EnhancingandComplementaryMechanismsofSynergistic ... · 2020. 6. 25. · CR5 EIC OH O H H H H 41.9...

Research ArticleEnhancing and Complementary Mechanisms of SynergisticAction of Acori Tatarinowii Rhizoma and Codonopsis Radix forAlzheimerrsquos Disease Based on Systems Pharmacology

Shengwei Liu 12 Cui He1 Yuan Liao3 Hailin Liu24 Wanli Mao5 and Zhengze Shen 1

1Department of Pharmacy Yongchuan Hospital of Chongqing Medical University Chongqing 402160 China2Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology School of Pharmacy Chongqing Medical UniversityChongqing 400016 China3Zhejiang Key Laboratory of Organ Development and Regeneration College of Life and Environmental SciencesHangzhou Normal University Hangzhou Zhejiang 310018 China4Department of Pharmacy First Peoplersquos Hospital of Chongqing Liangjiang New District Chongqing 401121 China55e Peoplersquos Hospital of Yongchuan District Chongqing 402160 China

Correspondence should be addressed to Zhengze Shen shenpharm163com

Received 10 January 2020 Revised 20 May 2020 Accepted 1 June 2020 Published 25 June 2020

Academic Editor Francesca Mancianti

Copyright copy 2020 Shengwei Liu et al is 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

Background and Aim Alzheimerrsquos disease (AD) is a common neurological disorder worldwide In traditional Chinese medicine(TCM) Acori Tatarinowii Rhizoma (ATR) and Codonopsis Radix (CR) are common herbs used to treat AD However due to themany active ingredients and targets in these herbs it is difficult to clarify the synergistic mechanism of ATR and CR To reveal themulticomponent synergistic mechanism of ATR and CR in Alzheimerrsquos disease we analyzed important components drug targetsand crucial pathways using a systems pharmacology strategyMaterials andMethods In this study a systems pharmacology-basedstrategy was used to elucidate the synergistic mechanism of Acori Tatarinowii Rhizoma and Codonopsis Radix for the treatment ofAD is novel systems pharmacology model consisted of component information pharmacokinetic analysis and pharma-cological data Additionally the related pathways were compressed using the Kyoto Encyclopedia of Genes and Genomes (KEGG)database and the organ distributions were determined in the BioGPS bank Results Sixty-eight active ingredients with suitablepharmacokinetic profiles and biological activities were selected through ADME screening in silico Based on 62 AD-related targetssuch as APP CHRM1 and PTGS1 systematic analysis showed that these two herbs were mainly involved in the PI3K-Aktsignaling pathway MAPK signaling pathway neuroactive ligand-receptor interaction and fluid shear stress and atherosclerosisindicating that they had a synergistic effect on AD However ATR acted on the KDR gene while CR acted on IGF1R MET IL1Band CHUK showing that they also had complementary effects on AD e ingredient contribution score involved 29 ingredientscontributing 9014 of the total contribution score of this formula for AD treatment which emphasized that the effectivetherapeutic effects of these herbs for AD were derived from both ATR and CR not a single herb Organ distribution showed thatthe targets of the active ingredients were mainly located in the whole blood the brain and the muscle which are associated withAD Conclusions In sum our findings suggest that the systems pharmacology methods successfully revealed the synergistic andcomplementary mechanisms of ATR and CR for the treatment of AD

1 Introduction

More than 25 million people suffer from dementia world-wide and Alzheimerrsquos disease (AD) accounts for approxi-mately 70 of patients with dementia [1ndash3] AD is aprogressive neurodegenerative disorder caused by extensive

synapse loss the formation of intracellular neurofibrillarytangles extracellular deposits of β-amyloid peptides (Aβ)inflammation and oxidative stress in neurons [4ndash6] Clinicaldata also showed that cerebral vascular diseases especiallyatherosclerosis are established risk factors for dementiaparticularly AD [7 8] All this evidence suggests that the

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2020 Article ID 6317230 26 pageshttpsdoiorg10115520206317230

clinical features of AD are diverse and that the pathologicalfactors are complicated erefore current pharmacologyfocusing on acetylcholine esterase inhibitors and an N-methyl-D-aspartic acid receptor (NMDAR) modulator isunsatisfactory for ameliorating the symptoms of AD [9] Forexample donepezil the most effective drug for the treatmentof AD can only temporarily relieve the symptoms andcannot inhibit the progression of AD [10] Development ofLY450139 which has been investigated in a phase III trial ofanti-Aβ drug candidates has been halted due to its inhi-bition of the NOTCH protein even though it can signifi-cantly reduce Aβ levels in patients [5] Currently approveddrugs for the treatment of AD such as rivastigmine andmemantine result in various side effects such as bradycardiaor hepatotoxicity [11ndash13] Hence it is critical to exploremore systemic effective and harmless anti-AD agents

Traditional Chinese medicine (TCM) has a long historyin the treatment of dementia [3 14] For example Kai-Xin-San the representative prescription written by Sun Simiao inBeiji Qianjin Yaofang during the Tang Dynasty is a TCMformula with antidementia effects [15] Modern pharma-cological research also verified that active ingredientsextracted from Chinese herbs such as apigenin β-asaroneand huperzine A exert curative effects against AD in vivoand in vitro indeed some of them have been used in clinicaltrials [15] Notably Acori Tatarinowii Rhizoma (ATR therhizome of A calamus also named Acorus calamus varangustatus Shi Chang Pu in Chinese) is widely used to treatmemory and cognitive dysfunction due to its anti-inflam-matory antifibrillar amyloid plaque and anti-tau phos-phorylation activities [16ndash19] In TCM Codonopsis Radix(CR the roots of C pilosula also named Codonopsis pilosula(Franch) Nannf Dang Shen in Chinese) functions byreinforcing qi (vital energy) improving the immune systemand reducing blood pressure and also has an antidiabeticeffect by reducing the blood glucose level and inhibitingreactive oxygen species (ROS)-induced damage [20 21]Injection of CR has neuroprotective effects based onblockade of brain Ca2+ accumulation and improvement insuperoxide dismutase activity [22] For enhanced efficiencyCR is usually combined with ATR such as Tiaoxin Recipe[23] and Shen-Zhi-Ling oral liquid [24] and it is known as amonarch minister assistant and guide in TCM Howeverconsidering the complexity of traditional experimentalmethods it is difficult to explore the detailed synergisticmechanism of ATR and CR

A single formula of TCM usually comprises many herbsand exerts its curative effect by additive and complementaryeffects of multiple herbs [25] erefore treating AD withTCM shows the following advantages (1) TCM includesmultiple active ingredients that may activate various kinds ofbiological targets and pathways to provide synergistic andoradditive effects to benefit patients with AD (2) TCM isderived from natural products so it may have low toxicityand few side effects [26] However owing to themultiple andcomplex characteristics of these formulas their exactmechanisms of action are still unclear and difficult to de-termine by traditional experimental assays For example thefamous formula Shi-Quan-Da-Bu-Tang in TCM improves

the intestinal immune system but its ten single herbs showno such activity indicating certain synergistic effects amongmultiple herbs [25] is result again demonstrated that it isdifficult to explore the mechanisms of action of TCM Inrecent years based on chemical pharmacokinetic andpharmacological data the methodology of systems phar-macology has helped us to interpret the details of thesynergistic mechanisms in Chinese formulas [27ndash29] Sys-tems pharmacology integrates pharmacokinetics synthesisdata target screening pathway interaction and networkanalysis to elucidate the therapeutic mechanisms of drugsfrom the molecular and cellular levels to the tissueand organism levels [26 30] Following a systems phar-macology-based strategy many reports explain the poly-pharmacological and synergistic mechanisms and predictthe principal ingredients and signaling pathways of herbpairs for various diseases [31ndash34] Using this model Lu et alrevealed that Huangqi and Huanglian exert synergistictherapeutic effects on diabetes mellitus based on five pivotalingredients [35] Zhi-Zhu-Wan has efficacious therapeuticeffects on functional dyspepsia due to 29 major activecomponents [16] Based on systems pharmacology the in-gredients from the herb Cistanche tubulosa show synergisticeffects on neuroinflammation [36] and the compoundsrutin and amentoflavone exert synergistic effects on relievingdepression [37]

