review article systematic analysis of the multiple...

Review ArticleSystematic Analysis of the Multiple Bioactivities ofGreen Tea through a Network Pharmacology Approach

Shoude Zhang1 Lei Shan2 Qiao Li1 Xia Wang1 Shiliang Li1 Yuan Zhang1 Jianjun Fu1

Xiaofeng Liu1 Honglin Li1 and Weidong Zhang12

1 Shanghai Key Laboratory of New Drug Design State Key Laboratory of Bioreactor Engineering School of PharmacyEast China University of Science and Technology Shanghai 200237 China

2 School of Pharmacy Second Military Medical University Shanghai 200433 China

Correspondence should be addressed to Honglin Li hlliecusteducn and Weidong Zhang wdzhangyhotmailcom

Received 17 May 2014 Revised 5 November 2014 Accepted 13 November 2014 Published 30 November 2014

Academic Editor Kuang C Lai

Copyright copy 2014 Shoude Zhang et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

During the past decades a number of studies have demonstrated multiple beneficial health effects of green tea Polyphenolics arethe most biologically active components of green tea Many targets can be targeted or affected by polyphenolics In this study weexcavated all of the targets of green tea polyphenolics (GTPs) though literature mining and target calculation and analyzed themultiple pharmacology actions of green tea comprehensively through a network pharmacology approach In the end a total of 200Homo sapiens targets were identified for fifteen GTPsThese targets were classified into six groups according to their related diseasewhich included cancer diabetes neurodegenerative disease cardiovascular diseasemuscular disease and inflammationMoreoverthese targetsmapped into 143KEGGpathways 26 ofwhichweremore enriched as determined thoughpathway enrichment analysisand target-pathway network analysis Among the identified pathways 20 pathways were selected for analyzing the mechanisms ofgreen tea in these diseases Overall this study systematically illustrated the mechanisms of the pleiotropic activity of green tea byanalyzing the corresponding ldquodrug-target-pathway-diseaserdquo interaction network

1 Introduction

Tea is a traditional medicinal plant and the most widelyconsumed beverage in the world Among all teas consumedworldwide green tea is the best studied in terms of healthbenefits because its chemistry is more well known than thatof other teas [1] A number of studies have demonstratedthe beneficial health effects of green tea which include thereduction of serum cholesterol the prevention of low-densitylipoprotein oxidation and a decreased risk of cardiovasculardisease and cancer [2 3] It is generally agreed that many ofthe effects of green tea are mediated by its polyphenols asshown in Figure 1 which include flavanols and flavonoidsThe flavanols which are also known as catechins including(minus)-epiafzelechin (EZ 1) (+)-catechin (C 9) (minus)-epicatechin(EC 2) (+)-gallocatechin (GC 10) (minus)-epigallocatechin(EGC 3) their respective 3-gallate esters (minus)-EZG (4) (+)-CG (11) (minus)-ECG (5) (+)-GCG (12) and (minus)-EGCG (6)

and two 3-(31015840-methy)gallate esters (minus)-ECMG (7) and (minus)-EGCMG (8) account for 40ndash50 of the dry weight of tealeaves [4 5] In addition three flavonoids namely kaempferol(13) quercetin (14) and myricetin (15) have been isolatedas components of green tea [6] The diverse bioactivities ofgreen tea have prompted comprehensive research which hasled to hundreds of published studies However most of thesestudies mainly focused on the anticancer activity of EGCGa major catechin of green tea Such one-sided studies arenot aligned with the diverse bioactivities of green tea Inaddition many of the other GTPs also have been provento present multiple bioactivities such as the kaempferoland quercetin which exert potentially beneficial effects oninflammation [7] Moreover GTPs often play target multipleproteins For example EGCG has been shown to mediatemultiple signal pathways by binding to many targets incancer cells [8] Therefore it is reasonable to systematicallyand comprehensively analyze the mechanisms of action of

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2014 Article ID 512081 11 pageshttpdxdoiorg1011552014512081

2 Evidence-Based Complementary and Alternative Medicine

= R1 = R2 = R3 = H R2 = OH= R1 = H R2 = R3 = OH= H R1 = R2 = R3 = OH= gallate R1 = R3 = H R2 = OH= gallate R1 = H R2 = R3 = OH= gallate R1 = R2 = R3 = OH= 3998400-methylgallate R1 = H R2 = R3 = OH= 3998400-methylgallate R1 = R2 = R3 = OH

= R1 = H R2 = R3 = OH= H R1 = R2 = R3 = OH= gallate R1 = H R2 = R3 = OH= gallate R1 = R2 = R3 = OH

= R3 = H R2 = OH= H R2 = R3 = OH= R2 = R3 = OH

R1

R2

R3

O

OR

HO

OH

R1

R2

R3

O

R1

R2

R3O

OR

HO

OH

OH

HO

OH O

(1) R(2) R(3) R(4) R(5) R(6) R(7) R(8) R

(9) R(10) R(11) R(12) R

(13) R1

(14) R1

(15) R1

Figure 1 Structures of green tea polyphenols

green tea based on the ldquomulticomponent network targetrdquomodel

Network pharmacology updates the research paradigmfrom the current ldquoone target one drugrdquo model to a newldquomulticomponent network targetrdquo model which enhancesour knowledge of multipathway interactions and helps inter-pret drug-response signature datasets that collectively decodethe complex mechanisms of drug actions [9] Unlike earlierreductionist ldquoone drug one targetrdquo approaches networkpharmacology invokes the idea that a drug engages withmultiple targets and rarely interacts with a single protein inisolation [10] This approach utilizes principles of systemsbiology and network analysis to advance drug discoverythrough the identification of connectivity redundancy andpleiotropy in biological pathways and has allowed a deeperunderstanding of the drug interactions by revealing thatthis promiscuity often engages a synergistic combination ofappropriate high-value targets in a complex disease such ascancer and diabetes to produce treatment success [11]

To explore the mechanism of action of green tea froma holistic perspective the network pharmacology methodwas employed to investigate the molecular behavior of GTPsWe collected all available target information for fifteen GTPsthrough literature mining and computational chemistry (3Dsimilarity search and reverse docking) to construct a networkof the ldquodrug-target-pathway-diseaserdquo interactions (Figure 2)In the end 200 Homo sapiens targets were identified forfifteen GTPs These targets were classified into six groupsaccording to their related disease which included cancerdiabetes neurodegenerative disease cardiovascular diseasemuscular disease and inflammation in agreement with theapplications of green tea Pathways analysis was used toillustrate the mechanism of action through which the GTPsexert their comprehensive therapeutic effects A total of143 KEGG pathways were identified and 26 of these weremore enriched as determined through pathway enrichmentanalysis and target-pathway network analysis Twenty ofthe identified pathways that play a role in the GTP-related

Lite

ratu

re

ChemMapper PubMed PharmMapper

287 targets 289 targets339 targets

200 targets

Drug Target

Pathway Disease

O

OR

HO

OH

OH

Revers dockingSimila

rity s

earch

R1R2

Figure 2 Analysis overview The methods of similarity searchliterature mining and reverse docking were utilized to identifythe confirmed and potential targets of GTPs and these methodsprovides 287 339 and 289 targets respectivelyUltimately 200Homotargetswere selected after removing any redundant and other sapienstargets and used to construct the ldquodrug-target-pathway-diseaserdquointeraction network

diseases were selected for analyzing the mechanisms ofaction of green tea By integrating the ldquodrug-target-pathway-diseaserdquo interactions we found the green tea exerts a varietyof therapeutic effects though the modulation of multiplepathway by itsmain components which is in accordancewiththe ldquomulticomponent network targetrdquo model

Evidence-Based Complementary and Alternative Medicine 3

2 Material and Methods

21 Literature Mining All available information on thetargets of fifteen GTPs in the literature was collected bysearching PubMed using the Structure search Only theconfirmed and active targets were selected from the categoryof biological test results

22 Similarity Search The online web server ChemMapper[12] which is based on the 3D similarity procedure ShAFTSwas used to predict the potent targets according to the similarproperty principle which suggests that structurally similarmolecules should exhibit the same (or similar) bioactivities[13] SHAFTS provides a ShapeScore (based on the shapeoverlap) and a FeatureScore (based on the pharmacophorefit) and the weighted sum of the two scores is consideredthe hybrid similarityHybridScore [14] A higherHybridScoreimplies a better alignment in terms of both shape andchemotype identities between the query and target molecules[15] In this study the targets with aHybridScore value higherthan 1400 were selected as potent targets

23 Reverse Docking Reverse docking is a novel technologythat allows the docking of a compound with a known biolog-ical activity into the binding sites of all of the 3D structuresin a given protein database The PharmMapper server isa freely accessed web server designed to identify potentialtarget candidates for a specific small molecule probe (drugsnatural products or other newly discovered compounds withunidentified binding targets) using the pharmacophore map-ping approach [16] It is backed up by a database with a largerepertoire of pharmacophores extracted fromall of the targetsin TargetBank DrugBank BindingDB and PDTD Morethan 7000 receptor-based pharmacophore models (covering1627 drug targets 459 of which are human protein targets)are stored and accessed by PharmMapper This programfinds the best mapping poses of the user-uploaded moleculesagainst all of the targets in PharmTargetDB and the top Npotential drug targets as well as the respective moleculesrsquoaligned poses are outputted In this study the cutoff Fit Scorevalue was set to 4000 The targets with a Fit Score valuehigher than 4000 were selected as potential targets

24 NetworkConstruction andAnalysis The individual inter-action networks for each protein were built by use ofthe STRING database which is integration of known andpredicted protein interactions [17] The network interactionswere selected according to STRING-computed confidencescores (medium confidence 04000) The Cytoscape soft-ware (Version 283 httpwwwcytoscapeorg) and the Net-work Analyzer plugin (Version 10 httpmedbioinfmpi-infmpgdenetanalyzer) were used to visualize the networkand calculate the basic network parameters including degreeof distribution degree exponent shortest-path-length dis-tribution and clustering coefficient The interactions in theldquotarget-pathwayrdquo network were selected from the pathwayenrichment results The sizes of the nodes correspond to thenode degree

25 Pathway Enrichment 119875 values were used to determine ifa specific pathway in the KEGG database was more enrichedwith the related proteins than by chance Assuming that atotal of 119870 proteins related to the GTPs were mapped intoKEGG which contains 119873 distinct proteins and 119896 proteinsfrom a pathway of size 119899 are related to the GTPs the 119875 valueis given by

119875 = 1 minus

119896minus1

sum

119894=0

119891 (119894) = 1 minus

119896minus1

sum

119894=0

(

119870

119894) (

119873minus119870

119899minus119894)

(

119873

119899)

(1)

The two-sided hypergeometric test and the Bonferroni cor-rection were used

3 Results and Discussion

31 Data Preparation The 15GTPs shown in Figure 1 weresearched by PubMed ChemMapper and PharmMapperFrom the results from the PubMed search only the active andconfirmed targetswere selected resulting in the identificationof 339 targets for the 15 components The web serviceChemMapper which is based on a 3D similarity search pro-vided 287 targets with a HybridScore value of at least 1400and the web service PharmMapper provided 289 targets witha Fit Score value of at least 4000 Because polyphenols havea similar skeleton most of these compounds often share thesame targets After removing any redundant andother sapienstargets 200Homo sapiens targets were selected for the subse-quent analysis (see Table S1 in the Supplementary Materialavailable online at httpdxdoiorg1011552014512081)

32 Drug-Target Interactions The network of drug-targetinteractions is shown in Figure 3 The target proteins wereclassified into six groups according to their related disease asdetermined using the database of Disease and Gene Anno-tations (DGA) [18] Among all 200 Homo sapiens targets120 targets were related to cancer which is in agreementwith previous research results showing that green tea hasanticancer activity [19] In addition the other 80 targets wereassociated with diabetes cardiovascular disease Alzheimerrsquosdisease muscular disease mental disease and inflammationThe sizes of the nodes correspond to the degree It was easilydetermined that most of the GTPs shared multiple targetsparticularly 13 (kaempferol) 14 (quercetin) 6 ((minus)-EGCG)and 15 (quercetin) which exhibited node degrees greater than40 Simultaneously most of the targets can be targeted bymore than one GTP

33 Protein-Protein Interactions The protein-protein net-work was constructed via mapping the 200 putative targetsinto the String database which is a collection of knownand predicted protein-protein interactions After excludingisolated nodes the protein interaction network induced bygreen tea components was composed of 187 nodes (proteins)and 1500 edges (interactions) (Figure 4(a) Table S1) Thetopological properties of the network rewired by the GTPswere analyzed with the network analyzer plugin Amongthese properties the node degree can be used to distinguish


