethresholds were included which were reported to be relatedto oxytocin In total 65 active compounds were filtered

Although ligustilide and ferulic acid have a DL of lt008both were included in this study Since ligustilide (C12 DL =007 OB = 5372 Caco-2 = 13) was reported to be the maincompound of DG in uterine contraction [31] and ferulic acid(C42DL=006OB=5497 Caco-2= 053) has been reportedto be useful for the treatment of vascular diseases [6 32] andblood deficiency syndrome [33] in China and to suppressinflammatory responses and tumor progression [34] Someother compounds also have been shown experimentally tohave various biological activities for example crysophanol(C42 DL = 021 OB = 1864 Caco-2 = 062) can be usedto treat menorrhagia and thrombocytopenia [35] Perlolyrine


Table 1 65 Potential active compounds of BSS (compound with lowast was present in both herbs)

ID Active compounds OB () Caco-2 DL HerbC1 ()-alpha-Terpineol 463 128 003 DGC2 ()-Aromadendrene 5574 181 01 CGC3 ()-Terpinen-4-ol 8141 136 003 CGC4 (+)-alpha-Funebrene 5287 179 01 CGC5 (+)-Ledol 1696 143 012 DGC6 (1R5R7S)-47-Dimethyl-7-(4-methylpent-3-enyl)bicyclo[311]hept-3-ene 1623 186 009 CG

C7 (1S4aR8aR)-1-Isopropyl-7-methyl-4-methylene-234a568a-hexahydro-1H-naphthalene 198 186 008 DG

C8 (1S4E8E10R)-481111-tetramethylbicyclo[810]undeca-48-diene 2169 186 008 CGC9 (3E)-3-butylidene-7-hydroxy-2-benzofuran-1-one 4217 103 008 DGC10 (L)-alpha-Terpineol 488 139 003 CGC11 (R)-Linalool 398 133 002 CGC12 (Z)-Ligustilide 5372 13 007 CGC13 1-Acetyl-beta-carboline 6712 118 013 CGC14 1-beta-Ethylacrylate-7-aldehyde-beta-carboline 2853 045 031 CG

C15 1H-Cycloprop(e)azulen-7-ol decahydro-117-trimethyl-4-methylene-(1aR-(1aalpha4aalpha7beta7abeta7balpha))- 8233 137 012 CG

C16 1-Terpineol 4983 124 003 CGC17 26-Di(phenyl)thiopyran-4-thione 6913 174 015 DGC18 2-[(2S5S6S)-610-Dimethylspiro[45]dec-9-en-2-yl]propan-2-ol 3762 144 009 CGC19lowast 3-Butylidene-7-hydroxyphthalide 6268 1 008 CGampDGC20 47-Dihydroxy-3-butylphthalide 10609 069 01 CGC21 49070 FLUKA 8551 129 012 CGC22 4-Hydroxy-3-butylphthalide 7031 09 008 CGC23 58870 FLUKA 4901 182 01 CGC24lowast Adenine 6281 minus03 003 CGampDGC25 ADO 1598 minus156 018 CGC26 alpha-Cubebene 1673 183 011 CGC27 alpha-Selinene 3181 182 01 CGC28 Aromadendrene oxide 2 651 156 014 CGC29lowast BdPh 4244 132 007 CGampDGC30 beta-Chamigrene 3199 182 008 DGC31lowast beta-Selinene 2439 183 008 CGampDGC32 beta-Cubebene 3216 182 011 CGC33 Cadinene 1712 188 008 DGC34 Caffeic acid 2576 021 005 CGC35 Carotol 14903 146 009 CGC36 Cedrene 5114 182 011 CGC37 Chuanxiongol 2219 094 01 CGC38 cis-Thujopsene 5643 184 012 DGC39 Coniferyl ferulate 454 071 039 DGC40 Crysophanol 1864 062 021 CGC41 FA 6896 minus15 071 CGC42 Ferulic acid (CIS) 5497 053 006 DG

C43 InChI=1C15H24c1-10-7-8-15-9-12(10)14(34)13(15)6-5-11(15)2h711-13H5-68-9H21-4H 5556 179 01 DG

C44 L-Bornyl acetate 6552 129 008 CGC45 Methyl palmitate 1809 137 012 CGC46 Myricanone 406 067 051 CGC47 Nicotinic acid 4765 034 002 DG


Table 1 Continued

ID Active compounds OB () Caco-2 DL HerbC48 Oleic acid 3313 117 014 CGC49lowast Palmitic acid 193 109 01 CGampDGC50 Perlolyrine 6595 088 027 CGC51 PLO 1407 069 043 CGC52 Scopoletol 2777 071 008 DGC53 Senkyunolide A 2656 13 007 CGC54 Senkyunolide G 3952 063 008 CGC55lowast Senkyunolide-C 468 087 008 CGampDGC56lowast Senkyunolide-D 7913 012 01 CGampDGC57lowast Senkyunolide-E 344 055 008 CGampDGC58 Senkyunolide-K 6175 052 008 CGC59 Sinapic acid 6415 048 008 CGC60 Sphingomyelin 031 minus046 051 DGC61 Stearic acid 1783 115 014 CGC62 Stigmasterol 4383 144 076 DGC63 Succinic acid 2962 minus044 001 DGC64 Sucrose 717 minus289 023 CGC65 Wallichilide 4231 082 071 CG

(C52 DL = 027 OB = 6595 Caco-2 = 088) was confirmedto have a protective effect on injured human umbilical veinendothelial cells [36] and myricanone (C48 DL = 051 OB= 5761 Caco-2 = 067) was found to best inhibit mouse skintumor progression [37]

32 Target Fishing The 65 active compounds interact with185 target proteins as shown in Table 2 in other wordson average each compound on average interacts with 285target proteinsThis result confirms the polypharmacologicalcharacter of oriental medicine and demonstrates the syn-ergistic effects of multiple compounds on multiple targets[38] Different compounds in CG and DG can directly affectcommon targets for example the target protein ldquocalmodulin(CALM1)rdquo interacts with crysophanol fromCG and coniferylferulate from DG at the same time which implies thesynergetic or cumulative effects of herbal medicine

33 GO Analysis 397 biological process terms with 119875 valuesof lt001 were sorted using the functional annotation chart ofthe DAVID 68 Gene Functional Classification Tool basedon 185 filtered target genes and 119875 values were adjustedusing the Benjamini-Hochberg method 30 enriched GO BPterms extracted by 119875 value and gene counts are displayed inFigure 2 It is meaningful that most of the target genes aresignificantly related to the various BP involved in parturitionFor instance 30 extracted GO BP terms include ldquoMAPKsignaling pathwaysrdquo ldquosteroid hormone mediated signalingpathwayrdquo ldquoresponse to glucocorticoidrdquo ldquoresponse to estra-diolrdquo and ldquopositive regulation of ERK1 and ERK2 cascaderdquoldquoMAPK signaling pathwaysrdquo were reported to be activatedin human uterine cervical ripening during parturition [39]ldquoSteroid hormone mediated signaling pathwayrdquo is highly

related to parturition process as estrogen and progesteroneplay important roles in pregnancy and parturition andestrogen induceS the principal stimulatory myometrial con-tractility [40] Also estradiol takes key place in parturitionprocess [41] It was identified that increased ERK activationis observed at the onset of labor and it promotes myometrialcontractility and development of parturition [42 43] To sumup the target genes of BSS are highly associated with thebiological process (BP) of parturition