Consequently we constructed a systems pharmacologymodel to explore the therapeutic mechanism of ATR and CRfor treating AD First the active ingredients selected fromthe database were screened by two ADME parameters toensure comprehensiveness Second a large-scale analysis oftargets was performed by target identification to establish thenetwork Finally network construction including com-pound-target (C-T) target-pathway (T-P) and compound-target-organ (C-T-O) networks was applied to reveal theunderlying mechanism of the combination of ATR and CRon AD in our study (Figure 1)

2 Materials and Methods

21 Chemical Ingredients Database Construction All of theconstituent data of ATR and CR were retrieved from theTCM Systems Pharmacology Database and Analysis Plat-form (TCMSP httplspnwueducn) [38] Subsequentlythe initial structures of all ingredients were depicted in TIFformat using ChemDraw (version 160) Additionally thepharmacology-related properties including oral bioavail-ability (OB) drug-likeness (DL) molecular weight (MW)octanol-water partition coefficient predicted by ACDPhysChem Suite (AlogP) number of acceptor atoms forH-bonds (nHAcc) and number of donor atoms for H-bonds(nHDon) were obtained from TCMSP

22 Active Ingredient Screening by ADME An early phar-macokinetic evaluation is important due to the failurescaused by limited pharmacokinetic profiles in modern drugdiscovery [39] However identifying the pharmacokineticproperties by traditional biological experiments is expensive

2 Evidence-Based Complementary and Alternative Medicine

and time-consuming and in silico methods are efficientstrategies for subsequent analysis [36 40] In our currentstudy to identify the active ingredients we used OB and DLas criteria to select components of ATR and CR

e OB is the key factor for evaluating the ability ofdrugs to deliver the compound to the systemic circulation byoral administration Based on 805 structurally definedWestern drugs and drug-like molecules a novel in silicosystem OBioavail 11 was used to calculate the OB values ofall ingredients [41] and those ingredients with OBge 30were preserved for further analysis

e values of the DL evaluation approach based on theTanimoto coefficient were calculated using the followingequation T(A B) ((A times B)(|A|2 + |B|2 minus A times B)) In thisequation A represents the molecular descriptors of herbalcompounds and B displays the average molecular propertiesof all compounds in DrugBank [42] Although DLge 018 wasa common criterion for ADME screening [43] the numberof ingredients of ATR with DLge 018 andOBge 30was onlyfourus to obtain more details and information about thetwo herbs those ingredients with suitable DLge 010 wereselected as candidates for active ingredients as in a previousstudy [21 44] Additionally some ingredients with a low OBor DL were supplemented because of their high bioactivityand enrichment through a text-mining method

23 Target Collection Based on the performance of severalapproaches integrated with chemometrics methods messagecollection and data mining the related targets of the activeingredients of ATR and CR were searched First the targets

of active ingredients were obtained from TCMSP Secondthe active ingredients were submitted to various serversviz BindingDB database (httpwwwbindingdborgbindindexjsp) [45] and STITCH (httpstitchemblde) [46]Finally the targets obtained from the databases were input toUniProt (httpwwwuniprotorg) to standardize the namesof the targets

en for further elucidation of the role of ATR and CRin AD treatment targets of AD were obtained from variousservers viz erapeutic Target Database (TTD httpbiddnusedusggroupcjttd) [47] Comparative ToxicogenomicsDatabase (CTD httpctdbaseorg) [48] Online MendelianInheritance in Man database (OMIM httpwwwomimorg) PharmGKB (httpwwwpharmgkborg) [49] andDrugBank (httpswwwdrugbankca) [50] Finally thecommon targets of ATR and AD or CR and AD were se-lected for further analysis Importantly all targets kept forfurther analysis were only derived from Homo sapiens

24 Gene Ontology (GO) Analysis and Network ConstructionTo better decipher the function of the identified targets weperformed GO enrichment analysis for the 62 target proteinsby Clue GO a widely used Cytoscape plugin [51] e P

values were corrected with a Bonferroni step-down methoden for elucidation of the underlying molecular

mechanism of action of ATR and CR three correspondingnetworks were constructed (1) A compound-target network(C-T network) was constructed to identify the key targetsbased on the active ingredients of ATR and CR and theircorresponding targets (2) A target-pathway network (T-P

Synergistic mechanisms

Synergistic mechanisms of ATR and CR for AD

GO analysis CS calculation

C-T networkIntegrated pathway

T-P network C-T-O network

CR ATR

AD

ME

scre

enin

g

OB DL

TCM

SP

sear

chin

g

Target fishing

Target identification

Active ingredients

AD-related targets

Figure 1 e complete framework of the systems pharmacology approach

Evidence-Based Complementary and Alternative Medicine 3

network) was built by determining the relationship betweentargets and pathways that were extracted fromKEGG (KyotoEncyclopedia of Genes and Genomes httpwwwkeggjp)P values were set at 005 as the cut-off criterion (3) erelated targets and their tissue types were used in thecompound-target-organ network (C-T-O network) etarget organ location was determined in the BioGPS bank(httpbiogpsorg) [52] All visualized networks were con-structed by the open software Cytoscape 370 (httpwwwcytoscapeorg) [53]

25 Contribution Score Calculation For further elucidationof the role of each active ingredient of ATR and CR on ADtreatment a contribution score based on the degree listed byCytoscape 370 was calculated by the following equation[16]

Aij ωei +CAi + CBi

CAi minus CBi

11138681113868111386811138681113868111386811138681113868

11138681113868111386811138681113868111386811138681113868

ωei Cedge

Tedge

CS(i) 1113944n

ij

Ci times Aij times Pj1113960 1113961

(1)

where i and j represent the number of components andproteins respectively C is the degree of each componentand P is the degree of each protein CAi represents the degreeof each component only in the CR C-T network and CBirepresents the degree of each ingredient only in the ATRC-Tnetwork ωei is the ratio of the degree of each ingredient to allingredients Aij is the index of affinity determined from theωei value All degrees in this equation are calculated byCytoscape 370 e contribution score (CS) represents thenetwork contribution of one ingredient and its effectivenessin AD

3 Results

31 Differences between ATR and CR A total of 239 in-gredients were retrieved in ATR (105) and CR (134) based onsearching in a series of public databases Lignans and volatileoil were the major components in ATR whereas polysac-charides and volatile oil were the major components in CRMore details about these ingredients are listed in Table S1

To explore the molecular differences between ATR andCR we compared six parameters of these components MWAlogP nHDon nHAcc OB and DL As shown in Figure 2the values of these components mainly followed Lipinskirsquosrule of five [54] (1) For MW the average value of thecomponents in ATR (22744) was significantly lower thanthat in CR (31617) (P 358E minus 06) (2)e AlogP values ofATR and CRwere 299 and 396 respectively demonstratingthat both components of these two herbs were hydrotropic(3) For nHDon and nHAcc the ATR values (099 and 242)were all significantly lower than those in CR (175 and 384)(P 616E minus 03 410E minus 03) (4) For OB unlike the values

mentioned above ATR possessed a higher average OB value(3797) than CR (2798) (P 435E minus 05) indicating thatATR had better pharmacokinetic properties (5) For DL theDL value of ATR (0147) was significantly lower than that ofCR (0289) (P 180E minus 05)