MMP14

AHRAPOBEC3G

ASCC3

KCNH2

PIM1

PRKCA

AKT1

FAS

SULT2B1XIAP

CCNB1

STK33

SULT1A1

PLA2G1B

TP53

TERT

CYP3A4INSR

EHMT2

MAPK14

PLG

FOLH1

MMP9

HIF1A

UBE2I

PIM2

RAP2A

CDK1POLI

MET

PRKACA

GSTA1

BAXPTGS1

MME

MAPK3

IGF1R

HIF1AN

CDC42

PABPC1

MMP14

CDK6

STK16

EGFR

APEX1CYCLIN D1

PDK1

PPARGCDK4

LCK

CYP19A1UBE2N

ANGMMP2

AKR1C3

PTEN

ABCC4

KDR

ALOX12

MAP2K1

SQLE

MMP7

HPRT1

CD38

HIF1A

HSD17B10

POLHCYP1A1

HSD17B2 CDK2

CLK1

ABCC1

NEU1

SYK

MCL1

CDKN1 RB1

ABCC2

CDK5

CYP1B1UCK2

POLB

SRC

HPGDPREP

CRABP2

GPI

GNAO1

MMP3PIK3R1

GLO1 XDHCREB1

MMP13

ESR1

HSP90

HRAS

HSD17B1

CDK5R1

AKT2

APOBEC3A

PRKAA2

ABCG2PIP4K2A

ARNT

ESRRG

HCK

PTGS2

SORDGRIA1

NR1H4

FGFR1

NFKB1

AURKA

TAP1

PRSS1

BTKMYLK

GALK1PAFAH1B3

ALB

MAOB

DLD

GSTO1

GFPT1

GFER

CHRM1

PAH

FXR1

GSK3B

MAOA

VCP

KARS

BACE1

OPRK1

OPRM1

OPRD1

TUBB1

DRD1

ABO NOX4

ADORA3

CALM1

ALB

ALOX5PDE4D

MPO

CYP1A2

OPRK1

GSK3A

FKBP1A

NR3C1

DYRK1A

MAPTDYRK1A

PGD

AKR1A1

GAAGSTA3

NFE2L2

PDPK1

ALPI

ALPL

CCNB3BAZ2B ALOX15

ALPPL2

GART

PCTP

MPI

GPR35

LAP3KDM4DL

TGM3

CALM3NFKB2

ELANE

MMP12

CAMK2B

CTDSP1

BCHE

RDRP

PECR

MEX-5

11

1

3

2

1412

6

9

GSTP1

MMP2

RACGAP1

UCK2

CCNB2

DCK

NOTCH4

RXRB

HGF

MMP7 HSP90AA1

7

8

4

13

15

10

5

AKR1B1

CYP2C9SHBG

AMY1C

VDRAKR1B1

VDR

PTPN1

HK1PLCG1

CA2

ZAP70

PLCG2

TYR

AR

POLB

CES2

CancerDiabeticCardiovascularNeurodegenerative disease

Muscular diseaseInflammationUncertainGreen tea components

Figure 3 The drug-target-disease network Two-hundred Homo sapiens targets targeted by fifteen GTPs were classified into seven groupsaccording to their related disease as determined by the Disease and Gene Annotations The circles represent the targets and the rhombirepresent the GTPs

between random and scale-free network topologies In arandom network the node degrees often follow a Poissondistribution whereas these exhibit a nonuniformdistributionin a scale-free network Most network models based on abiological system are scale-free In the network rewired byGTPs the node degree distribution was in accordance witha power law indicating that the constructed network is scale-free and does not present a random topology (Figure S1)

34 Pathway Enrichment Because green tea exhibits diversebioactivities mediated by multiple pathways it is reasonableto analyze the potential pathways In this study pathwayenrichment based on the hypergeometric test was utilizedto analyze the potential pathways mediated by the GTPsUltimately 143 KEGG pathways were identified and 26 ofthese were found to be more enriched (119875 value lt 005

Table 1 Table S2)These results were confirmed by construct-ing the protein-pathway network As shown in Figure 4(b)the pathwayswith a lower119875 value exhibited a larger node sizethat is a greater node degree thus the five pathways withthe greatest degrees namely hsa05200 hsa05215 hsa05214hsa04510 and hsa05218 also presented the six highest 119875values In addition because green tea has previously beenassociated with cancer diabetes cardiovascular diseasesneurodegenerative disease muscular disease and inflamma-tion 20 pathways related with these diseases were selected forfurther analysis (Table 2)

35 Anticancer Mechanism Anticancer is one of most com-monly reported effect of green tea Numerous studies haveprovided evidence that green tea has potential chemother-apeutic activity against a wide range of cancers including


PRKACA

APOBEC3G

OPRD1MCL1

HCK

MMP14

BTK

PRKAA2

NOTCH4

MMP9PIK3R1PPARG

CDKN1A

KDR

IGF1RSRC

CD38

ADORA3

OPRM1

HPRT1

HIF1ANAKT2

PLCG1PRKCA

PDPK1

PDK1

PLCG2

MYLK

OPRK1

GNAO1NOX4

PECR

MET

ZAP70 PIP4K2A

PDE4D

GSK3A

PABPC1DCK

CLK1

PIM1

GSTA1 MMP3FGFR1PTPN1

ALPPL2GFPT1

ANG

AKR1C3

NR1H4

ABCC1

ABCC2

AKR1A1

MAOB

CALM3

HGF

MAOA

FXR1

CYP19A1

ALOX5SULT1A1

CYP2C9

AHR

CDK2

CYP1B1

GSTP1

HIF1ACDK4

HSD17B1ALOX12

NFE2L2

BACE1

MAPT

CYP1A1

POLIGFER

BAX

RXRB

AMY1C

FKBP1AEHMT2

GSTT2BGSTO1

NFKB2SQLE

FOLH1

HSD17B2ESRRG

EGFR

TYR

GSTA3

ALPL

ELANE

LCKPLG

PTGS2

HRAS

CALM1

MMP2 MPO

CHRM1

NFKB1

MMP7

PLA2G1BPREP

LAP3

NANH

SORD

MMP13

HPGD

GALK1 PGD

HSD17B10GLO1

ABCC4

ABCG2

TUBB1

ALOX15

ESR1

CYP1A2

CYP3A4

AKR1B1

ALB

INSR

CREB1

PTGS1

ARNT

HK1

MMEPRSS1

XDH

GPIPAFAH1B3

TAP1

VDR

MMP12

PAH

MPI

DLDABO

SHBG

BCHE

NR3C1

MAP2K1 TP53

CCNB1CCND1POLH

CDK6

AR

GRIA1XIAP

SYK

HSP90AA1

RB1

GSK3B

UBE2ITERT

EIF4H

KCNH2

CAMK2BKARS FASGART

AURKA

UCK2

VCP

CDK1CCNB3

RACGAP1

CDK5CCNB2

SULT2B1

APEX1

UBE2N

POLB

CDK5R1

DYRK1A

MAPK14CA2

CDC42

PTEN

MAPK3

AKT1

(a)

MPI

hsa00620

AKR1B1

hsa00051hsa00052

SORD

hsa00500

hsa00520

hsa00561

hsa04920

hsa04070

hsa04810

hsa04270

hsa05020hsa05100

hsa04062 hsa04960

hsa04144

hsa04910

hsa04930hsa05223MMP14

CALM3

hsa04970

hsa04340

hsa04744

GSK3B

CDK5

hsa04360

HSD17B10

hsa00250

MMP7 hsa04912

hsa00280GALK1AMY1C

GFPT1

GAAHK1hsa04142 CES2

hsa00983hsa04146

XDH hsa00830

hsa00232

AKR1C3hsa01040

CYP1A2

SULT1A1

hsa00920

GART

PDE4D

hsa00010hsa00040

AKR1A1

PIP4K2APIM1

hsa05144hsa00340

hsa04630hsa04670 hsa00360

ALOX5

hsa04150

PTGS1

MAOA

ALOX12

hsa00591

hsa00590

hsa00564

hsa05211 hsa05410

hsa04140

LAP3

DLD

hsa00565

PGD

PAFAH1B3

hsa00330

GSTP1GSTA3

GSTO1

CYP2C9

GSTA1

MAOB

hsa00982

PAHhsa00400

ALOX15

CYP1A1

CYP19A1

hsa00140

HSD17B2

HSD17B1SULT2B1

hsa00380

UCK2hsa00240

hsa00230 CYP3A4

DCK

PECRhsa00480

HPRT1

GLO1 hsa00030

NANHhsa00980

CYP1B1

GPI

PRKAA2hsa04530INSR

hsa00592

hsa04520

PLGOPRM1

PRSS1

GPR35

NR3C1ADORA3

OPRD1

OPRK1

hsa05146

hsa05014

hsa04115

hsa05340hsa04962

hsa04660

hsa05218

MAPK3

PLCG1 BTK

DRD1MAPT

TAP1

GRIA1hsa04740

RB1

hsa04010hsa00910

hsa04650 hsa04210

hsa04540

hsa00760

CD38

MME

hsa04640hsa04614

CHRM1

hsa05010 hsa04971

CDK5R1

BACE1hsa04080

hsa05222

hsa05214

hsa04310

hsa04662

hsa04720

hsa04722

hsa05130

hsa04114

hsa04664

hsa04012hsa04964hsa04666

hsa04020 hsa04621

hsa04966

hsa05110hsa04145

TUBB1ABCC4

ABCC1 hsa02010

ABCG2

ABCC2hsa04940

hsa04612hsa04914

hsa05332

hsa05330hsa05320

hsa04320

hsa04916

hsa05213

PTGS2CDKN1A KDR

hsa04622

ARhsa04110

MAPK14

CCNB1hsa04060

CDK2

MET

AKT2 EGFR

CDK4PIK3R1

ZAP70CA2

AURKA

SYK

LCKFAS

CDK6MPO

PRKCAPDK1

TP53

PLCG2

CREB1

MAP2K1

PRKACA

FGFR1

BAXAKT1

SRCMYLKGSK3A

CCND1

HRAS

IGF1R

HSP90AA1

UBE2I

NFKB2

hsa05220

NOTCH4

CAMK2B

HCKGNAO1

CDC42

CALM1

hsa00100hsa05322hsa00790

hsa00970hsa03410 hsa00601

KARS SQLEAPEX1 ELANE ABO

CCNB2

ALPLUBE2N

hsa05142

ALPPL2

hsa04120

hsa05215

POLB

CCNB3

TYR

hsa00740

hsa05016

hsa04510

hsa05216 hsa04620

hsa00350

hsa04350

XIAP

NFKB1hsa04623PPARG

hsa03320

hsa05200

hsa00260

hsa04370hsa00562

hsa04730

hsa05210

hsa05221

hsa05219

hsa05212

PTPN1PLA2G1B

ARNT

hsa05120MMP2

HIF1A

PDPK1MMP9PIM2

hsa05217

PTEN

hsa05131

RXRB

HGF

hsa05140 hsa05416

(b)

Figure 4 Protein-protein network and protein-pathway network (a) Protein-protein network The proteins are colored pink and shown ascircles (b) Protein-pathway network The proteins are colored pink and shown as circles and the pathways are colored blue and shown astriangles All of the graphs are shown through an organic layout and the node size corresponds to the degree


Table 1 Enriched KEGG pathways

Pathway ID Term Number of proteins P valuehsa05214 Glioma 21 886E minus 11hsa05200 Pathways in cancer 39 241E minus 09hsa05215 Prostate cancer 22 826E minus 09hsa05223 Non-small-cell lung cancer 17 449E minus 08hsa05218 Melanoma 18 621E minus 07hsa04370 VEGF signaling pathway 15 900E minus 06hsa05212 Pancreatic cancer 13 589E minus 05hsa05213 Endometrial cancer 12 190E minus 04hsa04115 p53 signaling pathway 12 239E minus 04hsa05219 Bladder cancer 11 374E minus 04hsa04914 Progesterone-mediated oocyte maturation 13 884E minus 04hsa05222 Small cell lung cancer 14 884E minus 04hsa04664 Fc epsilon RI signaling pathway 14 884E minus 04hsa04510 Focal adhesion 20 116E minus 03hsa04722 Neurotrophin signaling pathway 18 168E minus 03hsa05220 Chronic myeloid leukemia 13 245E minus 03hsa04660 T cell receptor signaling pathway 15 303E minus 03hsa04012 ErbB signaling pathway 14 466E minus 03hsa04666 Fc gamma R-mediated phagocytosis 11 631E minus 03hsa04520 Adherens junction 9 774E minus 03hsa04662 B cell receptor signaling pathway 11 128E minus 02hsa05221 Acute myeloid leukemia 10 158E minus 02hsa00140 Steroid hormone biosynthesis 8 215E minus 02hsa04912 GnRH signaling pathway 15 243E minus 02hsa05210 Colorectal cancer 9 299E minus 02hsa05211 Renal cell carcinoma 11 347E minus 02

those involving the skin lungs gastrointestinal tract breastcolon and the head and neck [20] Extensive research studieshave attempted to elucidate the molecular mechanisms ofcancer chemoprevention by green tea However these studieshave mainly focused on the anticancer activity of EGCGand its targeting of specific cell signaling pathways hasreceived considerable attention for the regulation of cellularproliferation and apoptosis Recent studies have shown thatEGCG can target multiple signaling pathways in cancerincluding the epidermal growth factor receptor (EGFR)insulin-like growth factor (IGF) mitogen-activated proteinkinase (MAPK)extracellular signal-regulated kinase (ERK)and NF-120581B pathways [8 21] Although EGCG is the mainpolyphenol and has higher anticancer activity the otherGTPs such as kaempferol [22] and quercetin [23] alsopresent anticancer activityTherefore a systematic analysis ofthe anticancer mechanism of all GTPs is necessary