34 Network Construction and Analysis Network analysis isan efficient tool for visualizing and understanding multipletargeted drug actions and demonstrates drug actions withinthe context of the whole genome [44 45] For a better insightof therapeutic impacts H-C-T and T-P networks were con-structed and displayed in Figures 3 and 4 respectively In theH-C-T network nodes represent herb names compoundsand targets Also in the T-P network circular nodes representtargets and triangle nodes represent pathways Besides nodesize is relative to the degree and edges show interactionsbetween nodes

H-C-T network confirmed that there were 739 interac-tions between 185 targets and 65 active compounds of CGand DG oleic acid (C48 degree = 42) with the highestnumber of interactions with targets followed by succinicacid (C63 degree = 40) and stigmasterol (C62 degree =37) It shows that single molecules target multiple recep-tors [46] Also some compounds from CG and DG werefound to share common targets Likewise prostaglandinGH synthase 2 (PTGS2 degree = 56) displayed the mostaffinitive connections with compounds followed by gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1 degree= 48) prostaglandin GH synthase 1 (PTGS1 degree = 37)


Table 2 Related targets of potential compounds in BSS

UniProt ID Target name Gene NameP80404 4-aminobutyrate aminotransferase mitochondrial ABATP33121 Long-chain-fatty-acid--CoA ligase 1 ACSL1O60488 Long-chain-fatty-acid--CoA ligase 4 ACSL4P00813 Adenosine deaminase ADAP07327 Alcohol dehydrogenase 1A ADH1AP00325 Alcohol dehydrogenase 1B ADH1BP00326 Alcohol dehydrogenase 1C ADH1CP29274 Adenosine A2a receptor ADORA2AP35348 Alpha-1A adrenergic receptor ADRA1AP35368 Alpha-1B adrenergic receptor ADRA1BP25100 Alpha-1D adrenergic receptor ADRA1DP08913 Alpha-2A adrenergic receptor ADRA2AP18089 Alpha-2B adrenergic receptor ADRA2BP18825 Alpha-2C adrenergic receptor ADRA2CP08588 Beta-1 adrenergic receptor ADRB1P07550 Beta-2 adrenergic receptor ADRB2Q5SY84 Adenylosuccinate synthetase ADSSP21549 Serine--pyruvate aminotransferase AGXTO43865 Putative adenosylhomocysteinase 2 AHCYL1P15121 Aldose reductase AKR1B1P13716 Delta-aminolevulinic acid dehydratase ALADP51649 Succinate semialdehyde dehydrogenase mitochondrial ALDH5A1P04745 Alpha-amylase 1 AMY1AP04746 Pancreatic alpha-amylase AMY2AP04114 Apolipoprotein B-100 APOBP10275 Androgen receptor ARP06576 ATP synthase subunit beta mitochondrial ATP5BP06276 Cholinesterase BCHEP10415 Apoptosis regulator Bcl-2 BCL2Q06187 Tyrosine-protein kinase BTK BTKP00915 Carbonic anhydrase I CA1P62158 Calmodulin CALM1P42574 Caspase-3 CASP3P04040 Catalase CATP06307 Cholecystokinin CCKP20248 Cyclin-A2 CCNA2P30305 M-phase inducer phosphatase 2 CDC25BP24941 Cell division protein kinase 2 CDK2P11597 Cholesteryl ester transfer protein CETPP28329 Choline O-acetyltransferase CHATO14757 Serinethreonine-protein kinase Chk1 CHEK1P36222 Chitinase-3-like protein 1 CHI3L1P11229 Muscarinic acetylcholine receptor M1 CHRM1P08172 Muscarinic acetylcholine receptor M2 CHRM2P20309 Muscarinic acetylcholine receptor M3 CHRM3Q15822 Neuronal acetylcholine receptor subunit alpha-2 CHRNA2P36544 Neuronal acetylcholine receptor protein alpha-7 chain CHRNA7Q99966 Cbpp300-interacting transactivator 1 CITED1P02452 Collagen alpha-1(I) chain COL1A1Q02388 Collagen alpha-1(VII) chain COL7A1P17538 Chymotrypsinogen B CTRB1P07339 Cathepsin D CTSDP04798 Cytochrome P450 1A1 CYP1A1


Table 2 Continued

UniProt ID Target name Gene NameP05177 Cytochrome P450 1A2 CYP1A2Q9ULA0 Aspartyl aminopeptidase DNPEPP27487 Dipeptidyl peptidase IV DPP4P21728 Dopamine D1 receptor DRD1P14416 D(2) dopamine receptor DRD2P25101 Endothelin-1 EDNRAQ07075 Glutamyl aminopeptidase ENPEPQ6UWV6 Ectonucleotide pyrophosphatasephosphodiesterase family member 7 ENPP7P04626 Receptor tyrosine-protein kinase erbB-2 ERBB2P03372 Estrogen receptor ESR1Q92731 Estrogen receptor beta ESR2P00742 Coagulation factor Xa F10P00734 Thrombin F2P08709 Coagulation factor VII F7P07148 Fatty acid-binding protein liver FABP1P01100 Proto-oncogene c-Fos FOSP15408 Fos-related antigen 2 FOSL2P35575 Glucose-6-phosphatase G6PCP14867 Gamma-aminobutyric acid receptor subunit alpha-1 GABRA1P47869 Gamma-aminobutyric-acid receptor alpha-2 subunit GABRA2P34903 Gamma-aminobutyric-acid receptor alpha-3 subunit GABRA3P48169 Gamma-aminobutyric-acid receptor subunit alpha-4 GABRA4P31644 Gamma-aminobutyric-acid receptor alpha-5 subunit GABRA5Q16445 Gamma-aminobutyric-acid receptor subunit alpha-6 GABRA6P17677 Neuromodulin GAP43P47871 Glucagon GCGRP14136 Glial fibrillary acidic protein GFAPQ2TU84 Growth-inhibiting protein 18 GIG18P23415 Glycine receptor alpha-1 chain GLRA1P00367 Glutamate dehydrogenase 1 mitochondrial GLUD1P17174 Aspartate aminotransferase cytoplasmic GOT1P00505 Aspartate aminotransferase mitochondrial GOT2P42262 Glutamate receptor 2 GRIA2P49841 Glycogen synthase kinase-3 beta GSK3BQ15486 Putative beta-glucuronidase-like protein SMA3 GUSBP1P19367 Hexokinase-1 HK1P04035 3-hydroxy-3-methylglutaryl-coenzyme A reductase HMGCRP00738 Haptoglobin HPO14756 Oxidoreductase HSD17B6P08238 Heat shock protein HSP 90 HSP90AB1P28223 5-hydroxytryptamine 2A receptor HTR2AP01344 Insulin-like growth factor II IGF2P01857 Ig gamma-1 chain C region IGHG1P22301 Interleukin-10 IL10P05231 Interleukin-6 IL6P01308 Insulin INSQ12809 Potassium voltage-gated channel subfamily H member 2 KCNH2Q12791 Calcium-activated potassium channel subunit alpha 1 KCNMA1P35968 Vascular endothelial growth factor receptor 2 KDRP09848 Lactase-phlorizin hydrolase LCTQ32P28 Prolyl 3-hydroxylase 1 LEPRE1Q8IVL6 Prolyl 3-hydroxylase 3 LEPREL2P06858 Lipoprotein lipase LPL