In summary these data showed a variation between theingredients of ATR and CR because of their distinctchemicophysical properties Our results suggested that ATRshowed better pharmacokinetic properties but the ingre-dients in CR had a better DL ese two herbs containeddifferent main ingredients which may explain why ATR andCR could produce synergistic and complementary effects

32 Identification of Active Ingredients in ATR and CRe TCM formula usually contains multiple ingredients butseveral of them possess unsatisfactory pharmacodynamicand pharmacokinetic properties influencing the therapeuticresponses [55] erefore it is essential to identify thecomponents with favorable properties and ADMEscreening is a useful way to select suitable ingredients fromherbs or TCM formulas that have many components In ourcurrent work we employed two major ADME parameters tofilter the active ingredients from ATR and CR As a result atotal of 68 active ingredients from the 239 ingredients werechosen for further analysis (Table 1)

33 Active Ingredients from ATR irty-three active ingre-dients were selected from ATR through strict ADMEscreening rules and most of them showed ideal biologicalactivities For instance kaempferol (OB 4188 DL 02)attenuates oxidative stress by regulating Bcl-2 in neuronal cells[56] Marmesin (OB 5028 DL 018) forms hydrogenbonds with paraoxonase to reduce nitric oxide levels to protectrats against myocardial infarction [57] Cycloartenol(OB 3869 DL 078) can reduce oxidase activity [58]Majudin (OB 4221 DL 013) inhibits cholinesterase to

200300400500600

20

40

60

80

Val

ue

02468

10

OB ()nHDon nHAccAlogPMW DL

CRATR

lowast

lowast

lowast

lowast

lowast

lowast

Figure 2 e molecular variation of all ingredients in ATR andCR lowastPlt 001 by two tailed t-test (vs CR)


Table 1 Information on the active ingredients in ATR and CR

ID Molecule name Structure OB() DL

CR1 Poriferasta-722E-dien-3beta-ol HH

H

HHO

H

H

4298 076

CR2 2-methoxyfuranodiene

OO

5358 013

CR5 EIC

OH

O

H

HH

H

419 014

CR14 Methyl linoleate

O

O

H

HH

H

4193 017

CR16 (+minus)-Isoborneol

OH

H

8698 005

CR21 Perlolyrine HN

N

O

OH

6595 027

CR28 DIOP

O

O O O4359 039


Table 1 Continued


CR32 ZINC03978781

HOH

H

HH H

H

4383 076

CR37 Stigmasterol

HOHH

HH H

H

4383 076

CR38 Syringin

OH

OH

OH

HO

HO

HH

O O

O O1464 032

CR43 Tectorigenin

OHOH

O

O

O

HO

2841 027

CR45 7-Methoxy-2-methyl isoflavone

O

O

O

4256 02

CR48 Spinasterol

HOH

HH H

H

H

4298 076

CR49 Atractylenolide II

H

O

O

H

475 015

CR52 Atractylenolide III

H

H OH

O

O 6811 017


Table 1 Continued


CR61 Frutinone A

O

OO

O

659 034

CR63 Luteolin O

O

OH

OH

OH

HO

3616 025

CR67 Taraxerol

H

H

HO

H 384 077

CR69 Stigmast-7-enol

HOH

HH

H

3742 075

CR70 Norharman

NHN

1888 008

CR73 3-Beta-hydroxymethyllenetanshiquinone

O

O

O

HO

3216 041

CR75 HMFHO

O

O4507 002

CR76 Methyl icosa-1114-dienoateH H

H H OO 3967 023


Table 1 Continued


CR77 ApigeninO

O

OH

OH

HO

2306 021

CR81 (1R)-2349-Tetrahydro-1H-pyrido[34-b]indol-2-ium-1-carboxylate

NH2+

Ondash

OHN

529 013

CR97 5-Alpha-stigmastan-36-dione

OO

3312 079

CR99 7-(Beta-xylosyl)cephalomannine_qt

O

HN

HO

OH

HOO

OO

OO

O

O

O

O3833 029

CR101 Codonopsine

O

O

OH

OHHN

4583 013

CR103 DaturilinO O

O

O

5037 077

CR106 Glycitein

HO

OH

O

O

O 5048 024


Table 1 Continued


CR112 Spinoside A

HO

HO OH

OH

O

OO

O O

O

O

3997 04

CR113(8S9S10R13R14S17R)-17-[(E2R5S)-5-ethyl-6-methylhept-3-en-

2-yl]-1013-dimethyl-124789111214151617-dodecahydrocyclopenta[a]phenanthren-3-one

HO

H

HH

H

H 454 076

CR117 11-Hydroxyrankinidine

O

O

O

HN

N

40 066

CR123 Ethyl-β-D-fructofuranoside O

OO

OO

O

3384 015

CR130 Furanodiene O 4511 01

CR132 (+)-Beta-pinene 4477 005


Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004

ATR6 (minus)-Alloaromadendrene

HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013

ATR23 (minus)-Caryophyllene oxide

O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006

ATR30 beta-Gurjunene

H

HH

H5136 01

ATR35 beta-Cubebene 3281 011

ATR40 2prime-01Methylisoliquiritigenin

H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01

ATR53 (+)-alpha-Longipinene 5747 012


Table 1 Continued


ATR54 8-Isopentenyl-kaempferol O

O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued


ATR73 Isocalamendiol

OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015

ATR79 Murolan-39(11)-diene-10-peroxy

OOH

3672 011

ATR81 Patchoulene 4906 011

ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01

ATR88 α-Panasinsene

H

5677 012


increase acetylcholine and butyrylcholine levels [59] Sur-prisingly asarones accounting for more than 90 of ATR oilhave low DL values [60] However β-asarone (OB 3561DL 006) and azaron (OB 3889 DL 006) could promoteneuronal differentiation and reduce intracellular reactive oxy-gen species accumulation [18 60] P-coumaric acid (OB 4329DL 004) can relieve the neuroinflammatory responses in-duced by amyloid-beta peptide [61] Vanillic acid exhibitsmarked antioxidant properties [62] P-MCA (p-methoxycin-namic acid OB 31 DL 005) exerts antihyperglycemic [63]and neuroprotective effects [64] Bisasaricin (OB 2894DL 05) exhibits antibacterial and anti-inflammatory activity[65] Above all a total of 33 active ingredients including somementioned above were preserved for the active ingredients ofATR

34 Active Ingredients from CR Among the 134 ingredientsin CR 36 ingredients were selected by ADME screening EIC(linoleic acid OB 4190 DL 014) could reduce the de-velopment of atherosclerosis having a strong associationwith AD and vascular dementia due to its antioxidant andanti-inflammatory effects [66 67] Stigmasterol (OB 4383DL 076) has beneficial effects on vascular function byimproving the lipoprotein profile [68] DIOP (OB 4359DL 039) exhibits anti-inflammatory activity based on itscholinesterase inhibitory activity [51] Evidence proves thatsyringin (OB 1464 DL 032) is an efficient treatment forAD [69] Luteolin (OB 3616 DL 025) depresses theproliferation and migration of vascular smooth muscle cellsto prevent atherosclerosis [70] Hydroxymethylfurfural(HMF OB 4507 DL 002) and apigenin (OB 2306