To fully elucidate the molecular mechanisms in cancerprevention we collected all of the potential and confirmedtargets of the GTPs to identify all of the related pathwaysIn the end 12 pathways in cancer were identified throughpathway enrichment analysis (Table 2) To better understandthe anticancer mechanisms of green tea we constructed asimplified pathway covering most of the targets related to theGTPs based on the hsa05200 pathway (pathways in cancer)

which is an integration of other pathways including gliomaprostate cancer non-small-cell lung cancer melanoma pan-creatic cancer endometrial cancer bladder cancer smallcell lung cancer acute myeloid leukemia colorectal cancerand renal cell carcinoma (Figure 5) Our analysis revealeda total of 29 targets that are modulated by the polyphenolsof green tea (colored in red) These were distributed indifferent signaling pathways and regulated by one or morepolyphenols (Table S2) GSK-3120573 belongs to theWnt signalingpathway and was modulated by compounds 13 14 and 15FAS and Bax belong to the apoptosis signaling pathwayand were modulated by compounds 5 and 6 respectivelyThese pathways affect the growth of cancer cells by regulatingtheir apoptosis In addition the targets cIAPs and P53 werealso related with apoptosis The other targets modulated byGTPs were mainly distributed in the HGF-PI3KAkt-NF120581Bsignaling pathway (HGF MET PKBAkt p21 NF-120581B andCOX-2) the EGFRFGFRIGFR-MAPK signaling pathway(EGFR FGFR IGFR PLCy PKC Ras MEK and ERK)and other related downstream signal transduction pathwaysIn addition to apoptosis the final impact of these targetsin a cancer cell is mainly associated with angiogenesisproliferation and genomic damage Importantly most ofthese targets or pathways such as Bax [24] NF-120581B [25]MAPKpathway [26] EGFR [27] IGFR [28] andCOX-2 [29]


Table 2 Diseases affected by GTPs and related pathways

Disease Related pathway

Cancer

Glioma (hsa05214)a

Pathways in cancer (hsa05200)a

Prostate cancer (hsa05215)a

Non-small-cell lung cancer(hsa05223)a

Melanoma (hsa05218)a

Pancreatic cancer (hsa05212)a

Endometrial cancer (hsa05213)a

Bladder cancer (hsa05219)a

Small cell lung cancer (hsa05222)a

Acute myeloid leukemia (hsa05221)a

Colorectal cancer (hsa05210)a

Renal cell carcinoma (hsa05211)a

Diabetic p53 signaling pathway (hsa04115)a

Type II diabetes mellitus (hsa04930)b

Neurodegenerativedisease

Fc epsilon RI signaling pathway(hsa04664)a

Fc gamma R-mediated phagocytosis(hsa04666)a

Alzheimerrsquos disease (hsa05010)b

Cardiovasculardiseases

Vascular smooth muscle contraction(hsa04270)b

Muscular disease Chemokine signaling pathway(hsa04062)b

Inflammation B cell receptor signaling pathway(hsa04662)a

a119875 value lt 005 b119875 value gt 005

have been confirmed to bemodulated by EGCG However asshown in Figure 3 these targets can bemodulated by not onlyEGCGbut also other polyphenols which is in agreementwiththe ldquomulticomponent network targetsrdquo model

36 Antidiabetic Mechanism Various studies have shownthe beneficial effects of green on diabetes [30] Japaneseresearchers have showed that drinking more cups of greentea can reduce the risk of diabetes by 33 [31] Moreoverindividuals who have habitually consumed tea for a long timepresent lower body fat which is the property that is mostrelated to diabetes [32] Although several mechanisms havebeen proposed to explain the positive effect of green tea ondiabetes [30 33] these have not been confirmed Fortunatelywe identified three pathways (p53 signaling pathway neu-rotrophin signaling pathway and type II diabetes mellituspathway) related to diabetes from all 147 pathways Amongthese the p53 signaling pathway and the neurotrophin signal-ing pathway were also found in the list of enriched pathwayswith 119875 values of 239 times 10minus4 and 168 times 10minus3 respectively Eventhough the 119875 value found for the type II diabetes mellituspathway was less than the set significance level it still wasselected for further analysis because it is closely correlatedwith diabetes We constructed a diabetes-related pathway

(Figure 6) by integrating these three pathways As shownin Figure 6 22 targets (colored in red) could be modulatedby the GTPs Previous studies on the p53 pathway haveproven that hyperglycemia with diabetes promotes myocyteapoptosis mediated by the activation of p53 [34] whichcan be modulated by compound 6 Downstream of p53GTPs can affect the cell cycle by mediating the targets p21cyclin D CDK46 and Cdc2 Moreover the apoptosis ofcells can be modulated by GTPs through targeting Fas andBAX The ICF-1mTOR pathway driving insulin resistanceand diabetic complications [35] can also be mediated byGTPs through targeting its upstream protein PTEN In thetype II diabetes mellitus pathway the proteins INSR ERKand PI3K contributing to insulin resistance are affected bythe GTPs In addition the key protein GK (HK1) whichis associated with the conversion from glucose to ATP andthereby contributes to impaired insulin secretion through theinduction of mitochondrial dysfunction can be regulated bycompound 3

37 Antineurodegenerative DiseaseMechanism Neurodegen-eration which occurs in Parkinsonrsquos Alzheimerrsquos and otherneurodegenerative diseases appears to be multifactorial inwhich a complex set of toxic reactions including oxidativestress (OS) inflammation reduced expression of trophicfactors and accumulation of protein aggregates lead tothe demise of neurons One of the prominent pathologicalfeatures is the abnormal accumulation of iron on top of thedying neurons and in the surrounding microglia [36] Teaflavonoids (catechins) have been reported to penetrate thebrain barrier and to protect against neuronal death in a widearray of cellular and animal models of neurological diseases[36 37] In this analysis we identified two enriched pathwaynamely the Fc epsilon RI signaling pathway and Fc gammaR-mediated phagocytosis relatedwith brain iron accumulationFifteen proteins in these pathways can be regulated by theGTPs (Table S2) Although the 119875value found for Alzheimerrsquosdisease pathway was less than the set significance level someof its proteins can be regulated by the GTPs Alzheimerrsquosdisease (AD) is a progressive neurodegenerative disorderthat is pathologically characterized by the deposition of 120573-amyloid (A120573) peptides as senile plaques in the brain EGCGhas been proven to reduce A120573 generation [38] Moreovermany key targets in Alzheimerrsquos disease pathway can alsobe mediated by the GTPs As shown in Figure 7 the 120573-site APP cleaving enzyme 1 (BACE) which promotes theformation of A120573 by cleaving APP can be regulated by theGTPs The membrane metalloendopeptidase (NEP) whichinactivates the degradation of A120573 can also be targeted by theGTPs Evidence from several studies has indicated that thehyperphosphorylation of the Tau protein is responsible forits loss of biological activity and its resistance to proteolyticdegradation and likely plays a key role in neurofibrillarydegeneration in AD [39 40] Based on our analysis the Tauproteins and their upstream proteins (p35 p25 PSEN Cdk5and GSK3B) can be modulated by GTPs In addition threeproteins (Fas CaM and ERK12) leading to cell death can bemodulated by GTPs


HGF

MET

PI3K

PKBAkt

IKK

iNOSCOX-2

Sustained angiogenesis

MDM2

P53

Evadingapoptosis

HPH

VEGF

FGF

FGFR

PLCy

PKC

Raf

MEK

ERK

c-Jun c-Fos c-Myc

2RAC

Ets1

MMPS Cyclin D1 CDK4

Proliferation

P53 P21CDK46

Cyclin D1Rb E2F

Genomic damage

CarcinogensLigands

ARHSP

ARAR

PSA

Ligands

FXRcIAPs

TRAFs

FasL

FAS

FADD

CASP8

Bid

Mitochondrion

CytCCASP9

Apoptosis

BCL2

Bax

PPARG

RasRalGDS

Ral

RalBP1

CDC4

CDK2Cyclin E

IGF-1

IGFR

P21

EGF

EGFR

PTEN

Wnt

Frizzled

Dvl

TCFLEF

Survivin

I120581B120572

NF120581B

HIF-120572

PDGF120573TGF120573

HIF-120573

HIF-120573GSK-3120573

120573-catenin

Figure 5 Simplified pathways in cancer All of the targets are shown by the gene name The GTP-regulated targets are labeled in red

38 Anticardiovascular Disease Mechanism Previous epide-miological clinical and experimental studies have estab-lished a positive correlation between green tea consumptionand cardiovascular health Catechins have been proven toexert vascular protective effects through multiple mecha-nisms including antioxidative antihypertensive anti-inflam-matory antiproliferative antithrombogenic and lipid lower-ing effects [41] Therefore green tea plays a role in anticar-diovascular diseases by affecting many pathways shared withcancer diabetes and inflammation In this study only onepathway namely the vascular smooth muscle contractionpathway was found to be directly related to cardiovasculardiseases Eight proteins (Cyt p450 PLA CaM MLCK PKCMEK PKA and MLCK) can be targeted by the GTPs whichcan thus affect myosin (Figure S2)

39 Antimuscular Disease Mechanism Duchenne musculardystrophy (DMD) is a progressive muscle wasting diseasethat leads to early disability and death [42] The disease ischaracterized by the absence of the dystrophin protein fromthe inner surface of the muscle cell sarcolemma Musclecells lacking dystrophin undergo cycles of degeneration andregeneration and are considered susceptible to contraction-induced injury [43] In particular the satellite cell pro-liferative capacity is exhausted and the muscle fibers are

replaced by connective and adipose tissue resulting in aprogressive loss of force generating capability [44] Previousresearch studies have suggested that green tea can improvemuscle health by reducing or delaying necrosis through anantioxidant mechanism [45] In addition to this mechanismwe identified one pathway the chemokine signaling pathwayrelated to macular degeneration Through this pathwayGTPs can mediate the apoptosis migration survival andgrowth and differentiation of macular cells by affecting thePI3KAktNF-120581B signaling pathway (Figure S3) Moreoverthe key target Cdc42 which regulates the actin cytoskeletoncan be affected by compounds 4 and 5 which may promotethe differentiation and migration of muscle cells

310 Anti-Inflammation Mechanism The anti-inflammationactivity of green tea has been demonstrated in many studiesPrevious research has mainly focused on EGCG which candisturb many inflammation-related pathways such as theMAPKs AP-1 and NF120581B pathways and STAT signaling [46]In addition to these pathways we identified an additionalpathway namelym the B cell receptor signaling pathwayrelated to inflammation and immunity In this pathway nineproteins (BTK SYK Ras MEK12 Erk PI3K AKT GSK3120573and NF120581B) that contribute to the immune response can bemodulated by GTPs (Figure S4)


P14ARF MDM2 P53

P21

Cyclin DCDK46

Cyclin ECDK2

G1 arrest

Cell cycle arrest

FasPIDD

DR5 CASP8

BAX Noxa PUMA P53AIP CytC CASP9 CASP3 Apoptosis

Bid

Gadd45B99

Cyclin BCdc2

G2 arrest

PTEN TSC2 IGF-BP3 Inhibition ofICF-1mTOR pathway

INS INSR ERK IRS1IRS

PI3K

GlucoseGLUT2 GK PYK

Pyruvate

ATP

Insulin resistance

Impaired insulin secretion

Transient hyperglycemiahyperinsulinism Type II diabetes mellitus

DNA

Figure 6 Simplified pathways in diabetes All of the targets are shown by the gene name The GTP-regulated targets are labeled in red