Table 2 Continued

UniProt ID Target name Gene NameP09960 Leukotriene A-4 hydrolase LTA4HP21397 Amine oxidase [flavin-containing] A MAOAP27338 Amine oxidase [flavin-containing] B MAOBQ16539 Mitogen-activated protein kinase 14 MAPK14Q00266 S-adenosylmethionine synthetase isoform type-1 MAT1AP31153 S-adenosylmethionine synthetase isoform type-2 MAT2AP23368 NAD-dependent malic enzyme mitochondrial ME2Q16798 NADP-dependent malic enzyme mitochondrial ME3Q3SYC2 2-acylglycerol O-acyltransferase 2 MOGAT2P05164 Myeloperoxidase MPOQ15788 Nuclear receptor coactivator 1 NCOA1Q15596 Nuclear receptor coactivator 2 NCOA2P29475 Nitric-oxide synthase brain NOS1P35228 Nitric oxide synthase inducible NOS2P29474 Nitric oxide synthase endothelial NOS3P16083 NRH dehydrogenase [quinone] 2 NQO2Q14994 Nuclear receptor subfamily 1 group I member 3 NR1I3P04150 Glucocorticoid receptor NR3C1P08235 Mineralocorticoid receptor NR3C2Q16620 BDNFNT-3 growth factors receptor NTRK2P04181 Ornithine aminotransferase mitochondrial OATP00480 Ornithine carbamoyltransferase mitochondrial OTCQ9BYC2 Succinyl-CoA3-ketoacid-coenzyme A transferase 2 mitochondrial OXCT2O15460 Prolyl 4-hydroxylase subunit alpha-2 P4HA2P49585 Choline-phosphate cytidylyltransferase A PCYT1AQ14432 CGMP-inhibited 3101584051015840-cyclic phosphodiesterase A PDE3AO00330 Pyruvate dehydrogenase protein X component mitochondrial PDHXP52945 Pancreasduodenum homeobox protein 1 PDX1P06401 Progesterone receptor PGRP48736 Phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit gamma isoform PIK3CGP11309 Proto-oncogene serinethreonine-protein kinase Pim-1 PIM1P61925 cAMP-dependent protein kinase inhibitor alpha PKIAP14618 Pyruvate kinase isozymes M1M2 PKM2P04054 Phospholipase A2 PLA2G1BP00749 Urokinase-type plasminogen activator PLAUP00747 Plasminogen PLGP00491 Purine nucleoside phosphorylase PNPP27169 Serum paraoxonasearylesterase 1 PON1Q07869 Peroxisome proliferator-activated receptor alpha PPARAQ03181 Peroxisome proliferator-activated receptor delta PPARDP37231 Peroxisome proliferator activated receptor gamma PPARGQ9UBK2 Peroxisome proliferator-activated receptor gamma coactivator 1-alpha PPARGC1AP17612 mRNA of PKA Catalytic Subunit C-alpha PRKACAP05771 Protein kinase C beta type PRKCBP35030 Trypsin-3 PRSS3P60484 Phosphatidylinositol-345-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN PTENP43115 Prostaglandin E2 receptor EP3 subtype PTGER3P23219 Prostaglandin GH synthase 1 PTGS1P35354 Prostaglandin GH synthase 2 PTGS2P18031 mRNA of Protein-tyrosine phosphatase non-receptor type 1 PTPN1P10082 Peptide YY PYYP63000 Ras-related C3 botulinum toxin substrate 1 RAC1P50120 Retinol-binding protein 2 RBP2P08100 Rhodopsin RHO


Table 2 Continued

UniProt ID Target name Gene NameP19793 Retinoic acid receptor RXR-alpha RXRAO00767 Acyl-CoA desaturase SCDQ14524 Sodium channel protein type 5 subunit alpha SCN5AP31040 Succinate dehydrogenase [ubiquinone] flavoprotein subunit mitochondrial SDHAP16109 P-selectin SELPP05121 Plasminogen activator inhibitor 1 SERPINE1P14410 Sucrase-isomaltase intestinal SIO76082 Solute carrier family 22 member 5 SLC22A5Q9UBX3 Mitochondrial dicarboxylate carrier SLC25A10P11168 Solute carrier family 2 facilitated glucose transporter member 2 SLC2A2P23975 Sodium-dependent noradrenaline transporter SLC6A2Q01959 Sodium-dependent dopamine transporter SLC6A3P31645 Sodium-dependent serotonin transporter SLC6A4P35610 Sterol O-acyltransferase 1 SOAT1P00441 Superoxide dismutase [Cu-Zn] SOD1P08047 Transcription factor Sp1 SP1P12931 Proto-oncogene tyrosine-protein kinase SRC SRCP36956 Sterol regulatory element-binding protein 1 SREBF1Q12772 Sterol regulatory element-binding protein 2 SREBF2Q9P2R7 Succinyl-CoA ligase [ADP-forming] beta-chain mitochondrial SUCLA2Q99973 Telomerase protein component 1 TEP1P01375 Tumor necrosis factor TNFQ16881 Thioredoxin reductase cytoplasmic TXNRD1P55851 Mitochondrial uncoupling protein 2 UCP2P55916 Mitochondrial uncoupling protein 3 UCP3

and muscarinic acetylcholine receptor M1 (CHRM1 degree= 37) Except for C60 (PLA2G1B degree = 1) the rest ofthe 64 active compounds are connected with more thanone target likewise 73 (395) target genes out of 185interactedwithmore than one compoundThis result demon-strates the multicompounds and multitarget properties ofherbal compounds and there was a report that compoundswith multiple targets could have greater therapeutic efficacy[47]

In addition the top 40 pathways were extracted basedon gene counts and 119875 value (lt005) and 119875 value wasadjusted by Benjamini-Hochbergmethod T-P network usingrelevant targets of herbal compounds is demonstrated inFigure 4 There were 485 interactions between the top 40pathways and 135 of 185 target genes ldquoMetabolic pathwaysrdquo(degree = 49) and ldquoneuroactive ligand-receptor interactionpathwayrdquo (degree = 32) had the highest and the secondhighest numbers of connections with the targets followedby ldquocalcium signalingrdquo (degree = 21) ldquocAMP signaling path-wayrdquo (degree = 17) and ldquocGMP PKG signaling pathwayrdquo(degree = 15) These are compelling results that parturitionprocesses are the complex hormone interactions and it iswell known that calcium signals within the myometrium arepivotal for uterine contractions [48] In the same mannersome target genes demonstrated higher degree centralitywith top 40 pathways namely PI3-kinase subunit gamma(PIK3CG degree = 23) cAMP-dependent protein kinase

catalytic subunit alpha (PRKACA degree = 20) proteinkinase C beta type (PRKCB degree = 18) and calmodulin(CALM1 degree = 11) We can confirm the same result in theprevious researches For instance PI3-kinase subunit gammaplays the key role in regulating cAMP calcium cyclingand beta-adrenergic signaling [49] Moreover during thelabor calmodulin-calcium complex activates myosin light-chain kinase which causes the generation of ATPase activityeventually uterine contraction is promoted [50]