Table 1 Continued


ATR89 (1R3aS4R6aS)-14-bis(34-dimethoxyphenyl)-133a466a-hexahydrofuro[43-c]furan

OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024

ATR98 (minus)-alpha-Cedrene 5556 01

ATR102 p-Coumaric acid

OH

OH

HH

O

4329 004


Table 2 Information on AD-related targets

Gene Target name UniProt IDABCA1 ATP-binding cassette subfamily A member 1 O95477ABCB1 Multidrug resistance protein 1 P08183ACHE Acetylcholinesterase P22303ADH1C Alcohol dehydrogenase 1C P00326ADRA2C Alpha-2C adrenergic receptor P18825ADRB2 Beta-2 adrenergic receptor P07550AHR Aryl hydrocarbon receptor P35869ALOX5 Arachidonate 5-lipoxygenase P09917APP Amyloid beta A4 protein P05067BACE1 Beta-secretase 1 P56817BAX Apoptosis regulator BAX Q07812BCHE Cholinesterase P06276BCL2 Apoptosis regulator Bcl-2 P10415CALM1 Calmodulin P0DP23CASP3 Caspase-3 P42574CASP7 Caspase-7 P55210CDK5 Cyclin-dependent kinase 5 (CDK5) Q00535CHRM1 Muscarinic acetylcholine receptor M1 P11229CHRM2 Muscarinic acetylcholine receptor M2 P08172CHRM3 Muscarinic acetylcholine receptor M3 P20309CHRNA2 Neuronal acetylcholine receptor subunit alpha-2 Q15822CHRNA7 Neuronal acetylcholine receptor protein alpha-7 chain P36544CHUK Inhibitor of NF-kappa-B kinase (IKK) O15111CYP1A2 Cytochrome P450 1A2 P05177CYP2A6 Cytochrome P450 2A6 P11509CYP2D6 Cytochrome P450 2D6 (2D6) P10635CYP3A4 Cytochrome P450 3A4 P08684DIO1 Type I iodothyronine deiodinase P49895ESR1 Estrogen receptor P03372F2 rombin P00734F7 Coagulation factor VII P08709FLT3 Tyrosine-protein kinase receptor FLT3 P36888GABRA1 Gamma-aminobutyric acid receptor subunit alpha-1 P14867GABRA2 Gamma-aminobutyric-acid receptor alpha-2 subunit P47869GABRA5 Gamma-aminobutyric-acid receptor alpha-5 subunit P31644GSK3B Glycogen synthase kinase-3 beta P49841HMOX1 Heme oxygenase 1 P09601HTR2A 5-Hydroxytryptamine 2A receptor P28223IGF1R Insulin-like growth factor 1 receptor P08069IKBKB Inhibitor of nuclear factor kappa-B kinase subunit beta O14920IL10 Interleukin-10 P22301IL1B Interleukin-1 beta P01584INS Insulin P01308INSR Insulin receptor P06213KDR Vascular endothelial growth factor receptor 2 P35968MAOA Amine oxidase [flavin-containing] A P21397MAOB Amine oxidase [flavin-containing] B P27338MAPK10 Mitogen-activated protein kinase 10 P53779MET Hepatocyte growth factor receptor P08581NOS3 Nitric-oxide synthase endothelial P29474NR1I2 Nuclear receptor subfamily 1 group I member 2 O75469PLAU Urokinase-type plasminogen activator P00749PPARG Peroxisome proliferator activated receptor gamma P37231PTGES Prostaglandin E synthase O14684PTGS1 Prostaglandin GH synthase 1 P23219PTGS2 Prostaglandin GH synthase 2 P35354RXRA Retinoic acid receptor RXR-alpha P19793RXRG Retinoic acid receptor RXR-gamma P48443SLC2A4 Solute carrier family 2 facilitated glucose transporter member 4 P14672SOAT1 Acyl-cholesterol acyltransferase 1 P35610TNF Tumor necrosis factor P01375VEGFA Vascular endothelial growth factor A P15692


DL 021) were shared by two herbs HMF was selectedbecause of its therapeutic effect on AD and it providedeffective protection against cognitive impairment via theactivation of NMDA receptor signaling [71] Oral treatmentwith apigenin plays an important role in the neuroprotectiveeffects by relieving Aβ deposition and improving anti-oxidative activity [72] All these components are listed aspotential active ingredients for CR and the details of the 68ingredients of the two herbs are shown in Table 1

35TargetProteinsofATRandCR Identifying the targets ofcandidate ingredients based on experimental approaches iscomplex and time-consuming Recently an integrated insilico approach was used to identify the correspondingtargets for the active ingredients of ATR and CR In ourstudy predictive models including TCMSP SEA andSTITCH were used to search for the targets of ATR andCR and 218 and 229 proteins were identified as targets ofATR and CR respectively (Figure S1) Next these targetswere sent to TTD CTD OMIM DrugBank andPharmGKB to determine whether they were related to ADIn total for ATR and CR by target fishing 53 out of 68active ingredients (15 active ingredients have no AD-re-lated targets) were valid for binding with 62 AD-relatedtarget proteins and the details of 62 AD-related targets arelisted in Table 2

In ATR 52 AD-related target proteins were validated tobind with 30 active ingredients For example the majorityof ingredients in ATR such as ATR6 ATR19 ATR30ATR54 and ATR93 exhibited strong activation of theneurotransmitter receptors CHRM1 CHRM2 CHRM2GABRA1 and GABRA2 modulating neurotransmissiondysfunction in the AD brain [73 74] Intriguingly ATR93also interacted with CYP1A2 and CYP3A which are majordrug-metabolizing enzymes and can prevent cholinergicsymptoms such as nausea and vomiting in patients with AD[75 76] Furthermore three active ingredients ATR3ATR15 and ATR102 were shown to interact with MAOAMAOB and NOS3 which are related to inflammation andplay a role in the pathogenesis and symptoms of mentaldisorders [77 78]

In CR 52 AD-related target proteins were validated tobind with 25 active ingredients including ACHE APPBCHE BCL2 BAX CASP3 and CASP7 and are implicatedin cell apoptosis and vascular and nervous system diseasesFor instance ACHE and BCHE are the major therapeutictargets of AD that improve β-amyloid plaques and cho-linergic function in AD patients [79 80] Remarkablyluteolin (CR63) and glycitein (CR106) interact with APPthe central pathological target of AD [81] Indeed luteolincan prevent the formation of β-amyloid protein byinhibiting ppGalNAc-T activity [82] Glycitein can alsosuppress β-amyloid deposition and has antioxidative ac-tivity [83] Additionally our results found that the apo-ptosis-related genes BCL2 BAX CASP3 and CASP7associated with AD were potential targets of CR63 andCR77 [84 85] All these findings may explain why CR cantreat AD with ATR

36 Synergistic Mechanisms of ATR and CR

361 GO Enrichment Analysis for Targets To clarify thesynergistic mechanism of ATR and CR we performed GOenrichment analysis on Clue Go In Figure 3 the top 10significantly enriched terms are ranked in the biologicalprocess (BP) molecular function (MF) and cellular com-ponent (CC) categories (Plt 005 P values are correctedusing the BenjaminindashHochberg procedure) including reg-ulation of neurotransmitter levels reactive oxygen speciesbiosynthesis and regulation of blood vessel diameter in thepre- and prosynaptic membrane nuclear envelope lumenand plasma membrane to exert anti-AD potential Partic-ularly the neurotransmitter imbalance caused by dysfunc-tion of cholinergic neurons contributed to the cognitivedeficits associated with AD [86 87] Studies have demon-strated that the degeneration of cholinergic neurons givesrise to memory loss in AD patients [88] In the early stage ofAD the generation of reactive oxygen species is theprominent feature [89] Oxidative stress is reported to beinvolved in the disruption of Aβ clearance in the brainwhich contributes to the accumulation of Aβ [90] Abnormalblood vessel diameters reduce blood flow and lead to aninadequate blood supply in the cortex [91 92] Undoubtedlythese BP terms are all closely associated with AD For in-stance synaptic dysfunction caused by disruption of neu-rotransmitter transmission and increased formation ofreactive oxygen species in neural cells are the main path-ogenic mechanisms of AD [93 94] Additionally the lowercerebral blood flow caused by blood vessel size is a major riskfactor for AD [95] e results of GO enrichment analysisindicated that the combination of ATR and CR treats ADmainly by neuroprotective antioxidative and antiathero-sclerotic effects