NMDAR

VDCC

CaM Cn Bad CytC CASP9 CASP3 Cell death

Calpain P35 P25

Cdk5

TauPaired helical

filamentsNeurofibrillarytangles (NFTS)

PSENRyR

GSK3B

Degradation

NEP

ERK12

BACE

APP

FasTNFR FADD CASP8 Bid

Oligomeric A120573

Amyloid 120573

Ca2+

120573-Secretase

(Tau-P)n

Figure 7 Simplified pathways in neurodegenerative disease All of the targets are shown by the gene name and the GTP-regulated targetsare labeled in red

4 Conclusions

Green tea is commonly associated with traditional beveragerituals and particular lifestyles and is currently considered asource of dietary constituents endowed with biological andpharmacological activities that result in potential benefits to

human health Indeed the novel pharmacological activitiesof green tea are arousing interest in the possible clinical useof green tea components for the prevention and treatmentof several diseases Although numerous studies are attempt-ing to elucidate the molecular mechanisms through whichgreen tea exerts its diverse biological activities particularly


its anticancer activity a systematic understanding of themechanisms through which green tea reduces disease risk isnecessary to establish its efficacy for the population for whichit could be most useful The favorable properties of greentea have been ascribed to the high content of polyphenolicflavonoids It is possible that different GTPs act on differenttargets in the signaling network of complex disease resultingin a synergistic effect which is in accordance with theholistic philosophy of network pharmacology that followsthe ldquomulticomponent network targetrdquo model Therefore tosystematically and comprehensively understand the mecha-nisms responsible for the diverse biological activities of greentea a network pharmacology approach was used to ana-lyze the ldquodrug-target-pathway-diseaserdquo interaction networkwhich are constructed by collecting all of the confirmed andpotential targets of GTPs Six classes of diseases experiencedbeneficial therapeutic effects by green tea as was determinedat the molecular and signaling pathway levels based on theinteraction network which provides a better understandingof how themultiple ingredients in green tea act in synergy andthe effects that these can have onmultiple targets of a disease

Moreover this research study provides comprehensiveand useful data for more in-depth studies of mechanisms ofaction of green tea In addition the understanding of thecell signaling pathways and the molecular events leading toa therapeutic effect will provide further insight for the iden-tification and development of potent agents that specificallytarget these pathways

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The work was supported by the National Natural Sci-ence Foundation of China (Grants 81302651 81230090 and81222046) Fundamental Research Funds for the CentralUniversities (222201314041) the Global Research Networkfor Medicinal Plants (GRNMP) of King Saud UniversityShanghai Leading Academic Discipline Project (B906) KeyLaboratory of Drug Research for Special Environments PLAShanghai Engineering Research Center for the Preparation ofBioactive Natural Products (10DZ2251300) and the ScientificFoundation of Shanghai China (12401900801 09DZ197570009DZ1971500 and 10DZ1971700)

References

[1] H Mukhtar and N Ahmad ldquoTea polyphenols prevention ofcancer and optimizing healthrdquoTheAmerican Journal of ClinicalNutrition vol 71 no 6 supplement pp 1698Sndash1702S 2000

[2] D L McKay and J B Blumberg ldquoThe role of tea in humanhealth an updaterdquo Journal of the American College of Nutritionvol 21 no 1 pp 1ndash13 2002

[3] F L Chung J Schwartz C R Herzog and Y M Yang ldquoTeaand cancer prevention studies in animals and humansrdquo Journalof Nutrition vol 133 no 10 pp 3268Sndash3274S 2003

[4] M Reto M E Figueira H M Filipe and C M M AlmeidaldquoChemical composition of green tea (Camellia sinensis) infu-sions commercialized in Portugalrdquo Plant Foods for HumanNutrition vol 62 no 4 pp 139ndash144 2007

[5] S B Wan D Chen Q P Dou and T H Chan ldquoStudy of thegreen tea polyphenols catechin-3-gallate (CG) and epicatechin-3-gallate (ECG) as proteasome inhibitorsrdquo Bioorganic andMedicinal Chemistry vol 12 no 13 pp 3521ndash3527 2004

[6] K H Miean and S Mohamed ldquoFlavonoid (myricetinquercetin kaempferol luteolin and apigenin) content of edibletropical plantsrdquo Journal of Agricultural and Food Chemistryvol 49 no 6 pp 3106ndash3112 2001

[7] M Hamalainen R Nieminen P Vuorela M Heinonen and EMoilanen ldquoAnti-inflammatory effects of flavonoids Genisteinkaempferol quercetin and daidzein inhibit STAT-1 and NF-120581B activations whereas flavone isorhamnetin naringenin andpelargonidin inhibit only NF-120581B activation along with theirinhibitory effect on iNOS expression and NO production inactivated macrophagesrdquo Mediators of Inflammation vol 2007Article ID 45673 10 pages 2007

[8] N Khan F Afaq M Saleem N Ahmad and H MukhtarldquoTargetingmultiple signaling pathways by green tea polyphenol(-)-epigallocatechin-3-gallaterdquo Cancer Research vol 66 no 5pp 2500ndash2505 2006

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

[10] A S Azmi ldquoNetwork pharmacology for cancer drug discoveryare we there yetrdquo Future Medicinal Chemistry vol 4 no 8 pp939ndash941 2012

[11] J von Eichborn M S Murgueitio M Dunkel S Koerner PE Bourne and R Preissner ldquoPROMISCUOUS a database fornetwork-based drug-repositioningrdquoNucleic Acids Research vol39 no 1 pp D1060ndashD1066 2011

[12] J Gong C Cai X Liu et al ldquoChemMapper a versatile webserver for exploring pharmacology and chemical structureassociation based on molecular 3D similarity methodrdquo Bioin-formatics vol 29 no 14 pp 1827ndash1829 2013

[13] G AMaggiora andMA JohnsonConcepts andApplications ofMolecular Similarity John Wiley amp Sons New York NY USA1990

[14] X Liu H Jiang and H Li ldquoSHAFTS a hybrid approach for3D molecular similarity calculation 1 method and assessmentof virtual screeningrdquo Journal of Chemical Information andModeling vol 51 no 9 pp 2372ndash2385 2011

[15] W Lu X Liu X Cao et al ldquoSHAFTS a hybrid approach for3D molecular similarity calculation 2 Prospective case studyin the discovery of diverse p90 ribosomal S6 protein kinase2 inhibitors to suppress cell migrationrdquo Journal of MedicinalChemistry vol 54 no 10 pp 3564ndash3574 2011

[16] X Liu S Ouyang B Yu et al ldquoPharmMapper server a webserver for potential drug target identification using pharma-cophore mapping approachrdquoNucleic Acids Research vol 38 no2 pp W609ndashW614 2010

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

[18] K Peng W Xu J Zheng et al ldquoThe disease and geneannotations (DGA) an annotation resource for human diseaserdquoNucleic Acids Research vol 41 no 1 pp D553ndashD560 2013


[19] X Liu D Y ZhangW Zhang X Zhao C Yuan and F Ye ldquoTheeffect of green tea extract and EGCG on the signaling networkin squamous cell carcinomardquo Nutrition and Cancer vol 63 no3 pp 466ndash475 2011

[20] S Shankar S Ganapathy and R K Srivastava ldquoGreen teapolyphenols biology and therapeutic implications in cancerrdquoFrontiers in Bioscience vol 12 no 13 pp 4881ndash4899 2007

[21] N Khan and H Mukhtar ldquoMultitargeted therapy of cancer bygreen tea polyphenolsrdquo Cancer Letters vol 269 no 2 pp 269ndash280 2008

[22] H Luo G O Rankin N Juliano B-H Jiang and Y CChen ldquoKaempferol inhibits VEGF expression and in vitroangiogenesis through a novel ERK-NF120581B-cMyc-p21 pathwayrdquoFood Chemistry vol 130 no 2 pp 321ndash328 2012

[23] P Bulzomi P Galluzzo A Bolli S Leone F Acconcia andM Marino ldquoThe pro-apoptotic effect of quercetin in cancercell lines requires ER120573-dependent signalsrdquo Journal of CellularPhysiology vol 227 no 5 pp 1891ndash1898 2012

[24] J D Lambert J Hong G-Y Yang J Liao and C S YangldquoInhibition of carcinogenesis by polyphenols evidence fromlaboratory investigationsrdquo The American Journal of ClinicalNutrition vol 81 no 1 pp 284Sndash291S 2005

[25] F Afaq V M Adhami N Ahmad and H Mukhtar ldquoInhibitionof ultraviolet B-mediated activation of nuclear factor 120581B in nor-mal human epidermal keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallaterdquo Oncogene vol 22 no 7 pp 1035ndash1044 2003

[26] Z Dong W Y Ma C Huang and C S Yang ldquoInhibition oftumor promoter-induced activator protein 1 activation and celltransformation by tea polyphenols (-)-epigallocatechin gallateand theaflavinsrdquo Cancer Research vol 57 no 19 pp 4414ndash44191997

[27] M Shimizu A Deguchi J T E Lim H Moriwaki LKopelovich and I B Weinstein ldquo(minus)-Epigallocatechin gallateand polyphenon E inhibit growth and activation of the epider-mal growth factor receptor and human epidermal growth factorreceptor-2 signaling pathways in human colon cancer cellsrdquoClinical Cancer Research vol 11 no 7 pp 2735ndash2746 2005

[28] V M Adhami I A Siddiqui N Ahmad S Gupta andH Mukhtar ldquoOral consumption of green tea polyphenolsinhibits insulin-like growth factor-I-induced signaling in anautochthonous mouse model of prostate cancerrdquo CancerResearch vol 64 no 23 pp 8715ndash8722 2004

[29] D S Wheeler J D Catravas K Odoms A Denenberg VMalhotra and H R Wong ldquoEpigallocatechin-3-gallate a greentea-derived polyphenol inhibits IL-1120573-dependent proinflam-matory signal transduction in cultured respiratory epithelialcellsrdquo Journal of Nutrition vol 134 no 5 pp 1039ndash1044 2004

[30] H M Kim and J Kim ldquoThe effects of green tea on obesity andtype 2 diabetesrdquoDiabetes and Metabolism Journal vol 37 no 3pp 173ndash175 2013

[31] H Iso C Date KWakai et al ldquoThe relationship between greentea and total caffeine intake and risk for self-reported type 2diabetes among Japanese adultsrdquo Annals of Internal Medicinevol 144 no 8 pp 554ndash562 2006

[32] C-HWu F-H Lu C-S Chang T-C Chang R-HWang andC-J Chang ldquoRelationship among habitual tea consumptionpercent body fat and body fat distributionrdquo Obesity Researchvol 11 no 9 pp 1088ndash1095 2003

[33] O H Ryu J Lee K W Lee et al ldquoEffects of green teaconsumption on inflammation insulin resistance and pulse

wave velocity in type 2 diabetes patientsrdquoDiabetes Research andClinical Practice vol 71 no 3 pp 356ndash358 2006

[34] F Fiordaliso A Leri D Cesselli et al ldquoHyperglycemia activatesp53 and p53-regulated genes leading to myocyte cell deathrdquoDiabetes vol 50 no 10 pp 2363ndash2375 2001

[35] M V Blagosklonny ldquoTOR-centric view on insulin resistanceand diabetic complications perspective for endocrinologistsand gerontologistsrdquoCell Death and Disease vol 4 no 12 articlee964 2013

[36] S Mandel T Amit L Reznichenko O Weinreb and M B HYoudim ldquoGreen tea catechins as brain-permeable natural ironchelators-antioxidants for the treatment of neurodegenerativedisordersrdquo Molecular Nutrition and Food Research vol 50 no2 pp 229ndash234 2006

[37] S Mandel G Maor and M B Youdim ldquoIron and 120572-synucleinin the substantia nigra of MPTP-treated mice effect of neuro-protective drugs R-apomorphine and green tea polyphenol (-)-epigallocatechin-3-gallaterdquo Journal ofMolecular Neurosciencevol 24 no 3 pp 401ndash416 2004

[38] K Rezai-Zadeh D Shytle N Sun et al ldquoGreen teaepigallocatechin-3-gallate (EGCG) modulates amyloidprecursor protein cleavage and reduces cerebral amyloidosis inAlzheimer transgenic micerdquo Journal of Neuroscience vol 25no 38 pp 8807ndash8814 2005

[39] C-X Gong T Lidsky J Wegiel L Zuck I Grundke-Iqbal andK Iqbal ldquoPhosphorylation of microtubule-associated proteintau is regulated by protein phosphatase 2A inmammalian brainImplications for neurofibrillary degeneration in AlzheimerrsquosdiseaserdquoThe Journal of Biological Chemistry vol 275 no 8 pp5535ndash5544 2000