H-C-T network explains the multitarget multicom-pounds properties and accumulates effect of herbalmedicines and T-P network shows that target genes of BSSare highly related to the pathway associated with parturi-tion process

35 Target Organ Location Map It is important to confirmthe tissue mRNA expression profiles of the target genes atthe organ level to identify the effects of BSS on parturi-tion Since there was no mRNA expression information inBioGPS of muscarinic acetylcholine receptor M1 (CHRM1)putative beta-glucuronidase-like protein SMA3 (GUSBP1)and retinol-binding protein 2 (RBP2) excluding these 3targets from 185 filtered targets totally 182 genes mRNAexpression profiles were analyzed in this studyTherewere 519interactions between target genes and organ locations Thenetworks of target genes tissuemRNAexpression profiles andcompounds of BSS are shown in Figure 5


GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233

0 10 20 30 40 50response to fatty acid

circadian rhythmresponse to nutrient

glucose transportcellular response to lipopolysaccharide

steroid hormone mediated signaling pathwayresponse to ethanol

response to hydrogen peroxidepositive regulation of protein kinase B signaling

positive regulation of MAPK cascaderesponse to nicotine

response to coldcholesterol metabolic process

platelet activationpositive regulation of ERK1 and ERK2 cascade

response to lipopolysaccharidelipid metabolic process

response to estradioltranscription initiation from RNA polymerase II promoter

cell-cell signalingresponse to glucocorticoid

positive regulation of transcription DNA-templatedcell proliferation

positive regulation of cell proliferationoxidation-reduction process

aging

response to hypoxiaresponse to drug

Countminus ＦＩＡ (P-value)10



Figure 2GOanalysis 30 enriched biological process (BP) of gene ontology (GO) terms sorted by119875 valuelt 001 and gene counts are displayedThe 119910-axis represents enriched biological process (BP) terms for the target genes and the 119909-axis shows gene counts and minus log 10 (119875 value)

As a result 159 of 182 target genes displayed beyond aver-agemRNAexpression in relevant organ tissues such as uterusandor uterus corpus fetus andor placenta hypothalamusandor pituitary smoothmuscle andwhole bloodThe rest of23 genes of 182 targets did not display above average mRNAexpression in above organ tissues for example gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6) andcoagulation factor X (F10)

Nevertheless most genes of 159 demonstrated highexpression patterns in several organs of parturition relatedtissues at the same time In detail 60 genes showed mostsignificantmRNA expression in the uterus andor uterus cor-pus group 130 for placenta andor fetus 86 for hypothalamusandor pituitary 82 for smoothmuscle 80 for pituitary and 81for whole blood Besides 30 of 159 genes showed expression

in all of 6 groups For instance muscarinic acetylcholinereceptor M2 (CHRM2) neuronal acetylcholine receptorsubunit 120572-2 (CHRNA2) gamma-aminobutyric acid receptorsubunit alpha-3 (GABRA3) NO synthase inducible (NOS2)cGMP-inhibited 3101584051015840-cyclic phosphodiesterase A (PDE3A)and sodium-dependent dopamine transporter (SLC6A3)recorded beyond average mRNA expression in all six groupsFurthermore 79 of targets were expressed in two or moreorgan tissues which suggests that those organs and targetgenes of BSS are closely correlated

4 Discussion

In this study network pharmacology method with DL OBCaco-2 and LR evaluation multiple drug-target prediction


DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1

Figure 3 H-C-T network herb-compound-target (H-C-T) network demonstrated multicompound multitarget property of BSS In thisnetwork red and blue nodes represent herbs green nodes show compounds and pink nodes indicate targets and node size is relative to thedegree and edges demonstrate interactions between nodes

network analysis and relevant organ location mapping wasused to explain the targets of BSS in relation to the parturitionprocess There is no denying that network based analysis ispowerful approach for identifying the actions of multitarget-ing herbal medicines at the systems level and our study showstarget genes of BSS are strongly connected to parturitionrelated pathways biological processes and organs It wasconfirmed that 98 of the active compounds of BSS wereinteracted with more than two targets and 395 of thetargets related to more than one compound The synergeticmultitarget properties of BSS were visualized but furtherdiscussion about differentiated drug action based on degreecentrality and simultaneous targeting effect of more than onecompound is required [51] Also detailed potential pathwaysof BSS should be explored deeply in the future

Similar findings were identified in a few RCT researchesin China that using BSS in induction of labor can reduce

the delivery time the amount of bleeding and the residualrate of placenta [52 53] In addition BSS targets six genes ofGABA receptor and NOS which was reported to be relatedoxytocin neurons at the time of parturition in rats [54] AlsoBSS targets NOS and NO (nitric oxide) which are involved inthe regulation of uterine contractility during pregnancy andis a key factor for the onset of labor [55] and iNOS (induciblenitric oxide synthase) can be upregulated accordantly bysimilar inflammatory mediators during ripening [11]

In fact rather than DG Angelicae Gigantis Radix (Dang-gwi AGR) grows naturally in Korea for that reason thecombination of AGR and CG is commonly used as BSSin Korea Instead DG is named as Chinese Danggwi foraccurate classification in Korea Several studies have shownAGR is differs from DG in terms of its main active con-stituents and genetic form AGR is mainly composed of


SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C

Carbohydratedigestionandabsorption

NonalcoholicfattyliverdiseaseNAFLD

Insulinsignalingpathway

PRKACA

CHAT

cAMPsignalingpathway

CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse

Regulationoflipolysisinadipocytes

NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B

VEGFsignalingpathway

HIF1signalingpathway

PPARA

NR3C1

Calciumsignalingpathway

Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1

Vascularsmoothmusclecontraction

SOD1 Dopaminergicsynapse

PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA

cGMPPKGsignalingpathwayPTGER3MAPK14

BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1

Retrogradeendocannabinoidsignaling

CHRNA7Amphetamineaddiction

CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3

Neuroactiveligandreceptorinteraction

PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1

Arginineandprolinemetabolism

ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2

GABAergicsynapseSLC6A4

ME2

GLUD1

Carbonmetabolism AHCYL1

AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2

PPARsignalingpathway

CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A

Sphingolipidsignalingpathway

Pertussis

Adrenergicsignalingincardiomyocytes

CTSD

ERBB2

Amoebiasis

TNF

InsulinresistanceNCOA2

Proteoglycansincancer

IGF2

INS

NCOA1PLAU

yroidhormonesignalingpathway

PathwaysincancerProlactinsignalingpathway COL1A1

IL6

EstrogensignalingpathwaySERPINE1

PGRAMPKsignalingpathway

IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B

ChagasdiseaseAmericantrypanosomiasis

Progesteronemediatedoocytematuration

AmyotrophiclateralsclerosisALS

Figure 4 T-P network in target-pathway (T-P) network circular nodes represent compounds and triangles indicate pathways Node size isrelative to the degree and edges demonstrate interactions between nodes

water soluble polysaccharide but coumarin which is liposol-uble including nodakenin (1) peucedanone (2) marmesin(3) decursinol (4) 7-hydroxy-6-(2R-hydroxy-3-methylbut-3-enyl) coumarin (5) demethylsuberosin (6) decursin (7)decursinol angelate (8) and isoimperatorin (9) [56] Ofthese decursin and its isomer decursinol angelate have beenreported to be the active compounds in AGR [57] It wasidentified in the experimental studies that AGR and DGact via different mechanisms in the cardiovascular centralnervous system and anticancer activity but both have similarpharmacological effects [57] Since the compositions of DGand AGR differ further study on BSS with AGR is requiredCurrently BSS is commonly prescribed to treat cerebravascular and cardiovascular diseases in China [33] but inKorea BSS is widely applied in obstetrics