362 Compound-Target Network Analysis In Figure 4 53active ingredients and 62 AD-related targets were used toconstruct the C-T network ere were 373 component-target associations between 53 active ingredients and 62 AD-related targets e average number of targets per ingredientwas 60 and the mean degree of ingredients per target was70 indicating complicated and complementary relation-ships between ingredients and targets In total more thanhalf of the targets (677) such as ACHE BAX BCL2GABRA1 NOS3 and PTGS1 were synergistically regulatedby various components of ATR and CR However severaltargets (323) such as APP CYP1A2 IL10 MAPK10 andVEGFA were regulated by each ingredient of ATR and CRHowever this Chinese formula focused on the targets as-sociated with AD such as neurotransmitter release andinteraction between neuroactive ligands and receptors(ADRA2C APP CASP3 CHRM1 CHRNA7 GABRA1 andCYP2D6) It also modulated other targets involved in thepathogenesis of AD including oxidative stress atheroscle-rosis and inflammation (BCL2 IKBKB MAPK10 NOS3TNF PTGS2 and GSK3B) As shown in Figure 4 kaemp-ferol (degree 33) has the highest degree followedby apigenin (degree 30) stigmasterol (degree 16) 7-


methoxy-2-methyl isoflavone (degree 16) luteolin(degree 15) and 8-isopentenyl-kaempferol (degree 12)indicating that these ingredients play crucial roles in thetreatment of AD For instance kaempferol is reported topromote the level of antioxidants and alleviate neuro-inflammation in the hippocampus to protect against cog-nitive deficits in AD [96] Apigenin can suppress the

expression of cytokines and the production of nitric oxideindicating a potential drug for AD [97] Stigmasterol coulddecrease β-secretase activity and BACE1 internalizationwhich is related to APP β-secretase cleavage [98] Luteolinalso has several biological functions including anti-neuro-inflammatory and antioxidant activities which are beneficialfor the prevention of AD [99]

Integral component of presynaptic membraneCaveola

Postsynaptic specialization membraneIntrinsic component of postsynaptic specialization membraneIntegral component of postsynaptic specialization membrane

Plasma membrane raNuclear envelope lumen

Integral component of synaptic membraneIntrinsic component of postsynaptic membraneIntegral component of postsynaptic membrane

Cellular component

Regulation of reactive oxygen species metabolic processVascular process in circulatory system

Response to ammonium ionRegulation of tube size

Regulation of blood vessel sizeRegulation of blood vessel diameter

Regulation of tube diameterNeurotransmitter metabolic process

Reactive oxygen species biosynthetic processRegulation of neurotransmitter levels

Biological process

G-protein coupled acetylcholine receptor activityAmyloid-beta binding

Tetrapyrrole bindingOxidoreductase activity acting on paired donors with incorporation or reduction of molecular oxygen

Heme bindingG-protein coupled amine receptor activity

Transcription factor activity direct ligand regulated sequence-specific DNA bindingNuclear receptor activity

Neurotransmitter receptor activityAcetylcholine receptor activity

Molecular function

2 4 6 8 100ndashlog10 (P value)

5 10 150ndashlog10 (P value)

2 4 6 80ndashlog10 (P value)

Figure 3 GO enrichment analysis of the targets of ATR and CR

IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84

ATR54 ATR23 ATR73 ATR88

ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2

Ingredients of ATR and CRIngredients of CR

Ingredients of ATRTargets of ATR and CRTargets of CR

Targets of ATR

Figure 4 Component-target network of ATR and CRe orange and yellow rhombus nodes are the active ingredients of ATR and CR andthe pink and light blue ellipse nodes are related targetse blue rhombus nodes are the shared active ingredients HMF (DS75) and apigenin(DS77) e green ellipse nodes are the shared targets of ATR and CR


37 Target-Pathway Network Analysis All of the targetsinteracting with the active ingredients were mapped onto the67 KEGG pathways and the T-P network was generated Asshown in Figure 5 the PI3K-Akt signaling pathway showsthe highest number of target connections (degree 15)followed by the MAPK signaling pathway (degree 13)neuroactive ligand-receptor interaction (degree 12) fluidshear stress and atherosclerosis (degree 11) nonalcoholicfatty liver disease (NAFLD) (degree 11) and Ras signalingpathway (degree 11) ese pathways were related toneurofibromatosis antiatherosclerosis antioxidation andanti-inflammation e PI3K-Akt signaling pathway is in-volved in atherosclerosis by blocking blood flow andinhibiting the migration of fibroblasts [9] and can suppressneuronal cell death and improve tau hyperphosphorylationby BCL2 GSK3B and IGF1R [100ndash102] MAPK can directlyaffect AD contributing to neuroinflammation and acting insome processes such as excitotoxicity synaptic plasticityand tau phosphorylation [103 104] e neuroactive ligand-receptor interaction pathway has been applied in the analysisof neurodegenerative disorders [105] As expected our re-sults showed that the combined herbs modulated neuro-active receptors such as CHRM1 CHRM2 GABRA1GABRA2 etc which are involved in this pathway andprovide therapeutic benefits for AD patients e fluid shearstress and atherosclerosis pathway can regulate the size ofcerebral blood vessels [14] as well as plaque formation whichwill lead to vascular dementia [106]

e compressed pathway was constructed to furtherexplore the details of the synergetic mechanism of ATRand CR in the treatment of AD As shown in Figure 6 ATRcould act on the KDR gene which is one of the keymolecules related to angiogenesis and a strong risk factorfor atherosclerosis [107] while CR can act on its ligandVEGFAis result indicated that ATR and CR could treatAD through complementary effects on atherosclerosiswhich is a pathogenic factor of AD Additionally CR canact on the genes of the upstream pathway such as IL1Band TNF which are proinflammatory mediators [17 26]while ATR can act on downstream genes such as CALM1and NOS3 which are associated with learning andmemory and anti-inflammatory processes Consequentlythese results showed that ATR and CR have a synergisticeffect on antiatherosclerosis processes anti-inflammatoryprocesses learning and memory in a comprehensivepathway

38 Contribution Score Analysis To further explore thesynergetic mechanism of ATR and CR we performed CSanalysis following a previously described method [16] eCS value of each active ingredient is listed in Figure 7 andTable S2 e top 6 ingredients were kaempferol (SCP93)apigenin (DS77) 7-methoxy-2-methyl isoflavone (DS45)stigmasterol (DS37) syringin (DS38) and HMF (DS75) witha CS sum of 4520 these were active ingredients from bothATR and CR especially apigenin and HMF the sharedingredients For instance syringin exhibits anti-inflamma-tory activity and enhances the synthesis of acetylcholine in

the hippocampus [69 108] HMF can mitigate the im-pairment of cognition and memory function induced by Aβinhibit beta-secretase activity and increase antioxidativeenzyme activities [109] Moreover 29 ingredients couldcontribute to the effects of this formula on ADwith a CS sumof 9014 and ATR and CR accounted for 4313 and5687 respectively (Figure S2) Our data fully explainedwhy the combination of ATR and CR could generate syn-ergistic and combinatorial effects on AD