[40] A D C Alonso T Zaidi I Grundke-Iqbal and K IqballdquoRole of abnormally phosphorylated tau in the breakdown ofmicrotubules in Alzheimer diseaserdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no12 pp 5562ndash5566 1994

[41] P V A Babu and D Liu ldquoGreen tea catechins and cardiovascu-lar health an updaterdquo Current Medicinal Chemistry vol 15 no18 pp 1840ndash1850 2008

[42] T M Buetler M Renard E A Offord H Schneider andU T Ruegg ldquoGreen tea extract decreases muscle necrosis inmdx mice and protects against reactive oxygen speciesrdquo TheAmerican Journal of Clinical Nutrition vol 75 no 4 pp 749ndash753 2002

[43] B J Petrof J B Shrager H H Stedman A M Kelly andH L Sweeney ldquoDystrophin protects the sarcolemma fromstresses developed during muscle contractionrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 90 no 8 pp 3710ndash3714 1993

[44] P EM Smith PM A Calverley R H T Edwards G A Evansand E J Campbell ldquoPractical problems in the respiratory careof patients with muscular dystrophyrdquoThe New England Journalof Medicine vol 316 no 19 pp 1197ndash1205 1987

[45] M-H Disatnik J Dhawan Y Yu et al ldquoEvidence of oxidativestress in mdx mouse muscle studies of the pre- necrotic staterdquoJournal of the Neurological Sciences vol 161 no 1 pp 77ndash841998

[46] R Singh N Akhtar and T M Haqqi ldquoGreen tea polyphenolepigallocatechi3-gallate Inflammation and arthritisrdquo Life Sci-ences vol 86 no 25-26 pp 907ndash918 2010

Submit your manuscripts athttpwwwhindawicom

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


= R1 = R2 = R3 = H R2 = OH= R1 = H R2 = R3 = OH= H R1 = R2 = R3 = OH= gallate R1 = R3 = H R2 = OH= gallate R1 = H R2 = R3 = OH= gallate R1 = R2 = R3 = OH= 3998400-methylgallate R1 = H R2 = R3 = OH= 3998400-methylgallate R1 = R2 = R3 = OH

= R1 = H R2 = R3 = OH= H R1 = R2 = R3 = OH= gallate R1 = H R2 = R3 = OH= gallate R1 = R2 = R3 = OH

= R3 = H R2 = OH= H R2 = R3 = OH= R2 = R3 = OH

R1

R2

R3

O

OR

HO

OH

R1

R2

R3

O

R1

R2

R3O

OR

HO

OH

OH

HO

OH O

(1) R(2) R(3) R(4) R(5) R(6) R(7) R(8) R

(9) R(10) R(11) R(12) R

(13) R1

(14) R1

(15) R1

Figure 1 Structures of green tea polyphenols

green tea based on the ldquomulticomponent network targetrdquomodel

Network pharmacology updates the research paradigmfrom the current ldquoone target one drugrdquo model to a newldquomulticomponent network targetrdquo model which enhancesour knowledge of multipathway interactions and helps inter-pret drug-response signature datasets that collectively decodethe complex mechanisms of drug actions [9] Unlike earlierreductionist ldquoone drug one targetrdquo approaches networkpharmacology invokes the idea that a drug engages withmultiple targets and rarely interacts with a single protein inisolation [10] This approach utilizes principles of systemsbiology and network analysis to advance drug discoverythrough the identification of connectivity redundancy andpleiotropy in biological pathways and has allowed a deeperunderstanding of the drug interactions by revealing thatthis promiscuity often engages a synergistic combination ofappropriate high-value targets in a complex disease such ascancer and diabetes to produce treatment success [11]

To explore the mechanism of action of green tea froma holistic perspective the network pharmacology methodwas employed to investigate the molecular behavior of GTPsWe collected all available target information for fifteen GTPsthrough literature mining and computational chemistry (3Dsimilarity search and reverse docking) to construct a networkof the ldquodrug-target-pathway-diseaserdquo interactions (Figure 2)In the end 200 Homo sapiens targets were identified forfifteen GTPs These targets were classified into six groupsaccording to their related disease which included cancerdiabetes neurodegenerative disease cardiovascular diseasemuscular disease and inflammation in agreement with theapplications of green tea Pathways analysis was used toillustrate the mechanism of action through which the GTPsexert their comprehensive therapeutic effects A total of143 KEGG pathways were identified and 26 of these weremore enriched as determined through pathway enrichmentanalysis and target-pathway network analysis Twenty ofthe identified pathways that play a role in the GTP-related

Lite

ratu

re

ChemMapper PubMed PharmMapper

287 targets 289 targets339 targets

200 targets

Drug Target

Pathway Disease

O

OR

HO

OH

OH

Revers dockingSimila

rity s

earch

R1R2

Figure 2 Analysis overview The methods of similarity searchliterature mining and reverse docking were utilized to identifythe confirmed and potential targets of GTPs and these methodsprovides 287 339 and 289 targets respectivelyUltimately 200Homotargetswere selected after removing any redundant and other sapienstargets and used to construct the ldquodrug-target-pathway-diseaserdquointeraction network

diseases were selected for analyzing the mechanisms ofaction of green tea By integrating the ldquodrug-target-pathway-diseaserdquo interactions we found the green tea exerts a varietyof therapeutic effects though the modulation of multiplepathway by itsmain components which is in accordancewiththe ldquomulticomponent network targetrdquo model








119875 = 1 minus

119896minus1

sum

119894=0

119891 (119894) = 1 minus

119896minus1

sum

119894=0

(

119870

119894) (

119873minus119870

119899minus119894)

(

119873

119899)

(1)







MMP14

AHRAPOBEC3G

ASCC3

KCNH2

PIM1

PRKCA

AKT1

FAS

SULT2B1XIAP

CCNB1

STK33

SULT1A1

PLA2G1B

TP53

TERT

CYP3A4INSR

EHMT2

MAPK14

PLG

FOLH1

MMP9

HIF1A

UBE2I

PIM2

RAP2A

CDK1POLI

MET

PRKACA

GSTA1

BAXPTGS1

MME

MAPK3

IGF1R

HIF1AN

CDC42

PABPC1

MMP14

CDK6

STK16

EGFR

APEX1CYCLIN D1

PDK1

PPARGCDK4

LCK

CYP19A1UBE2N

ANGMMP2

AKR1C3

PTEN

ABCC4

KDR

ALOX12

MAP2K1

SQLE

MMP7

HPRT1

CD38

HIF1A

HSD17B10

POLHCYP1A1

HSD17B2 CDK2

CLK1

ABCC1

NEU1

SYK

MCL1

CDKN1 RB1

ABCC2

CDK5

CYP1B1UCK2

POLB

SRC

HPGDPREP

CRABP2

GPI

GNAO1

MMP3PIK3R1

GLO1 XDHCREB1

MMP13

ESR1

HSP90

HRAS

HSD17B1

CDK5R1

AKT2

APOBEC3A

PRKAA2

ABCG2PIP4K2A

ARNT

ESRRG

HCK

PTGS2

SORDGRIA1

NR1H4

FGFR1

NFKB1

AURKA

TAP1

PRSS1

BTKMYLK

GALK1PAFAH1B3

ALB

MAOB

DLD

GSTO1

GFPT1

GFER

CHRM1

PAH

FXR1

GSK3B

MAOA

VCP

KARS

BACE1

OPRK1

OPRM1

OPRD1

TUBB1

DRD1

ABO NOX4

ADORA3

CALM1

ALB

ALOX5PDE4D

MPO

CYP1A2

OPRK1

GSK3A

FKBP1A

NR3C1

DYRK1A

MAPTDYRK1A

PGD

AKR1A1

GAAGSTA3

NFE2L2

PDPK1

ALPI

ALPL

CCNB3BAZ2B ALOX15

ALPPL2

GART

PCTP

MPI

GPR35

LAP3KDM4DL

TGM3

CALM3NFKB2

ELANE

MMP12

CAMK2B

CTDSP1

BCHE

RDRP

PECR

MEX-5

11

1

3

2

1412

6

9

GSTP1

MMP2

RACGAP1

UCK2

CCNB2

DCK

NOTCH4

RXRB

HGF

MMP7 HSP90AA1

7

8

4

13

15

10

5

AKR1B1

CYP2C9SHBG

AMY1C

VDRAKR1B1

VDR

PTPN1

HK1PLCG1

CA2

ZAP70

PLCG2

TYR

AR

POLB

CES2









PRKACA

APOBEC3G

OPRD1MCL1

HCK

MMP14

BTK

PRKAA2

NOTCH4

MMP9PIK3R1PPARG

CDKN1A

KDR

IGF1RSRC

CD38

ADORA3

OPRM1

HPRT1

HIF1ANAKT2

PLCG1PRKCA

PDPK1

PDK1

PLCG2

MYLK

OPRK1

GNAO1NOX4

PECR

MET

ZAP70 PIP4K2A

PDE4D

GSK3A

PABPC1DCK

CLK1

PIM1


ALPPL2GFPT1

ANG

AKR1C3

NR1H4

ABCC1

ABCC2

AKR1A1

MAOB

CALM3

HGF

MAOA

FXR1

CYP19A1

ALOX5SULT1A1

CYP2C9

AHR

CDK2

CYP1B1

GSTP1

HIF1ACDK4

HSD17B1ALOX12

NFE2L2

BACE1

MAPT

CYP1A1

POLIGFER

BAX

RXRB

AMY1C

FKBP1AEHMT2

GSTT2BGSTO1

NFKB2SQLE

FOLH1

HSD17B2ESRRG

EGFR

TYR

GSTA3

ALPL

ELANE

LCKPLG

PTGS2

HRAS

CALM1

MMP2 MPO

CHRM1

NFKB1

MMP7

PLA2G1BPREP

LAP3

NANH

SORD

MMP13

HPGD

GALK1 PGD

HSD17B10GLO1

ABCC4

ABCG2

TUBB1

ALOX15

ESR1

CYP1A2

CYP3A4

AKR1B1

ALB

INSR

CREB1

PTGS1

ARNT

HK1

MMEPRSS1

XDH

GPIPAFAH1B3

TAP1

VDR

MMP12

PAH

MPI

DLDABO

SHBG

BCHE

NR3C1

MAP2K1 TP53

CCNB1CCND1POLH

CDK6

AR

GRIA1XIAP

SYK

HSP90AA1

RB1

GSK3B

UBE2ITERT

EIF4H

KCNH2

CAMK2BKARS FASGART

AURKA

UCK2

VCP

CDK1CCNB3

RACGAP1

CDK5CCNB2

SULT2B1

APEX1

UBE2N

POLB

CDK5R1

DYRK1A

MAPK14CA2

CDC42

PTEN

MAPK3

AKT1

(a)