The similarity between cervical ripening during partu-rition and inflammatory reaction has been pointed out inearlier studies this has been attributed to the inductionof leukocyte migration into tissue thus promoting cervical

remodeling and parturition by estrogen [58] Further studyis needed in terms of the effect of BSS on inflammatoryreactions and parturition

Furthermore theCG-DGherb pair has other names suchas Gunggui-tang (weight ratios of 2 3 or 1 1) Ogeum-san(1 1) Iphyo-san (1 1) and Sinmyo Bulsu-san (1 2) thoseare prepared at different weight ratios [3] Accordinglyweight ratio should be determined based on considerationsof targeted symptoms for relevant clinical applications

5 Conclusion

This study results show that Bulsu-san (BSS) is highlyconnected to the parturition related pathways biologicalprocesses and organsMost compounds inBSSwork togetherwith multiple target genes in a synergetic way and this wasconfirmed using herb-compound-target network and target-pathway network analysis The mRNA expression of relevanttarget genes of BSS was elevated significantly in parturition


ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7

hypothalamus andor pituitary

LEPREL2

NOS1

NCOA2

fetus andor placenta

SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP

uterus andor uterus corpus

IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1

Figure 5 Target organ location map it shows that tissue-specific patterns of mRNA expression are highly active in relative organs ofparturition process such as uterus fetus placenta hypothalamus pituitary and smooth muscle Yellow nodes show compounds and pinknodes indicate targets and node size is relative to the degree and edges demonstrate interactions between nodes

related organ tissues such as those of the uterus placentafetus hypothalamus and pituitary gland

This study employed the network analytical methodsto show the multicompound multitarget properties of BSSThe results not only support clinical applications of BSS oneasing childbirth but also suggest the related target genes andpathways of BSS on promoting parturition according to asystems-level in silico analytic approach However detailedmechanisms and other functions of BSS should be discussedfurther

Conflicts of Interest

The authors declare that there are no conflicts of interest

Acknowledgments

This research was supported by Basic Science ResearchProgram through the National Research Foundation ofKorea (NRF) funded by the Ministry of Education (NRF-2015R1D1A1A01059994)


References

[1] S Kim and Y Lee ldquoThe prescriptions of enriching blood andnourishing vital essence (Fill yin blood prescription)rdquo Journalof Korean Medical Classics vol 20 pp 67ndash77 2007

[2] Y Jin C Qu Y Tang et al ldquoHerb pairs containing AngelicaeSinensis Radix (Danggui) a review of bio-active constituentsand compatibility effectsrdquo Journal of Ethnopharmacology vol181 pp 158ndash171 2016

[3] J Lyu andC Jeong ldquoConstitution of prescription andmedicinaleffect adaptation diseases of rsquobullsoosan (berghean)rsquoin koreanmedical booksrdquo Journal of Korean Medical classics vol 29 pp17ndash41 2016

[4] W Li Y Tang J Guo et al ldquoEnriching blood effect comparisonin three kinds of blood deficiency model after oral administra-tion of drug pair of angelicae sinensis radix and chuanxiongrhizoma and each single herbrdquoChina Journal of ChineseMateriaMedica vol 36 no 13 pp 1808ndash1814 2011

[5] W Li M Huang Y Tang J Guo E Shang and X Liu ldquoEstab-lishment and optimization of acute blood stasis rat modelrdquoChinese Pharmacological Bulletin vol 12 p 032 2011

[6] Y-Z Hou G-R Zhao Y-J Yuan G-G Zhu and R HiltunenldquoInhibition of rat vascular smooth muscle cell proliferation byextract of Ligusticum chuanxiong andAngelica sinensisrdquo Journalof Ethnopharmacology vol 100 no 1-2 pp 140ndash144 2005

[7] C W C Bi L Xu X Y Tian et al ldquoFo Shou San an ancientchinese herbal decoction protects endothelial function throughincreasing endothelial nitric oxide synthase activityrdquoPLoSONEvol 7 no 12 Article ID e51670 2012

[8] W Li Y Hua Y Tang H Wang L Qian and M Gao ldquoEffectsof radix angelicae sinensis and rhizoma chuanxiong on mouseuterine contractions in vitrordquo Journal of Nanjing University ofTraditional Chinese Medicine vol 2 p 014 2010

[9] M McLean and R Smith ldquoCorticotrophin-releasing hormoneand human parturitionrdquo Reproduction vol 121 no 4 pp 493ndash501 2001

[10] S K Kota K Gayatri S Jammula et al ldquoEndocrinology of par-turitionrdquo Indian Journal of Endocrinology and Metabolism vol17 no 1 pp 50ndash59 2013

[11] M Ledingham A J Thomson I A Greer and J E NormanldquoNitric oxide in parturitionrdquo BJOG An International Journal ofObstetrics amp Gynaecology vol 107 pp 581ndash593 2000

[12] M Shen S Tian Y Li et al ldquoDrug-likeness analysis of tra-ditional Chinese medicines 1 property distributions of drug-like compounds non-drug-like compounds and natural com-pounds from traditional Chinese medicinesrdquo Journal of Chem-informatics vol 4 no 1 article 31 2012

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

[14] I Hubatsch E G E Ragnarsson and P Artursson ldquoDetermi-nation of drug permeability and prediction of drug absorptionin Caco-2 monolayersrdquo Nature Protocols vol 2 no 9 pp 2111ndash2119 2007

[15] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013

[16] J Zhang Y Li S-S Chen et al ldquoSystems pharmacology dis-section of the anti-inflammatory mechanism for the medicinal

herb Folium eriobotryaerdquo International Journal of MolecularSciences vol 16 no 2 pp 2913ndash2941 2015

[17] PWillett JM Barnard andGMDowns ldquoChemical similaritysearchingrdquo Journal of Chemical Information and ComputerSciences vol 38 no 6 pp 983ndash996 1998

[18] H Liu J Wang W Zhou Y Wang and L Yang ldquoSystemsapproaches and polypharmacology for drug discovery fromherbal medicines an example using licoricerdquo Journal of Ethno-pharmacology vol 146 no 3 pp 773ndash793 2013

[19] K S Pang ldquoModeling of intestinal drug absorption roles oftransporters and metabolic enzymes (for the gillette reviewseries)rdquoDrugMetabolismampDisposition vol 31 no 12 pp 1507ndash1519 2003

[20] T Pei C Zheng C Huang et al ldquoSystematic understandingthe mechanisms of vitiligo pathogenesis and its treatment byQubaibabuqi formulardquo Journal of Ethnopharmacology vol 190pp 272ndash287 2016