39 Compound-Target-Organ Network Analysis In TCMthe human body is considered an organic whole and theorgans are complementary to each othere curative effect ofdiseases is usually exerted by multiorgan cooperationerefore to better understand the synergistic mechanism ofATR and CR treatment for AD at the organ level we gen-erated a compound-target-organ network e mRNA ex-pression results were obtained from the BioGPS database andthe target was positioned in the organization where it had thehighest expression patterns As shown in Figure 8 the targetswere widely distributed on the brain heart kidney liver lungwhole blood and other tissues Particularly the top threedistributed organs of targets are whole blood brain andmuscle Undoubtedly the key pathogenic mechanism of ADis the degradation of the brain and the main targets located inthe brain are neurotransmitter receptors such as CHRM3GABRA1 and GABRA2 As a pivot between each tissuewhole blood improves the coordination of organs to provide apositive effect on AD Additionally the gene expressionpattern in blood indicates that biological pathways associatedwith oxidative stress inflammation apoptosis and immuneactivation are involved in AD [110 111] e dysfunction ofsmooth muscle which is responsible for regulating bloodvessels could lead to AD complications such as athero-sclerosis and other vascular diseases [22] In total these dataindicated that the combination of ATR and CR effectivelyprevents AD not only in the brain but also in other organsis evidence indicated that ATR and CR have synergisticeffects at the organ level as well

4 Discussion

AD is a neurodegenerative disease characterized by synapseloss [112] neurofibrillary tangles in the brain [113] andextracellular deposits of β-amyloid peptides (Aβ) [114] epathogenesis of AD also involves inflammatory and oxi-dative stress in neuronal cells [4 6] coronary heart disease[115 116] and cardiovascular disease [66] Our resultsdemonstrated that the combination of ATR and CR caneffectively relieve inflammation oxidative stress athero-sclerosis development and nervous system damage

First 68 active ingredients were chosen following ADMEscreening of 235 ingredients In particular apigenin andHMF were both shared ingredients of the two herbs that hadnot passed the screening criteria but they were preservedbecause of their neuroprotective effects [71 72] Moreoverthe volatile oils of ATR such as β-asarone and c-asaronecould improve learning and memory mitigate the deposits


of Aβ and prevent oxidative stress-induced apoptosis[17 56] e sterols of CR such as stigmasterol and spi-nasterol could attenuate the risk of coronary heart diseaseand inhibit the development of atherosclerosis [117 118]Consequently these results suggest that ATR and CR couldproduce a combinatorial effect on AD

Second according to the CS calculation of each ingre-dient ATR and CR can contribute to the effects for AD witha sum of 4313 and 5687 respectively and 29 ingredientsof the two herbs can contribute a sum of 9051 is resultsuggested that the therapeutic effect of this formula wasderived from ATR and CR not a single herb nor a handful ofingredients More remarkably the top ingredients of the CSin ATR such as kaempferol not only could inhibit in-flammation [119] but also attenuate glutamate-inducedoxidative stress [56] However for CR the top ingredientssuch as stigmasterol and syringin showed strong efficacyand treatment of atherosclerosis [68 120] ese resultssuggested that ATR provided neuroprotective effects such asantioxidation and anti-inflammation and subsequently CRaffected AD by inhibiting the development of atheroscle-rosis ese data proved evidence that the combination ofATR and CR had synergistic effects on AD

ird the GO enrichment analysis showed that the topten BP terms were all closely related to neurotransmittertransduction antioxidant effects and vasodilatation whichare associated with AD in the synaptic membrane andplasma membrane ese data implied that these two herbsdisplayed an excellent ability to treat AD and its accom-panying symptoms e results of C-T network analysisshowed that CR could act on AD-related genes includingAPP [120] IL10 [56] CASP7 [68] and SOAT1 [121] andATR could act on AD-related genes including CYP2D6[122] CHRNA2 [123] and ALOX5 [124] indicating thatthese two herbs displayed a complementary ability to treatAD Several AD-related genes such as ACHE [125] PTGS2[126] IKBKB [127] GABAR1 [128] CHRM23 [129] etcwere synergistically regulated by various ingredients of ATRand CR demonstrating that their combination enhances theability to treat AD Furthermore based on the T-P networkanalysis ATR and CR treatment of AD mainly depends onthe PI3K signaling pathway MAPK signaling pathwayneuroactive ligandndashreceptor interaction and fluid shearstress and atherosclerosis which regulate the nervous andvascular systems Additionally this combination activatesnonalcoholic fatty liver disease the Ras signaling pathway

hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418

Figure 5 Target-pathway networks of ATR and CR e green nodes are the targets of ATR and CR while the orange nodes represent thepathways


and human cytomegalovirus infection to relieve the AD-associated symptoms such as liver inflammation and cyto-megalovirus infection to benefit patients with AD [6 68]

Finally the integrated pathway analysis showed thatATR and CR could act on genes that were involved invarious signaling pathways In particular KDR was a unique

CR targets ATR targets

Shared targets Nonherbal targets

Learning and memoryCHRM1CHRM3

ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P

Depletion of Ca2+ stores

CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R

RAS RAL MAPK10 Gene expressionRGLRas signaling pathway

IRS1 PI3KPIP3

AKT GSK3B GYS Metabolism

BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3

RXRANR4A1 BCL2GRB2 SOS RAS RAF

CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA

PI3K-Akt signaling pathwayGβγ

MAPK signaling pathway

+P+P+P+P+P

+P

DNA TNFRTNF

ProliferationDifferentiationInflammation

TRADD CASP3 MAP3K1 MAP2K4 MAPK10 AP1 JUND

MYD88 IRAK TRAF6 TAB1 AKT NFKBIKBKBCHUK

ProliferationInflammationAntiapoptosis

IL1RIL1B

TNF signaling pathway

Calcium signaling pathwayCa2+

Figure 6 Distribution of partial targets of ATR and CR on the compressed pathway

000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s

Figure 7 CS and accumulative CS of active ingredients in ATR and CR


target of ATR while CR could act on its ligand VEGFAsuggesting a complementary effect Subsequently CR couldact on IGF1R MET IL1B and CHUK alone ese resultsprovided powerful evidence that each of them could act ongenes to activate the complementary signaling pathway fortreating AD e C-T-O network analysis also showed thatthe targets of ATR and CR had a wide distribution but thetop 3 organs were whole blood brain and muscle which arestrongly related to antioxidant anti-inflammatory anti-atherosclerotic and neuroprotective activities Conse-quently the synergistic effect of ATR and CR involved notonly the molecular and pathway levels but also the organlevel

In summary this novel systems pharmacology modelprovided a powerful method to explore the therapeuticmechanism of TCM which has multiple ingredients andtargets A combination of compatible remedies for nervoussystem diseases can relieve the symptoms of cardiovasculardiseases and oxidative stress which are the pathogenic

mechanisms of AD at different levels Given the abovefactors a mixture of ATR and CR possesses synergism onAD and this study provides a solid theoretical basis for theeffective prevention and treatment of the pain caused by ADHowever this conclusion mainly depends on model pre-diction and literature analysis andmore experiments shouldbe performed to verify our conclusion