MPI

hsa00620

AKR1B1

hsa00051hsa00052

SORD

hsa00500

hsa00520

hsa00561

hsa04920

hsa04070

hsa04810

hsa04270

hsa05020hsa05100

hsa04062 hsa04960

hsa04144

hsa04910


CALM3

hsa04970

hsa04340

hsa04744

GSK3B

CDK5

hsa04360

HSD17B10

hsa00250

MMP7 hsa04912

hsa00280GALK1AMY1C

GFPT1

GAAHK1hsa04142 CES2

hsa00983hsa04146

XDH hsa00830

hsa00232

AKR1C3hsa01040

CYP1A2

SULT1A1

hsa00920

GART

PDE4D

hsa00010hsa00040

AKR1A1

PIP4K2APIM1

hsa05144hsa00340

hsa04630hsa04670 hsa00360

ALOX5

hsa04150

PTGS1

MAOA

ALOX12

hsa00591

hsa00590

hsa00564

hsa05211 hsa05410

hsa04140

LAP3

DLD

hsa00565

PGD

PAFAH1B3

hsa00330

GSTP1GSTA3

GSTO1

CYP2C9

GSTA1

MAOB

hsa00982

PAHhsa00400

ALOX15

CYP1A1

CYP19A1

hsa00140

HSD17B2

HSD17B1SULT2B1

hsa00380

UCK2hsa00240

hsa00230 CYP3A4

DCK

PECRhsa00480

HPRT1

GLO1 hsa00030

NANHhsa00980

CYP1B1

GPI

PRKAA2hsa04530INSR

hsa00592

hsa04520

PLGOPRM1

PRSS1

GPR35

NR3C1ADORA3

OPRD1

OPRK1

hsa05146

hsa05014

hsa04115

hsa05340hsa04962

hsa04660

hsa05218

MAPK3

PLCG1 BTK

DRD1MAPT

TAP1

GRIA1hsa04740

RB1

hsa04010hsa00910

hsa04650 hsa04210

hsa04540

hsa00760

CD38

MME

hsa04640hsa04614

CHRM1

hsa05010 hsa04971

CDK5R1

BACE1hsa04080

hsa05222

hsa05214

hsa04310

hsa04662

hsa04720

hsa04722

hsa05130

hsa04114

hsa04664

hsa04012hsa04964hsa04666

hsa04020 hsa04621

hsa04966

hsa05110hsa04145

TUBB1ABCC4

ABCC1 hsa02010

ABCG2

ABCC2hsa04940

hsa04612hsa04914

hsa05332

hsa05330hsa05320

hsa04320

hsa04916

hsa05213

PTGS2CDKN1A KDR

hsa04622

ARhsa04110

MAPK14

CCNB1hsa04060

CDK2

MET

AKT2 EGFR

CDK4PIK3R1

ZAP70CA2

AURKA

SYK

LCKFAS

CDK6MPO

PRKCAPDK1

TP53

PLCG2

CREB1

MAP2K1

PRKACA

FGFR1

BAXAKT1

SRCMYLKGSK3A

CCND1

HRAS

IGF1R

HSP90AA1

UBE2I

NFKB2

hsa05220

NOTCH4

CAMK2B

HCKGNAO1

CDC42

CALM1

hsa00100hsa05322hsa00790

hsa00970hsa03410 hsa00601


CCNB2

ALPLUBE2N

hsa05142

ALPPL2

hsa04120

hsa05215

POLB

CCNB3

TYR

hsa00740

hsa05016

hsa04510

hsa05216 hsa04620

hsa00350

hsa04350

XIAP

NFKB1hsa04623PPARG

hsa03320

hsa05200

hsa00260

hsa04370hsa00562

hsa04730

hsa05210

hsa05221

hsa05219

hsa05212

PTPN1PLA2G1B

ARNT

hsa05120MMP2

HIF1A

PDPK1MMP9PIM2

hsa05217

PTEN

hsa05131

RXRB

HGF

hsa05140 hsa05416

(b)











Cancer

Glioma (hsa05214)a




























HGF

MET

PI3K

PKBAkt

IKK

iNOSCOX-2


MDM2

P53

Evadingapoptosis

HPH

VEGF

FGF

FGFR

PLCy

PKC

Raf

MEK

ERK

c-Jun c-Fos c-Myc

2RAC

Ets1

MMPS Cyclin D1 CDK4

Proliferation

P53 P21CDK46

Cyclin D1Rb E2F

Genomic damage

CarcinogensLigands

ARHSP

ARAR

PSA

Ligands

FXRcIAPs

TRAFs

FasL

FAS

FADD

CASP8

Bid

Mitochondrion

CytCCASP9

Apoptosis

BCL2

Bax

PPARG

RasRalGDS

Ral

RalBP1

CDC4

CDK2Cyclin E

IGF-1

IGFR

P21

EGF

EGFR

PTEN

Wnt

Frizzled

Dvl

TCFLEF

Survivin

I120581B120572

NF120581B

HIF-120572

PDGF120573TGF120573

HIF-120573

HIF-120573GSK-3120573

120573-catenin







P14ARF MDM2 P53

P21

Cyclin DCDK46

Cyclin ECDK2

G1 arrest

Cell cycle arrest

FasPIDD

DR5 CASP8


Bid

Gadd45B99

Cyclin BCdc2

G2 arrest



PI3K

GlucoseGLUT2 GK PYK

Pyruvate

ATP

Insulin resistance



DNA


NMDAR

VDCC


Calpain P35 P25

Cdk5

TauPaired helical


PSENRyR

GSK3B

Degradation

NEP

ERK12

BACE

APP


Oligomeric A120573

Amyloid 120573

Ca2+

120573-Secretase

(Tau-P)n


4 Conclusions








Acknowledgments


References






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























119875 = 1 minus

119896minus1

sum

119894=0

119891 (119894) = 1 minus

119896minus1

sum

119894=0

(

119870

119894) (

119873minus119870

119899minus119894)

(

119873

119899)

(1)







MMP14

AHRAPOBEC3G

ASCC3

KCNH2

PIM1

PRKCA

AKT1

FAS

SULT2B1XIAP

CCNB1

STK33

SULT1A1

PLA2G1B

TP53

TERT

CYP3A4INSR

EHMT2

MAPK14

PLG

FOLH1

MMP9

HIF1A

UBE2I

PIM2

RAP2A

CDK1POLI

MET

PRKACA

GSTA1

BAXPTGS1

MME

MAPK3

IGF1R

HIF1AN

CDC42

PABPC1

MMP14

CDK6

STK16

EGFR

APEX1CYCLIN D1

PDK1

PPARGCDK4

LCK

CYP19A1UBE2N

ANGMMP2

AKR1C3

PTEN

ABCC4

KDR

ALOX12

MAP2K1

SQLE

MMP7

HPRT1

CD38

HIF1A

HSD17B10

POLHCYP1A1

HSD17B2 CDK2

CLK1

ABCC1

NEU1

SYK

MCL1

CDKN1 RB1

ABCC2

CDK5

CYP1B1UCK2

POLB

SRC

HPGDPREP

CRABP2

GPI

GNAO1

MMP3PIK3R1

GLO1 XDHCREB1

MMP13

ESR1

HSP90

HRAS

HSD17B1

CDK5R1

AKT2

APOBEC3A

PRKAA2

ABCG2PIP4K2A

ARNT

ESRRG

HCK

PTGS2

SORDGRIA1

NR1H4

FGFR1

NFKB1

AURKA

TAP1

PRSS1

BTKMYLK

GALK1PAFAH1B3

ALB

MAOB

DLD

GSTO1

GFPT1

GFER

CHRM1

PAH

FXR1

GSK3B

MAOA

VCP

KARS

BACE1

OPRK1

OPRM1

OPRD1

TUBB1

DRD1

ABO NOX4

ADORA3

CALM1

ALB

ALOX5PDE4D

MPO

CYP1A2

OPRK1

GSK3A

FKBP1A

NR3C1

DYRK1A

MAPTDYRK1A

PGD

AKR1A1

GAAGSTA3

NFE2L2

PDPK1

ALPI

ALPL

CCNB3BAZ2B ALOX15

ALPPL2

GART

PCTP

MPI

GPR35

LAP3KDM4DL

TGM3

CALM3NFKB2

ELANE

MMP12

CAMK2B

CTDSP1

BCHE

RDRP

PECR

MEX-5

11

1

3

2

1412

6

9

GSTP1

MMP2

RACGAP1

UCK2

CCNB2

DCK

NOTCH4

RXRB

HGF

MMP7 HSP90AA1

7

8

4

13

15

10

5

AKR1B1

CYP2C9SHBG

AMY1C

VDRAKR1B1

VDR

PTPN1

HK1PLCG1

CA2

ZAP70

PLCG2

TYR

AR

POLB

CES2









PRKACA

APOBEC3G

OPRD1MCL1

HCK

MMP14

BTK

PRKAA2

NOTCH4

MMP9PIK3R1PPARG

CDKN1A

KDR

IGF1RSRC

CD38

ADORA3

OPRM1

HPRT1

HIF1ANAKT2

PLCG1PRKCA

PDPK1

PDK1

PLCG2

MYLK

OPRK1

GNAO1NOX4

PECR

MET

ZAP70 PIP4K2A

PDE4D

GSK3A

PABPC1DCK

CLK1

PIM1


ALPPL2GFPT1

ANG

AKR1C3

NR1H4

ABCC1

ABCC2

AKR1A1

MAOB

CALM3

HGF

MAOA

FXR1

CYP19A1

ALOX5SULT1A1

CYP2C9

AHR

CDK2

CYP1B1

GSTP1

HIF1ACDK4

HSD17B1ALOX12

NFE2L2

BACE1

MAPT

CYP1A1

POLIGFER

BAX

RXRB

AMY1C

FKBP1AEHMT2

GSTT2BGSTO1

NFKB2SQLE

FOLH1

HSD17B2ESRRG

EGFR

TYR

GSTA3

ALPL

ELANE

LCKPLG

PTGS2

HRAS

CALM1

MMP2 MPO

CHRM1

NFKB1

MMP7

PLA2G1BPREP

LAP3

NANH

SORD

MMP13

HPGD

GALK1 PGD

HSD17B10GLO1

ABCC4

ABCG2

TUBB1

ALOX15

ESR1

CYP1A2

CYP3A4

AKR1B1

ALB

INSR

CREB1

PTGS1

ARNT

HK1

MMEPRSS1

XDH

GPIPAFAH1B3

TAP1

VDR

MMP12

PAH

MPI

DLDABO

SHBG

BCHE

NR3C1

MAP2K1 TP53

CCNB1CCND1POLH

CDK6

AR

GRIA1XIAP

SYK

HSP90AA1

RB1

GSK3B

UBE2ITERT

EIF4H

KCNH2

CAMK2BKARS FASGART

AURKA

UCK2

VCP

CDK1CCNB3

RACGAP1

CDK5CCNB2

SULT2B1

APEX1

UBE2N

POLB

CDK5R1

DYRK1A

MAPK14CA2

CDC42

PTEN

MAPK3

AKT1

(a)

MPI

hsa00620

AKR1B1

hsa00051hsa00052

SORD

hsa00500

hsa00520

hsa00561

hsa04920

hsa04070

hsa04810

hsa04270

hsa05020hsa05100

hsa04062 hsa04960

hsa04144

hsa04910


CALM3

hsa04970

hsa04340

hsa04744

GSK3B

CDK5

hsa04360

HSD17B10

hsa00250

MMP7 hsa04912

hsa00280GALK1AMY1C

GFPT1

GAAHK1hsa04142 CES2

hsa00983hsa04146

XDH hsa00830

hsa00232

AKR1C3hsa01040

CYP1A2

SULT1A1

hsa00920

GART

PDE4D

hsa00010hsa00040

AKR1A1

PIP4K2APIM1

hsa05144hsa00340

hsa04630hsa04670 hsa00360

ALOX5

hsa04150

PTGS1

MAOA

ALOX12

hsa00591

hsa00590

hsa00564

hsa05211 hsa05410

hsa04140

LAP3

DLD

hsa00565

PGD

PAFAH1B3

hsa00330

GSTP1GSTA3

GSTO1

CYP2C9

GSTA1

MAOB

hsa00982

PAHhsa00400

ALOX15

CYP1A1

CYP19A1

hsa00140

HSD17B2

HSD17B1SULT2B1

hsa00380

UCK2hsa00240

hsa00230 CYP3A4

DCK

PECRhsa00480

HPRT1

GLO1 hsa00030

NANHhsa00980

CYP1B1

GPI

PRKAA2hsa04530INSR

hsa00592

hsa04520

PLGOPRM1

PRSS1

GPR35

NR3C1ADORA3

OPRD1

OPRK1

hsa05146

hsa05014

hsa04115

hsa05340hsa04962

hsa04660

hsa05218

MAPK3

PLCG1 BTK

DRD1MAPT

TAP1

GRIA1hsa04740

RB1

hsa04010hsa00910

hsa04650 hsa04210

hsa04540

hsa00760

CD38

MME

hsa04640hsa04614

CHRM1

hsa05010 hsa04971

CDK5R1

BACE1hsa04080

hsa05222

hsa05214

hsa04310

hsa04662

hsa04720

hsa04722

hsa05130

hsa04114

hsa04664

hsa04012hsa04964hsa04666

hsa04020 hsa04621

hsa04966

hsa05110hsa04145

TUBB1ABCC4

ABCC1 hsa02010

ABCG2

ABCC2hsa04940

hsa04612hsa04914

hsa05332

hsa05330hsa05320

hsa04320

hsa04916

hsa05213

PTGS2CDKN1A KDR

hsa04622

ARhsa04110

MAPK14

CCNB1hsa04060

CDK2

MET

AKT2 EGFR

CDK4PIK3R1

ZAP70CA2

AURKA

SYK

LCKFAS

CDK6MPO

PRKCAPDK1

TP53

PLCG2

CREB1

MAP2K1

PRKACA

FGFR1

BAXAKT1

SRCMYLKGSK3A

CCND1

HRAS

IGF1R

HSP90AA1

UBE2I

NFKB2

hsa05220

NOTCH4

CAMK2B

HCKGNAO1

CDC42

CALM1

hsa00100hsa05322hsa00790

hsa00970hsa03410 hsa00601


CCNB2

ALPLUBE2N

hsa05142

ALPPL2

hsa04120

hsa05215

POLB

CCNB3

TYR

hsa00740

hsa05016

hsa04510

hsa05216 hsa04620

hsa00350

hsa04350

XIAP

NFKB1hsa04623PPARG

hsa03320

hsa05200

hsa00260

hsa04370hsa00562

hsa04730

hsa05210

hsa05221

hsa05219

hsa05212

PTPN1PLA2G1B

ARNT

hsa05120MMP2

HIF1A

PDPK1MMP9PIM2

hsa05217

PTEN

hsa05131

RXRB

HGF

hsa05140 hsa05416

(b)