[21] C A Lipinski F Lambardo B W Dominy and P J FeeneyldquoExperimental and computational approaches to estimate sol-ubility and permeability in drug discovery and developmentsettingsrdquo Advanced Drug Delivery Reviews vol 64 pp 4ndash172012

[22] A K Ghose V N Viswanadhan and J J Wendoloski ldquoPredic-tion of hydrophobic (lipophilic) properties of small organicmolecules using fragmental methods an analysis of ALOGPand CLOGPmethodsrdquoThe Journal of Physical Chemistry A vol102 no 21 pp 3762ndash3772 1998

[23] P Rajasethupathy S J Vayttaden and U S Bhalla ldquoSystemsmodeling a pathway to drug discoveryrdquo Current Opinion inChemical Biology vol 9 no 4 pp 400ndash406 2005

[24] H Yu J Chen X Xu et al ldquoA systematic prediction of multipledrug-target interactions from chemical genomic and phar-macological datardquo PLoS ONE vol 7 no 5 Article ID e376082012

[25] C H Wu R Apweiler A Bairoch D A Natale W C BarkerB Boeckmann et al ldquoThe universal protein resource (UniProt)an expanding universe of protein informationrdquo Nucleic AcidsResearch vol 34 pp D187ndashD191 2006

[26] G Bindea B Mlecnik H Hackl et al ldquoClueGO a Cytoscapeplug-in to decipher functionally grouped gene ontology andpathway annotation networksrdquoBioinformatics vol 25 no 8 pp1091ndash1093 2009

[27] M E Smoot K Ono J Ruscheinski P L Wang and T IdekerldquoCytoscape 28 new features for data integration and networkvisualizationrdquo Bioinformatics vol 27 no 3 pp 431-432 2011

[28] J-B Pan S-C Hu D Shi et al ldquoPaGenBase a pattern genedatabase for the global and dynamic understanding of genefunctionrdquo PLoS ONE vol 8 no 12 Article ID e80747 2013

[29] W Zhang Q Tao Z Guo et al ldquoSystems pharmacologydissection of the integrated treatment for cardiovascular andgastrointestinal disorders by traditional chinese medicinerdquoScientific Reports vol 6 p 32400 2016

[30] Z Prevorsek G Gorjanc B Paigen and S Horvat ldquoCongenicand bioinformatics analyses resolved a major-effect Fob3b QTLon mouse Chr 15 into two closely linked locirdquo MammalianGenome vol 21 no 3-4 pp 172ndash185 2010

[31] J Du B Bai X Kuang et al ldquoLigustilide inhibits spontaneousand agonists- or K+ depolarization-induced contraction of ratuterusrdquo Journal of Ethnopharmacology vol 108 no 1 pp 54ndash58 2006


[32] K J Chen and K Chen ldquoIschemic stroke treated with ligus-ticum chuanxiongrdquo Chinese Medical Journal vol 105 pp 870ndash873 1992

[33] W Li J Guo Y Tang et al ldquoPharmacokinetic comparison of fer-ulic acid in normal and blood deficiency rats after oral admin-istration of angelica sinensis ligusticum chuanxiong and theircombinationrdquo International Journal of Molecular Sciences vol13 no 3 pp 3583ndash3597 2012

[34] W Karl W Cathy X Li and G Amy ldquoPharmacokineticanalyses of ferulic acid in rat plasma by liquid chromatog-raphytandem mass spectrometry a synergistic action of anancient herbal decoction fo shou sanrdquo Pharmaceutica AnalyticaActa vol 6 no 5 p 2 2015

[35] D Huang ldquo8 purgative herbsrdquo Chinese Materia Medica Chem-istry Pharmacology and Applications p 231 1998

[36] X Liu Q Zhao C Li R Zhang X Wang and W XuldquoSynthesis of chuanxiong perlolyrine and its protective effecton injured vascular endothelial cellsrdquo Journal of ShandongUniversity (Health Sciences) vol 41 pp 485ndash487 2003

[37] J Ishida M Kozuka H-K Wang et al ldquoAntitumor-promotingeffects of cyclic diarylheptanoids on Epstein-Barr virus activa-tion and two-stage mouse skin carcinogenesisrdquo Cancer Lettersvol 159 no 2 pp 135ndash140 2000

[38] J Liu T Pei and J Mu ldquoSystems pharmacology uncoversthe multiple mechanisms of Xijiao Dihuang decoction for thetreatment of viral hemorrhagic feverrdquo Evidence-Based Comple-mentary andAlternativeMedicine vol 2016Article ID902503617 pages 2016

[39] H Wang and Y V Stjernholm ldquoPlasma membrane receptormediated MAPK signaling pathways are activated in humanuterine cervix at parturitionrdquo Reproductive Biology and Endo-crinology vol 5 article 3 p 1 2007

[40] SMesiano andTNWelsh ldquoSteroid hormone control ofmyom-etrial contractility and parturitionrdquo Seminars in Cell amp Develop-mental Biology vol 18 no 3 pp 321ndash331 2007

[41] PWNathanielsz S L Jenkins J D Tame J AWinter S Gullerand D A Giussani ldquoLocal paracrine effects of estradiol arecentral to parturition in the rhesus monkeyrdquo Nature Medicinevol 4 no 4 pp 456ndash459 1998

[42] Y Li H Je S Malek and K G Morgan ldquoERK12-mediatedphosphorylation of myometrial caldesmon during pregnancyand laborrdquoAmerican Journal of PhysiologymdashRegulatory Integra-tive and Comparative Physiology vol 284 no 1 pp R192ndashR1992003

[43] Y Li H-D Je S Malek and K G Morgan ldquoRole of ERK12in uterine contractility and preterm labor in ratsrdquo AmericanJournal of Physiology-Regulatory Integrative and ComparativePhysiology vol 287 no 2 pp R328ndashR335 2004

[44] S I Berger and R Iyengar ldquoNetwork analyses in systems phar-macologyrdquo Bioinformatics vol 25 no 19 pp 2466ndash2472 2009

[45] P Li L-W Qi E-H Liu J-L Zhou and X-D Wen ldquoAnalysisof Chinese herbal medicines with holistic approaches and inte-grated evaluationmodelsrdquoTrACTrends inAnalytical Chemistryvol 27 no 1 pp 66ndash77 2008

[46] L M Espinoza-Fonseca ldquoThe benefits of the multi-targetapproach in drug design and discoveryrdquo Bioorganic ampMedicinalChemistry vol 14 no 4 pp 896-897 2006

[47] W Zhang Y Bai Y Wang andW Xiao ldquoPolypharmacology indrug discovery a review from systems pharmacology perspec-tiverdquo Current Pharmaceutical Design vol 22 no 21 pp 3171ndash3181 2016

[48] S Wray K Jones and S Kupittayanant ldquoCalcium signalingand uterine contractilityrdquo Journal of the Society for GynecologicInvestigation vol 10 no 5 pp 252ndash264 2003

[49] G Y Oudit and Z Kassiri ldquoRole of PI3 kinase gamma inexcitation-contraction coupling and heart diseaserdquo Cardiovas-cular and Hematological Disorders vol 7 no 4 pp 295ndash3042007

[50] R Smith ldquoParturitionrdquo The New England Journal of Medicinevol 356 no 3 pp 271ndash283 2007