41 Contribution to the Field Statements AD is a progressiveneurodegenerative disorder caused by extensive synapseloss the formation of intracellular neurofibrillary tanglesextracellular deposits of β-amyloid peptides (Aβ) and in-flammatory and oxidative stress in neurons It has beenreported that more than 35 million people suffer from ADIn this work we evaluated the systems pharmacology-basedstrategy to explore the pathogenic mechanism of AD at themolecular pathway and organ levels We first clarified thesynergistic and complementary mechanisms of the Chinese

ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules

Targets in other tissues

Heart target Organ

Whole blood target

Liver target

Figure 8 Compound-target-organ networks of ATR and CR


herbs ATR and CR in the treatment of AD without laboriousand time-consuming experiments In view of the rich naturalcompounds in Chinese herbs this combination will providean effective treatment for AD

Data Availability

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

Conflicts of Interest

e authors declare that they have no conflicts of interestregarding the publication of this paper

Authorsrsquo Contributions

ZS provided the concept and SL designed the study andperformed the experiments YL WM and HL participatedin data analysis and SL and CH contributed to writingrevising and proofreading the manuscript All authors readand approved the final manuscript

Acknowledgments

is work was supported by the Natural Science for YouthFoundation of China (Grant no 31701189) and the NaturalScience Foundation of Yongchuan District Chongqing City(Grant nos Ycstc and 2017nc5003)

Supplementary Materials

Figure S1 e number of targets of ATR (red) CR (blue)and Alzheimerrsquos disease (green) obtained from databasesFigure S2 CS and accumulative CS of the active ingredientsin ATR or CR Table S1 Detailed information on the in-gredients in ATR and CR Table S2 e value of activeingredients in ATR and CR (Supplementary Materials)

References

[1] N L Batsh and M S Mittelman World Alzheimer Report2012 Overcoming the Stigma of Dementia AlzheimerrsquosDisease International London UK 2012

[2] Acosta D A Ketteringham and C Ballard AlzheimerrsquosDisease International 2012

[3] Z-Y Wang J-G Liu H Li and H-M Yang ldquoPharma-cological effects of active components of Chinese herbalmedicine in the treatment of Alzheimerrsquos disease a reviewrdquo5e American Journal of Chinese Medicine vol 44 no 8pp 1525ndash1541 2016

[4] P Kovacic and R Somanathan ldquoRedox processes in neu-rodegenerative disease involving reactive oxygen speciesrdquoCurrent Neuropharmacology vol 10 no 4 pp 289ndash3022012

[5] S Misra and B Medhi ldquoDrug development status for Alz-heimerrsquos disease present scenariordquo Neurological Sciencesvol 34 no 6 pp 831ndash839 2013

[6] I Szaingurten-Solodkin N Hadad and R Levy ldquoRegulatoryrole of cytosolic phospholipase A2α in NADPH oxidaseactivity and in inducible nitric oxide synthase induction by

aggregated Aβ1-42 in microgliardquo Glia vol 57 no 16pp 1727ndash1740 2009

[7] A Hofman A Ott M M Breteler et al ldquoAtherosclerosisapolipoprotein E and prevalence of dementia and Alz-heimerrsquos disease in the Rotterdam studyrdquo 5e Lancetvol 349 no 9046 pp 151ndash154 1997

[8] Z Arvanitakis AW Capuano S E Leurgans D A Bennettand J A Schneider ldquoRelation of cerebral vessel disease toAlzheimerrsquos disease dementia and cognitive function in el-derly people a cross-sectional studyrdquo 5e Lancet Neurologyvol 15 no 9 pp 934ndash943 2016

[9] K Bettens K Sleegers and C Van Broeckhoven ldquoCurrentstatus on Alzheimer disease molecular genetics from past topresent to futurerdquo Human Molecular Genetics vol 19no R1 pp R4ndashR11 2010

[10] B Benjamin and A Burns ldquoDonepezil for Alzheimerrsquosdiseaserdquo Expert Review of Neurotherapeutics vol 7 no 10pp 1243ndash1249 2007

[11] H O Tayeb H D Yang B H Price and F I TarazildquoPharmacotherapies for Alzheimerrsquos disease beyond cho-linesterase inhibitorsrdquo Pharmacology amp 5erapeuticsvol 134 no 1 pp 8ndash25 2012

[12] T Silva J Reis J Teixeira and F Borges ldquoAlzheimerrsquosdisease enzyme targets and drug discovery struggles fromnatural products to drug prototypesrdquo Ageing Research Re-views vol 15 pp 116ndash145 2014

[13] A Kumar A Singh and Ekavali ldquoA review on Alzheimerrsquosdisease pathophysiology and its management an updaterdquoPharmacological Reports vol 67 no 2 pp 195ndash203 2015

[14] J Luo Q Shang M Han K Chen and H Xu ldquoTraditionalChinese medicine injection for angina pectoris an overviewof systematic reviewsrdquo 5e American Journal of ChineseMedicine vol 42 no 01 pp 37ndash59 2014

[15] Y Su Q Wang C Wang K Chan Y Sun and H Kuangldquoe treatment of Alzheimerrsquos disease using Chinese me-dicinal plants from disease models to potential clinicalapplicationsrdquo Journal of Ethnopharmacology vol 152 no 3pp 403ndash423 2014

[16] C Wang ldquoSystem pharmacology-based strategy to decodethe synergistic mechanism of Zhi-Zhu Wan for functionaldyspepsiardquo Frontiers in Pharmacology vol 9 no 1 p 8412018

[17] J Mao S Huang S Liu et al ldquoA herbal medicine forAlzheimerrsquos disease and its active constituents promoteneural progenitor proliferationrdquo Aging Cell vol 14 no 5pp 784ndash796 2015

[18] K Y C Lam P Yao H Wang R Duan T T X Dong andK W K Tsim ldquoAsarone from Acori Tatarinowii rhizomeprevents oxidative stress-induced cell injury in culturedastrocytes a signaling triggered by Akt activationrdquo PLoSOne vol 12 no 6 Article ID e0179077 2017

[19] M Agathocleous I Iordanova M I Willardsen et al ldquoAdirectional Wnt-catenin-Sox2-proneural pathway regulatesthe transition from proliferation to differentiation in theXenopus retinardquo Development vol 136 no 19 pp 3289ndash3299 2009

[20] Y Zhong Dictionary of Chinese Traditional MedicineShanghai Scientific and Technical Publishers ShanghaiChina 2nd edition 2006

[21] J Y-W Chan F-C Lam P-C Leung C-T Che andK-P Fung ldquoAntihyperglycemic and antioxidative effects of aherbal formulation of radix astragali radix codonopsis andcortex lyciiin a mouse model of type 2 diabetes mellitusrdquoPhytotherapy Research vol 23 no 5 pp 658ndash665 2009


[22] Y M Cai Y Zhang P B Zhang et al ldquoNeuroprotectiveeffect of Shenqi Fuzheng injection pretreatment in aged ratswith cerebral ischemiareperfusion injuryrdquo Neural Regen-eration Research vol 11 no 1 pp 94ndash100 2016

[23] S M Lin J Wang R Q Zhou and Z H Yu ldquoClinical studyon treatment of Alzheimerrsquos disease from the viewpoint ofXin and Shen in Chineserdquo Chinese Journal of IntegrativeMedicine vol 23 pp 583ndash586 2003

[24] W Pan ldquoShen-Zhi-Ling oral liquid improves behavioral andpsychological symptoms of dementia in Alzheimerrsquos diseaserdquoEvidence-Based Complementary and Alternative Medicinevol 2014 Article ID 913687 6 pages 2014

[25] H Kiyohara T Matsumoto and H Yamada ldquoCombinationeffects of herbs in a multi-herbal formula expression ofJuzen-taiho-torsquos immuno-modulatory activity on the intes-tinal immune systemrdquo Evidence-Based Complementary andAlternative Medicine vol 1 no 1 pp 83ndash91 2004