Cancer

Glioma (hsa05214)a




























HGF

MET

PI3K

PKBAkt

IKK

iNOSCOX-2


MDM2

P53

Evadingapoptosis

HPH

VEGF

FGF

FGFR

PLCy

PKC

Raf

MEK

ERK

c-Jun c-Fos c-Myc

2RAC

Ets1

MMPS Cyclin D1 CDK4

Proliferation

P53 P21CDK46

Cyclin D1Rb E2F

Genomic damage

CarcinogensLigands

ARHSP

ARAR

PSA

Ligands

FXRcIAPs

TRAFs

FasL

FAS

FADD

CASP8

Bid

Mitochondrion

CytCCASP9

Apoptosis

BCL2

Bax

PPARG

RasRalGDS

Ral

RalBP1

CDC4

CDK2Cyclin E

IGF-1

IGFR

P21

EGF

EGFR

PTEN

Wnt

Frizzled

Dvl

TCFLEF

Survivin

I120581B120572

NF120581B

HIF-120572

PDGF120573TGF120573

HIF-120573

HIF-120573GSK-3120573

120573-catenin







P14ARF MDM2 P53

P21

Cyclin DCDK46

Cyclin ECDK2

G1 arrest

Cell cycle arrest

FasPIDD

DR5 CASP8


Bid

Gadd45B99

Cyclin BCdc2

G2 arrest



PI3K

GlucoseGLUT2 GK PYK

Pyruvate

ATP

Insulin resistance



DNA


NMDAR

VDCC


Calpain P35 P25

Cdk5

TauPaired helical


PSENRyR

GSK3B

Degradation

NEP

ERK12

BACE

APP


Oligomeric A120573

Amyloid 120573

Ca2+

120573-Secretase

(Tau-P)n


4 Conclusions








Acknowledgments


References






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















MMP14

AHRAPOBEC3G

ASCC3

KCNH2

PIM1

PRKCA

AKT1

FAS

SULT2B1XIAP

CCNB1

STK33

SULT1A1

PLA2G1B

TP53

TERT

CYP3A4INSR

EHMT2

MAPK14

PLG

FOLH1

MMP9

HIF1A

UBE2I

PIM2

RAP2A

CDK1POLI

MET

PRKACA

GSTA1

BAXPTGS1

MME

MAPK3

IGF1R

HIF1AN

CDC42

PABPC1

MMP14

CDK6

STK16

EGFR

APEX1CYCLIN D1

PDK1

PPARGCDK4

LCK

CYP19A1UBE2N

ANGMMP2

AKR1C3

PTEN

ABCC4

KDR

ALOX12

MAP2K1

SQLE

MMP7

HPRT1

CD38

HIF1A

HSD17B10

POLHCYP1A1

HSD17B2 CDK2

CLK1

ABCC1

NEU1

SYK

MCL1

CDKN1 RB1

ABCC2

CDK5

CYP1B1UCK2

POLB

SRC

HPGDPREP

CRABP2

GPI

GNAO1

MMP3PIK3R1

GLO1 XDHCREB1

MMP13

ESR1

HSP90

HRAS

HSD17B1

CDK5R1

AKT2

APOBEC3A

PRKAA2

ABCG2PIP4K2A

ARNT

ESRRG

HCK

PTGS2

SORDGRIA1

NR1H4

FGFR1

NFKB1

AURKA

TAP1

PRSS1

BTKMYLK

GALK1PAFAH1B3

ALB

MAOB

DLD

GSTO1

GFPT1

GFER

CHRM1

PAH

FXR1

GSK3B

MAOA

VCP

KARS

BACE1

OPRK1

OPRM1

OPRD1

TUBB1

DRD1

ABO NOX4

ADORA3

CALM1

ALB

ALOX5PDE4D

MPO

CYP1A2

OPRK1

GSK3A

FKBP1A

NR3C1

DYRK1A

MAPTDYRK1A

PGD

AKR1A1

GAAGSTA3

NFE2L2

PDPK1

ALPI

ALPL

CCNB3BAZ2B ALOX15

ALPPL2

GART

PCTP

MPI

GPR35

LAP3KDM4DL

TGM3

CALM3NFKB2

ELANE

MMP12

CAMK2B

CTDSP1

BCHE

RDRP

PECR

MEX-5

11

1

3

2

1412

6

9

GSTP1

MMP2

RACGAP1

UCK2

CCNB2

DCK

NOTCH4

RXRB

HGF

MMP7 HSP90AA1

7

8

4

13

15

10

5

AKR1B1

CYP2C9SHBG

AMY1C

VDRAKR1B1

VDR

PTPN1

HK1PLCG1

CA2

ZAP70

PLCG2

TYR

AR

POLB

CES2









PRKACA

APOBEC3G

OPRD1MCL1

HCK

MMP14

BTK

PRKAA2

NOTCH4

MMP9PIK3R1PPARG

CDKN1A

KDR

IGF1RSRC

CD38

ADORA3

OPRM1

HPRT1

HIF1ANAKT2

PLCG1PRKCA

PDPK1

PDK1

PLCG2

MYLK

OPRK1

GNAO1NOX4

PECR

MET

ZAP70 PIP4K2A

PDE4D

GSK3A

PABPC1DCK

CLK1

PIM1


ALPPL2GFPT1

ANG

AKR1C3

NR1H4

ABCC1

ABCC2

AKR1A1

MAOB

CALM3

HGF

MAOA

FXR1

CYP19A1

ALOX5SULT1A1

CYP2C9

AHR

CDK2

CYP1B1

GSTP1

HIF1ACDK4

HSD17B1ALOX12

NFE2L2

BACE1

MAPT

CYP1A1

POLIGFER

BAX

RXRB

AMY1C

FKBP1AEHMT2

GSTT2BGSTO1

NFKB2SQLE

FOLH1

HSD17B2ESRRG

EGFR

TYR

GSTA3

ALPL

ELANE

LCKPLG

PTGS2

HRAS

CALM1

MMP2 MPO

CHRM1

NFKB1

MMP7

PLA2G1BPREP

LAP3

NANH

SORD

MMP13

HPGD

GALK1 PGD

HSD17B10GLO1

ABCC4

ABCG2

TUBB1

ALOX15

ESR1

CYP1A2

CYP3A4

AKR1B1

ALB

INSR

CREB1

PTGS1

ARNT

HK1

MMEPRSS1

XDH

GPIPAFAH1B3

TAP1

VDR

MMP12

PAH

MPI

DLDABO

SHBG

BCHE

NR3C1

MAP2K1 TP53

CCNB1CCND1POLH

CDK6

AR

GRIA1XIAP

SYK

HSP90AA1

RB1

GSK3B

UBE2ITERT

EIF4H

KCNH2

CAMK2BKARS FASGART

AURKA

UCK2

VCP

CDK1CCNB3

RACGAP1

CDK5CCNB2

SULT2B1

APEX1

UBE2N

POLB

CDK5R1

DYRK1A

MAPK14CA2

CDC42

PTEN

MAPK3

AKT1

(a)

MPI

hsa00620

AKR1B1

hsa00051hsa00052

SORD

hsa00500

hsa00520

hsa00561

hsa04920

hsa04070

hsa04810

hsa04270

hsa05020hsa05100

hsa04062 hsa04960

hsa04144

hsa04910


CALM3

hsa04970

hsa04340

hsa04744

GSK3B

CDK5

hsa04360

HSD17B10

hsa00250

MMP7 hsa04912

hsa00280GALK1AMY1C

GFPT1

GAAHK1hsa04142 CES2

hsa00983hsa04146

XDH hsa00830

hsa00232

AKR1C3hsa01040

CYP1A2

SULT1A1

hsa00920

GART

PDE4D

hsa00010hsa00040

AKR1A1

PIP4K2APIM1

hsa05144hsa00340

hsa04630hsa04670 hsa00360

ALOX5

hsa04150

PTGS1

MAOA

ALOX12

hsa00591

hsa00590

hsa00564

hsa05211 hsa05410

hsa04140

LAP3

DLD

hsa00565

PGD

PAFAH1B3

hsa00330

GSTP1GSTA3

GSTO1

CYP2C9

GSTA1

MAOB

hsa00982

PAHhsa00400

ALOX15

CYP1A1

CYP19A1

hsa00140

HSD17B2

HSD17B1SULT2B1

hsa00380

UCK2hsa00240

hsa00230 CYP3A4

DCK

PECRhsa00480

HPRT1

GLO1 hsa00030

NANHhsa00980

CYP1B1

GPI

PRKAA2hsa04530INSR

hsa00592

hsa04520

PLGOPRM1

PRSS1

GPR35

NR3C1ADORA3

OPRD1

OPRK1

hsa05146

hsa05014

hsa04115

hsa05340hsa04962

hsa04660

hsa05218

MAPK3

PLCG1 BTK

DRD1MAPT

TAP1

GRIA1hsa04740

RB1

hsa04010hsa00910

hsa04650 hsa04210

hsa04540

hsa00760

CD38

MME

hsa04640hsa04614

CHRM1

hsa05010 hsa04971

CDK5R1

BACE1hsa04080

hsa05222

hsa05214

hsa04310

hsa04662

hsa04720

hsa04722

hsa05130

hsa04114

hsa04664

hsa04012hsa04964hsa04666

hsa04020 hsa04621

hsa04966

hsa05110hsa04145

TUBB1ABCC4

ABCC1 hsa02010

ABCG2

ABCC2hsa04940

hsa04612hsa04914

hsa05332

hsa05330hsa05320

hsa04320

hsa04916

hsa05213

PTGS2CDKN1A KDR

hsa04622

ARhsa04110

MAPK14

CCNB1hsa04060

CDK2

MET

AKT2 EGFR

CDK4PIK3R1

ZAP70CA2

AURKA

SYK

LCKFAS

CDK6MPO

PRKCAPDK1

TP53

PLCG2

CREB1

MAP2K1

PRKACA

FGFR1

BAXAKT1

SRCMYLKGSK3A

CCND1

HRAS

IGF1R

HSP90AA1

UBE2I

NFKB2

hsa05220

NOTCH4

CAMK2B

HCKGNAO1

CDC42

CALM1

hsa00100hsa05322hsa00790

hsa00970hsa03410 hsa00601


CCNB2

ALPLUBE2N

hsa05142

ALPPL2

hsa04120

hsa05215

POLB

CCNB3

TYR

hsa00740

hsa05016

hsa04510

hsa05216 hsa04620

hsa00350

hsa04350

XIAP

NFKB1hsa04623PPARG

hsa03320

hsa05200

hsa00260

hsa04370hsa00562

hsa04730

hsa05210

hsa05221

hsa05219

hsa05212

PTPN1PLA2G1B

ARNT

hsa05120MMP2

HIF1A

PDPK1MMP9PIM2

hsa05217

PTEN

hsa05131

RXRB

HGF

hsa05140 hsa05416

(b)