[51] S Y Suh and W G An ldquoSystems pharmacological approachof pulsatillae radix on treating crohnrsquos diseaserdquo Evidence-BasedComplementary and Alternative Medicine vol 2017 Article ID4198035 21 pages 2017

[52] C l Chen and J Y Chen ldquoAnalysis on the effect of foshousancombined with ethacridine lactate in mid-term pregnancyrdquoJournal of Practical Traditional ChineseMedicine vol 30 pp 511-512 2014

[53] Y Sun ldquoModified Xiong Gui Tang with auricular acupoint pressfor 70 cases of late pregnancyrdquo Guide of China Medicine vol 7no 20 pp 92-93 2009

[54] J-J Koksma J-M Fritschy V MacK R E Van Kesterenand A B Brussaard ldquoDifferential GABA A receptor clusteringdetermines GABA synapse plasticity in rat oxytocin neuronsaround parturition and the onset of lactationrdquo Molecular andCellular Neuroscience vol 28 no 1 pp 128ndash140 2005

[55] HMaulM LongoG R Saade andR EGarfield ldquoNitric oxideand its role during pregnancy From ovulation to deliveryrdquoCurrent Pharmaceutical Design vol 9 no 5 pp 359ndash380 2003

[56] M-J Ahn M K Lee Y C Kim and S H Sung ldquoThe simul-taneous determination of coumarins in Angelica gigas root byhigh performance liquid chromatography-diode array detectorcoupled with electrospray ionizationmass spectrometryrdquo Jour-nal of Pharmaceutical and Biomedical Analysis vol 46 no 2 pp258ndash266 2008

[57] S Kim H Oh J Kim J Hong and S Cho ldquoA review of phar-macological effects of angelica gigas angelica sinensis angelicaacutiloba and their bioactive compoundsrdquo The Journal ofKorean Oriental Medicine vol 32 pp 1ndash24 2011

[58] J E Norman S Bollapragada M Yuan and S M NelsonldquoInflammatory pathways in the mechanism of parturitionrdquoBMC Pregnancy and Childbirth vol 7 supplement 1 article S72007

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


ADME Screening

Active Compound

Target Fishing

Potential Target

H-C-T Network

T-P Network

GO Analysis

Target organ location map

Angelicae Sinensis Radix Cnidium ocinale Makino

-aminobutyric acid receptor subunit -1-aminobutyric-acid receptor -2 subunit-aminobutyric-acid receptor -3 subunit-aminobutyric-acid receptor subunit -6

Glucocorticoid receptorGlutamate receptor 2

GABRA1GABRA2GABRA3GABRA6NR3C1GRIA2

Glycogen synthase kinase-3 Heat shock protein HSP 90

Ig -1 chain C regionLeukotriene A-4 hydrolase

GSK3BHSP90AB1

IGHG1LTA4H

transcription DNA-templated


negative regulation of transcription from RNA polymerase II promoter

chloride transport

gamma-aminobutyric acid signaling pathway

peptidyl-serine phosphorylation

protein autophosphorylation

regulation of cell proliferation

synaptic transmission cholinergic

adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signaling pathway

phospholipase C-activating G-protein coupled acetylcholine receptor signaling pathway

positive regulation of MAPK cascade

positive regulation of sequence-specic DNA binding transcription factor activity

regulation of blood pressure

regulation of smooth muscle contraction


cyclooxygenase pathway

Figure 1 The workflow the network pharmacological approach of Bulsu-san (BSS) namely active compounds screening target fishingnetwork analysis and relevant organ location mapping was performed in this study

The hypothesis of this study was that BSS may promotethe positive-feedback of hormone loops as well as a seriesof myometrial and cervical changes to ease parturition andsafely accelerate labor A network based in silico approachwas used to identify the effect of BSS on parturition relatedsystems and the aim of this study was to elucidate the effect ofBSS on the parturition by system-level analysisTheworkflowof the network pharmacological study is summarized inFigure 1

2 Material and Methods

21 Identification of Active Compounds Compounds in CGand DG were identified using a phytochemical databasethat is the Traditional Chinese Medicine Systems Phar-macology (TCMSP httpibtshkbueduhkLSPtcmspphp)We applied parameters related to absorption distributionmetabolism and excretion (ADME) namely human drug-likeness (DL) [12] oral bioavailability (OB) [13] and Caco-2 permeability (Caco-2) to screen the Potential active com-pounds in BSS [14]

211 Drug-Likeness Evaluation DL helps filter ldquodrug-likerdquocompounds in oriental herbs as DL represents a qualitativeconcept for valuations based on how ldquodrug-likerdquo a prospec-tive compound is [15] Accordingly a high DL may lead toa greater possibility of therapeutic success and compoundswith a higher DL value are more likely to possess certainbiological properties [16] The calculations of DL in TCMSP

database were based on Tanimoto coefficient formula [17] asfollows

119865 (119860 119861) =119860 times 119861

1198602 + 1198612 minus 119860 times 119861 (1)

where 119860 represents the molecular parameters of herbal com-pounds and119861 is the averagemolecular parameters of all com-pounds in theDrugbank database (httpwwwdrugbankca)[18] In the present study we excluded compounds with a DLof lt008 Other previous researches of herbal formulas set ahigher threshold in the range of 01 to 018However we foundout that most compounds of DG have low DL In detail only36 compounds of 125 in DG show higher or equal DL valuethan 008 For this reason this study sets a lower threshold ofDL than other previous researches to see the most potentialtargets of BSS

212 Oral Bioavailability (OB) Prediction OB is defined asthe ratio of active compoundsrsquo absorption into the systemiccirculation which represents the convergence of the ADMEprocess [13] OB values are dependent on drug dissolution inthe gastrointestinal (GI) tract and hepatic and intestinal first-pass metabolism as well as on intestinal membrane perme-ation whichmakes it a major pharmacokinetic parameter fordrug evaluations [16] In this study the OB threshold was setas ge15