Cancer

Glioma (hsa05214)a




























HGF

MET

PI3K

PKBAkt

IKK

iNOSCOX-2


MDM2

P53

Evadingapoptosis

HPH

VEGF

FGF

FGFR

PLCy

PKC

Raf

MEK

ERK

c-Jun c-Fos c-Myc

2RAC

Ets1

MMPS Cyclin D1 CDK4

Proliferation

P53 P21CDK46

Cyclin D1Rb E2F

Genomic damage

CarcinogensLigands

ARHSP

ARAR

PSA

Ligands

FXRcIAPs

TRAFs

FasL

FAS

FADD

CASP8

Bid

Mitochondrion

CytCCASP9

Apoptosis

BCL2

Bax

PPARG

RasRalGDS

Ral

RalBP1

CDC4

CDK2Cyclin E

IGF-1

IGFR

P21

EGF

EGFR

PTEN

Wnt

Frizzled

Dvl

TCFLEF

Survivin

I120581B120572

NF120581B

HIF-120572

PDGF120573TGF120573

HIF-120573

HIF-120573GSK-3120573

120573-catenin







P14ARF MDM2 P53

P21

Cyclin DCDK46

Cyclin ECDK2

G1 arrest

Cell cycle arrest

FasPIDD

DR5 CASP8


Bid

Gadd45B99

Cyclin BCdc2

G2 arrest



PI3K

GlucoseGLUT2 GK PYK

Pyruvate

ATP

Insulin resistance



DNA


NMDAR

VDCC


Calpain P35 P25

Cdk5

TauPaired helical


PSENRyR

GSK3B

Degradation

NEP

ERK12

BACE

APP


Oligomeric A120573

Amyloid 120573

Ca2+

120573-Secretase

(Tau-P)n


4 Conclusions








Acknowledgments


References






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















PRKACA

APOBEC3G

OPRD1MCL1

HCK

MMP14

BTK

PRKAA2

NOTCH4

MMP9PIK3R1PPARG

CDKN1A

KDR

IGF1RSRC

CD38

ADORA3

OPRM1

HPRT1

HIF1ANAKT2

PLCG1PRKCA

PDPK1

PDK1

PLCG2

MYLK

OPRK1

GNAO1NOX4

PECR

MET

ZAP70 PIP4K2A

PDE4D

GSK3A

PABPC1DCK

CLK1

PIM1


ALPPL2GFPT1

ANG

AKR1C3

NR1H4

ABCC1

ABCC2

AKR1A1

MAOB

CALM3

HGF

MAOA

FXR1

CYP19A1

ALOX5SULT1A1

CYP2C9

AHR

CDK2

CYP1B1

GSTP1

HIF1ACDK4

HSD17B1ALOX12

NFE2L2

BACE1

MAPT

CYP1A1

POLIGFER

BAX

RXRB

AMY1C

FKBP1AEHMT2

GSTT2BGSTO1

NFKB2SQLE

FOLH1

HSD17B2ESRRG

EGFR

TYR

GSTA3

ALPL

ELANE

LCKPLG

PTGS2

HRAS

CALM1

MMP2 MPO

CHRM1

NFKB1

MMP7

PLA2G1BPREP

LAP3

NANH

SORD

MMP13

HPGD

GALK1 PGD

HSD17B10GLO1

ABCC4

ABCG2

TUBB1

ALOX15

ESR1

CYP1A2

CYP3A4

AKR1B1

ALB

INSR

CREB1

PTGS1

ARNT

HK1

MMEPRSS1

XDH

GPIPAFAH1B3

TAP1

VDR

MMP12

PAH

MPI

DLDABO

SHBG

BCHE

NR3C1

MAP2K1 TP53

CCNB1CCND1POLH

CDK6

AR

GRIA1XIAP

SYK

HSP90AA1

RB1

GSK3B

UBE2ITERT

EIF4H

KCNH2

CAMK2BKARS FASGART

AURKA

UCK2

VCP

CDK1CCNB3

RACGAP1

CDK5CCNB2

SULT2B1

APEX1

UBE2N

POLB

CDK5R1

DYRK1A

MAPK14CA2

CDC42

PTEN

MAPK3

AKT1

(a)

MPI

hsa00620

AKR1B1

hsa00051hsa00052

SORD

hsa00500

hsa00520

hsa00561

hsa04920

hsa04070

hsa04810

hsa04270

hsa05020hsa05100

hsa04062 hsa04960

hsa04144

hsa04910


CALM3

hsa04970

hsa04340

hsa04744

GSK3B

CDK5

hsa04360

HSD17B10

hsa00250

MMP7 hsa04912

hsa00280GALK1AMY1C

GFPT1

GAAHK1hsa04142 CES2

hsa00983hsa04146

XDH hsa00830

hsa00232

AKR1C3hsa01040

CYP1A2

SULT1A1

hsa00920

GART

PDE4D

hsa00010hsa00040

AKR1A1

PIP4K2APIM1

hsa05144hsa00340

hsa04630hsa04670 hsa00360

ALOX5

hsa04150

PTGS1

MAOA

ALOX12

hsa00591

hsa00590

hsa00564

hsa05211 hsa05410

hsa04140

LAP3

DLD

hsa00565

PGD

PAFAH1B3

hsa00330

GSTP1GSTA3

GSTO1

CYP2C9

GSTA1

MAOB

hsa00982

PAHhsa00400

ALOX15

CYP1A1

CYP19A1

hsa00140

HSD17B2

HSD17B1SULT2B1

hsa00380

UCK2hsa00240

hsa00230 CYP3A4

DCK

PECRhsa00480

HPRT1

GLO1 hsa00030

NANHhsa00980

CYP1B1

GPI

PRKAA2hsa04530INSR

hsa00592

hsa04520

PLGOPRM1

PRSS1

GPR35

NR3C1ADORA3

OPRD1

OPRK1

hsa05146

hsa05014

hsa04115

hsa05340hsa04962

hsa04660

hsa05218

MAPK3

PLCG1 BTK

DRD1MAPT

TAP1

GRIA1hsa04740

RB1

hsa04010hsa00910

hsa04650 hsa04210

hsa04540

hsa00760

CD38

MME

hsa04640hsa04614

CHRM1

hsa05010 hsa04971

CDK5R1

BACE1hsa04080

hsa05222

hsa05214

hsa04310

hsa04662

hsa04720

hsa04722

hsa05130

hsa04114

hsa04664

hsa04012hsa04964hsa04666

hsa04020 hsa04621

hsa04966

hsa05110hsa04145

TUBB1ABCC4

ABCC1 hsa02010

ABCG2

ABCC2hsa04940

hsa04612hsa04914

hsa05332

hsa05330hsa05320

hsa04320

hsa04916

hsa05213

PTGS2CDKN1A KDR

hsa04622

ARhsa04110

MAPK14

CCNB1hsa04060

CDK2

MET

AKT2 EGFR

CDK4PIK3R1

ZAP70CA2

AURKA

SYK

LCKFAS

CDK6MPO

PRKCAPDK1

TP53

PLCG2

CREB1

MAP2K1

PRKACA

FGFR1

BAXAKT1

SRCMYLKGSK3A

CCND1

HRAS

IGF1R

HSP90AA1

UBE2I

NFKB2

hsa05220

NOTCH4

CAMK2B

HCKGNAO1

CDC42

CALM1

hsa00100hsa05322hsa00790

hsa00970hsa03410 hsa00601


CCNB2

ALPLUBE2N

hsa05142

ALPPL2

hsa04120

hsa05215

POLB

CCNB3

TYR

hsa00740

hsa05016

hsa04510

hsa05216 hsa04620

hsa00350

hsa04350

XIAP

NFKB1hsa04623PPARG

hsa03320

hsa05200

hsa00260

hsa04370hsa00562

hsa04730

hsa05210

hsa05221

hsa05219

hsa05212

PTPN1PLA2G1B

ARNT

hsa05120MMP2

HIF1A

PDPK1MMP9PIM2

hsa05217

PTEN

hsa05131

RXRB

HGF

hsa05140 hsa05416

(b)











Cancer

Glioma (hsa05214)a




























HGF

MET

PI3K

PKBAkt

IKK

iNOSCOX-2


MDM2

P53

Evadingapoptosis

HPH

VEGF

FGF

FGFR

PLCy

PKC

Raf

MEK

ERK

c-Jun c-Fos c-Myc

2RAC

Ets1

MMPS Cyclin D1 CDK4

Proliferation

P53 P21CDK46

Cyclin D1Rb E2F

Genomic damage

CarcinogensLigands

ARHSP

ARAR

PSA

Ligands

FXRcIAPs

TRAFs

FasL

FAS

FADD

CASP8

Bid

Mitochondrion

CytCCASP9

Apoptosis

BCL2

Bax

PPARG

RasRalGDS

Ral

RalBP1

CDC4

CDK2Cyclin E

IGF-1

IGFR

P21

EGF

EGFR

PTEN

Wnt

Frizzled

Dvl

TCFLEF

Survivin

I120581B120572

NF120581B

HIF-120572

PDGF120573TGF120573

HIF-120573

HIF-120573GSK-3120573

120573-catenin







P14ARF MDM2 P53

P21

Cyclin DCDK46

Cyclin ECDK2

G1 arrest

Cell cycle arrest

FasPIDD

DR5 CASP8


Bid

Gadd45B99

Cyclin BCdc2

G2 arrest



PI3K

GlucoseGLUT2 GK PYK

Pyruvate

ATP

Insulin resistance



DNA


NMDAR

VDCC


Calpain P35 P25

Cdk5

TauPaired helical


PSENRyR

GSK3B

Degradation

NEP

ERK12

BACE

APP


Oligomeric A120573

Amyloid 120573

Ca2+

120573-Secretase

(Tau-P)n


4 Conclusions








Acknowledgments


References






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























Cancer

Glioma (hsa05214)a




























HGF

MET

PI3K

PKBAkt

IKK

iNOSCOX-2


MDM2

P53

Evadingapoptosis

HPH

VEGF

FGF

FGFR

PLCy

PKC

Raf

MEK

ERK

c-Jun c-Fos c-Myc

2RAC

Ets1

MMPS Cyclin D1 CDK4

Proliferation

P53 P21CDK46

Cyclin D1Rb E2F

Genomic damage

CarcinogensLigands

ARHSP

ARAR

PSA

Ligands

FXRcIAPs

TRAFs

FasL

FAS

FADD

CASP8

Bid

Mitochondrion

CytCCASP9

Apoptosis

BCL2

Bax

PPARG

RasRalGDS

Ral

RalBP1

CDC4

CDK2Cyclin E

IGF-1

IGFR

P21

EGF

EGFR

PTEN

Wnt

Frizzled

Dvl

TCFLEF

Survivin

I120581B120572

NF120581B

HIF-120572

PDGF120573TGF120573

HIF-120573

HIF-120573GSK-3120573

120573-catenin







P14ARF MDM2 P53

P21

Cyclin DCDK46

Cyclin ECDK2

G1 arrest

Cell cycle arrest

FasPIDD

DR5 CASP8


Bid

Gadd45B99

Cyclin BCdc2

G2 arrest



PI3K

GlucoseGLUT2 GK PYK

Pyruvate

ATP

Insulin resistance



DNA


NMDAR

VDCC


Calpain P35 P25

Cdk5

TauPaired helical


PSENRyR

GSK3B

Degradation

NEP

ERK12

BACE

APP


Oligomeric A120573

Amyloid 120573

Ca2+

120573-Secretase

(Tau-P)n


4 Conclusions








Acknowledgments


References






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















HGF

MET

PI3K

PKBAkt

IKK

iNOSCOX-2


MDM2

P53

Evadingapoptosis

HPH

VEGF

FGF

FGFR

PLCy

PKC

Raf

MEK

ERK

c-Jun c-Fos c-Myc

2RAC

Ets1

MMPS Cyclin D1 CDK4

Proliferation

P53 P21CDK46

Cyclin D1Rb E2F

Genomic damage

CarcinogensLigands

ARHSP

ARAR

PSA

Ligands

FXRcIAPs

TRAFs

FasL

FAS

FADD

CASP8

Bid

Mitochondrion

CytCCASP9

Apoptosis

BCL2

Bax

PPARG

RasRalGDS

Ral

RalBP1

CDC4

CDK2Cyclin E

IGF-1

IGFR

P21

EGF

EGFR

PTEN

Wnt

Frizzled

Dvl

TCFLEF

Survivin

I120581B120572

NF120581B

HIF-120572

PDGF120573TGF120573

HIF-120573

HIF-120573GSK-3120573

120573-catenin







P14ARF MDM2 P53

P21

Cyclin DCDK46

Cyclin ECDK2

G1 arrest

Cell cycle arrest

FasPIDD

DR5 CASP8


Bid

Gadd45B99

Cyclin BCdc2

G2 arrest



PI3K

GlucoseGLUT2 GK PYK

Pyruvate

ATP

Insulin resistance



DNA


NMDAR

VDCC


Calpain P35 P25

Cdk5

TauPaired helical


PSENRyR

GSK3B

Degradation

NEP

ERK12

BACE

APP


Oligomeric A120573

Amyloid 120573

Ca2+

120573-Secretase

(Tau-P)n


4 Conclusions








Acknowledgments


References






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















P14ARF MDM2 P53

P21

Cyclin DCDK46

Cyclin ECDK2

G1 arrest

Cell cycle arrest

FasPIDD

DR5 CASP8


Bid

Gadd45B99

Cyclin BCdc2

G2 arrest



PI3K

GlucoseGLUT2 GK PYK

Pyruvate

ATP

Insulin resistance



DNA


NMDAR

VDCC


Calpain P35 P25

Cdk5

TauPaired helical


PSENRyR

GSK3B

Degradation

NEP

ERK12

BACE

APP


Oligomeric A120573

Amyloid 120573

Ca2+

120573-Secretase

(Tau-P)n


4 Conclusions








Acknowledgments


References






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Acknowledgments


References






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article systematic analysis of the multiple...

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