213 Caco-2 Permeability Screening Caco-2 permeability isused to predict the absorption of an orally administered









3 Results













Table 1 Continued












Table 2 Continued



Table 2 Continued



Table 2 Continued








GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233














aging









4 Discussion



DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























3 Results













Table 1 Continued












Table 2 Continued



Table 2 Continued



Table 2 Continued








GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233














aging









4 Discussion



DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























Table 1 Continued












Table 2 Continued



Table 2 Continued



Table 2 Continued








GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233














aging









4 Discussion



DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 1 Continued












Table 2 Continued



Table 2 Continued



Table 2 Continued








GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233














aging









4 Discussion



DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Table 2 Continued



Table 2 Continued



Table 2 Continued








GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233














aging









4 Discussion



DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 2 Continued



Table 2 Continued



Table 2 Continued








GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233














aging









4 Discussion



DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 2 Continued



Table 2 Continued








GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233














aging









4 Discussion



DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 2 Continued








GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233














aging









4 Discussion



DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















GO Analysis

688

79

89

899

88910111111

1012

915

1219

1820

2218

2820

34

61 48 49

59 46

56 48 60 55 56 70 70 62 54 47 50 51 63

62 110

62 101

50 64

62 58

117 53

136 233














aging









4 Discussion



DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















DPP4

CDK2

CHEK1

MAPK14

PIM1

CCNA2F7

PLG

ERBB2C41NTRK2

ESR2

CITED1

PON1

PLAU

SERPINE1RBP2

GSK3B

INS CETP

HP

C47

MOGAT2PPARA

APOB

PPARGC1A

ADH1C

EDNRA

HMGCR

ENPEP

PYY

GCGR

PDX1

PPARD

FABP1

SOAT1

TEP1

SOD1GAP43

MPO

UCP2

SLC2A2

SCDCAT

UCP3

C48

DNPEP

CCK

LPL

PDHX

NR3C1

C25

FOSL2

AMY2A

ACSL1

NR1I3

ADORA2A

ALAD

CYP1A2

PTEN

SREBF1FOS

AMY1A

PCYT1A

SLC22A5

PTPN1

G6PCACSL4

HK1

SREBF2 LCT

SI

COL7A1CHI3L1

C45

COL1A1

AKR1B1

GUSBP1

IL10

IL6PTGER3

C49C65

C64

C9C40

C20

C52

C59KDR

C22KCNH2

CYP1A1 NQO2

RAC1 CHATSELP

CA1

IGF2 GFAP

PKIAPDE3A

LTA4H

SCN5AHSP90AB1

C34

BTK

C13C17

ESR1

NCOA1

C46

F2

NOS2

C39

PRKACAPTGS2

PTGS1CG

C57

C62C14

RXRA

C50

C51

DG

NR3C2

TNF

GABRA1

IGHG1NOS3

NCOA2PGR

C61

SLC6A4

ADRA2B

ADRA2A

DRD2

HTR2A

ADRA1A

MAOA ADRB1

SLC6A3

CTRB1

MAOB

F10

ADRA2C

ADRB2

PIK3CG

CALM1

AR

PRKCB

ADRA1D

C4

C8

C27

C21

C2

C43

C56

C32

C58 C18C36

C15

C35

C28

C26

C23

C5

C38

C54

CHRM2

CHRM1

C3

C16 C44

CHRM3

C55

C11

C19C10

GRIA2 ADRA1B

C31

C7

C30

C33

C6

C53

PLA2G1B

ADA

PNP

SP1

AHCYL1

C60

C24

ENPP7

GABRA4DRD1

GABRA2

GABRA3

GABRA5

GABRA6

CHRNA2

SLC6A2

C1

CHRNA7

C12C29

C42

C37

KCNMA1

LEPREL2

P4HA2MAT1A

OATABAT

GIG18

ME3

PRSS3

GLRA1

HSD17B6

ALDH5A1

OXCT2

OTC

ADH1A

CASP3

PKM2

SDHA

GOT2

SLC25A10

BCHEME2

AGXT

SUCLA2 GOT1MAT2A

LEPRE1 BCL2

RHO

C63

ATP5B

ADH1B

CTSD

SRC

PPARG

ADSS

CDC25B GLUD1

NOS1

TXNRD1







SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















SDHA

KDR

ADSSALAD

ADH1A

HK1

ENPP7ADH1C




PRKACA

CHAT


CALM1

PRKCB

SLC6A3PLA2G1B

Cholinergicsynapse


NOS2

PIK3CG

NOS3

RAC1 SRC

CASP3

GSK3B



PPARA

NR3C1


Salivarysecretion

ADRB2

ADORA2ACHRM2

ADRB1



PTGS2

ATP5BPDHX

LCT

HSD17B6

AMY2A

SI

ACSL4

AMY1A

ACSL1

ADA


BCL2KCNMA1ADRA1A

FOS

EDNRA

ADRA1B

CHRM3

ADRA2C

ADRA1D

ADRA2B

ADRA2A

GABRA1

GABRA4

GABRA6 GABRA3

GABRA5

Nicotineaddiction

DRD1

Serotonergicsynapse

NOS1

PTGS1



CHRNA2

PDE3A

GLRA1

PLG

CHRM1

F2 GCGR

PRSS3


PNP

PCYT1A

Metabolicpathways

ADH1B

CYP1A2

CAT

MAT1AALDH5A1


ABATOAT

GOT1GABRA2LTA4H

PON1

CYP1A1P4HA2GOT2

Morphineaddiction

DRD2HTR2A

MAOB

MAOA GRIA2


ME2

GLUD1


AKR1B1

OTC

MAT2A SUCLA2

AGXT

ME3

FABP1

SREBF1

PTPN1

G6PC

HMGCR

SLC2A2


CDK2CCNA2

ESR2 AR

ESR1

HSP90AB1

PPARG

PPARD

RXRA

LPLPPARGC1A

SCD

SCN5A


Pertussis


CTSD

ERBB2

Amoebiasis

TNF



IGF2

INS

NCOA1PLAU



IL6



IL10Prostatecancer

SP1

PTEN

HepatitisB

CDC25B









5 Conclusion



ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ADORA2A

HTR2A

CTSD

PIK3CG

PKM2

PTGS1

KCNMA1

PRKACA

PON1

GCGR

SERPINE1PRKCB

LCT

GLRA1

SmoothMuscleNR1I3

SLC6A3ESR1

NOS2

Pituitary

IL6

MOGAT2

WholeBlood

PCYT1APPARD

IL10

LTA4H

PPARA

MAPK14

PTGS2

RXRANQO2

CDC25B ADRB2

GSK3B

CAT

UCP2HMGCR

NCOA1

NR3C1ACSL4

ENPP7 CHRNA2

CHRM2ADSS

SRC

ERBB2ESR2

CHRNA7


LEPREL2

NOS1

NCOA2


SDHA

SP1

F7SLC6A4

MAT2A

HP PLG

GRIA2

SLC22A5

GABRA4

BCL2NOS3

ABAT

ME2

DRD1

HK1

NTRK2

CETP

LEPRE1

CASP3

GIG18

AKR1B1

TXNRD1

PTEN

FOSL2

SLC6A2

SCN5A

ADRA1A

AGXT

SUCLA2

RAC1

ME3

OAT

UCP3

MAOB KDR

ADH1B

EDNRA

CDK2

COL7A1

NR3C2

DPP4

ADRA1D

ADRB1

COL1A1SOAT1ADRA1B

CHEK1

CA1

CHAT

PIM1ADRA2A

PTGER3

AR

GABRA3SELP

CHI3L1P4HA2

PDE3A

PGR

ADRA2B

ATP5B

DRD2PDX1

TEP1

ENPEP


IGHG1

KCNH2

FOS

CITED1

CCNA2

F2

SLC2A2

PTPN1

MAOA

LPL

ADH1A

OTC

MAT1A

APOB

PNP

PPARG

CHRM3

GABRA1

BCHE

ALDH5A1

AHCYL1

IGF2

PDHX

ADRA2C

SREBF2

ALAD

PPARGC1A

GOT2

SOD1

SCDGLUD1

GAP43

GOT1

PKIA SREBF1HSP90AB1

GFAP

FABP1

G6PC

ACSL1

GABRA5

PLAU GABRA2

CALM1






Acknowledgments



References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















References


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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Systems Pharmacological Approach to the Effect of Bulsu ...downloads.hindawi.com/journals/ecam/2017/7236436.pdf · Evidence-BasedComplementaryandAlternativeMedicine 5 Table1:Continued