[26] S-J Tsai C-Y Lin M-C Mong M-W Ho and M-C Yinldquos-Ethyl cysteine ands-propyl cysteine alleviate β-amyloidinduced cytotoxicity in nerve growth factor differentiatedPC12 cellsrdquo Journal of Agricultural and Food Chemistryvol 58 no 11 pp 7104ndash7108 2010

[27] Q Guo M Zhong H Xu X Mao Y Zhang and N Lin ldquoAsystems biology perspective on the molecular mechanismsunderlying the therapeutic effects of Buyang Huanwu de-coction on ischemic strokerdquo Rejuvenation Research vol 18no 4 pp 313ndash325 2015

[28] W Zhou Y Wang A Lu and G Zhang ldquoSystems phar-macology in small molecular drug discoveryrdquo InternationalJournal of Molecular Sciences vol 17 no 2 p 246 2016

[29] W Zhou and Y Wang ldquoA network-based analysis of thetypes of coronary artery disease from traditional Chinesemedicine perspective potential for therapeutics and drugdiscoveryrdquo Journal of Ethnopharmacology vol 151 no 1pp 66ndash77 2014

[30] J Liu ldquoSystems-pharmacology dissection of traditionalChinese medicine compound saffron formula reveals multi-scale treatment strategy for cardiovascular diseasesrdquo Scien-tific Reports vol 6 no 1 2016

[31] W Zhou ldquoSystems pharmacology exploration of botanicdrug pairs reveals the mechanism for treating differentdiseasesrdquo Scientific Reports vol 6 no 1 p 36985 2016

[32] C Huang C Zheng Y Li Y Wang A Lu and L YangldquoSystems pharmacology in drug discovery and therapeuticinsight for herbal medicinesrdquo Briefings in Bioinformaticsvol 15 no 5 pp 710ndash733 2014

[33] W Zhang ldquoSystems pharmacology dissection of the inte-grated treatment for cardiovascular and gastrointestinaldisorders by traditional Chinese medicinerdquo Scientific Re-ports vol 6 no 1 p 32400 2016

[34] C Zheng T Pei C Huang et al ldquoA novel systems phar-macology platform to dissect action mechanisms of tradi-tional Chinese medicines for bovine viral diarrhea diseaserdquoEuropean Journal of Pharmaceutical Sciences vol 94pp 33ndash45 2016

[35] D Lu L Liu X Ji et al ldquoe phosphatase DUSP2 controlsthe activity of the transcription activator STAT3 and regu-lates TH17 differentiationrdquo Nature Immunology vol 16no 12 pp 1263ndash1273 2015

[36] K-J Yun D-J Koh S-H Kim et al ldquoAnti-inflammatoryeffects of sinapic acid through the suppression of induciblenitric oxide synthase cyclooxygase-2 and proinflammatorycytokines expressions via nuclear factor-κb inactivationrdquo

Journal of Agricultural and Food Chemistry vol 56 no 21pp 10265ndash10272 2008

[37] P Gu L Zhu Y Liu L Zhang J Liu and H ShenldquoProtective effects of paeoniflorin on TNBS-induced ulcer-ative colitis through inhibiting NF-κB pathway and apoptosisin micerdquo International Immunopharmacology vol 50pp 152ndash160 2017

[38] J Ru ldquoTCMSP a database of systems pharmacology for drugdiscovery from herbal medicinesrdquo Journal of Chem-informatics vol 6 p 13 2014

[39] G Rogler ldquoChronic ulcerative colitis and colorectal cancerrdquoCancer Letters vol 345 no 2 pp 235ndash241 2014

[40] R Dirisina R B Katzman T Goretsky et al ldquop53 andPUMA independently regulate apoptosis of intestinal epi-thelial cells in patients and mice with colitisrdquo Gastroenter-ology vol 141 no 3 pp 1036ndash1045 2011

[41] X Xu W Zhang C Huang et al ldquoA novel chemometricmethod for the prediction of human oral bioavailabilityrdquoInternational Journal of Molecular Sciences vol 13 no 6pp 6964ndash6982 2012

[42] C Ma L Wang and X-Q Xie ldquoGPU accelerated chemicalsimilarity calculation for compound library comparisonrdquoJournal of Chemical Information and Modeling vol 51 no 7pp 1521ndash1527 2011

[43] W Tao X Xu X Wang et al ldquoNetwork pharmacology-based prediction of the active ingredients and potentialtargets of Chinese herbal radix curcumae formula for ap-plication to cardiovascular diseaserdquo Journal of Ethno-pharmacology vol 145 no 1 pp 1ndash10 2013

[44] Z Song F Yin B Xiang B Lan and S Cheng ldquoSystemspharmacological approach to investigate the mechanism ofacori tatarinowii rhizoma for Alzheimerrsquos diseaserdquo Evidence-Based Complementary and Alternative Medicine vol 2018Article ID 5194016 20 pages 2018

[45] M K Gilson T Liu M Baitaluk G Nicola L Hwang andJ Chong ldquoBindingDB in 2015 a public database for me-dicinal chemistry computational chemistry and systemspharmacologyrdquo Nucleic Acids Research vol 44 no D1pp D1045ndashD1053 2016

[46] M Kuhn D Szklarczyk A Franceschini C von MeringL J Jensen and P Bork ldquoSTITCH 3 zooming in on protein-chemical interactionsrdquo Nucleic Acids Research vol 40no D1 pp D876ndashD880 2012

[47] Y H Li C Y Yu X X Li et al ldquoerapeutic target databaseupdate 2018 enriched resource for facilitating bench-to-clinic research of targeted therapeuticsrdquo Nucleic Acids Re-search vol 46 no D1 pp D1121ndashD1127 2018

[48] A P Davis C J Grondin R J Johnson et al ldquoe com-parative toxicogenomics database update 2019rdquo NucleicAcids Research vol 47 no D1 pp D948ndashD954 2019

[49] M Whirl-Carrillo E M McDonagh J M Hebert et alldquoPharmacogenomics knowledge for personalized medicinerdquoClinical Pharmacology amp 5erapeutics vol 92 no 4pp 414ndash417 2012

[50] D S Wishart Y D Feunang A C Guo et al ldquoDrugBank50 a major update to the DrugBank database for 2018rdquoNucleic Acids Research vol 46 no D1 pp D1074ndashD10822018

[51] A N Syad K P Shunmugiah and P D Kasi ldquoAntioxidantand anti-cholinesterase activity of Sargassum wightiirdquoPharmaceutical Biology vol 51 no 11 pp 1401ndash1410 2013

[52] C Wu C Orozco J Boyer et al ldquoBioGPS an extensible andcustomizable portal for querying and organizing gene


annotation resourcesrdquo Genome Biology vol 10 no 11p R130 2009

[53] P Shannon ldquoCytoscape a software environment for inte-grated models of biomolecular interaction networksrdquo Ge-nome Research vol 13 no 11 pp 2498ndash2504 2003

[54] K Y Zhu S L Xu R C-Y Choi A L Yan T T-X Dongand K W-K Tsim ldquoKai-Xin-San a Chinese herbal de-coction containing ginseng radix et rhizoma polygalae radixacori tatarinowii rhizoma and poria stimulates the ex-pression and secretion of neurotrophic factors in culturedastrocytesrdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 731385 9 pages 2013

[55] T Lu J Yang X Gao et al ldquoPlasma and urinary tanshinolfrom Salvia miltiorrhiza (Danshen) can be used as phar-macokinetic markers for cardiotonic pills a cardiovascularherbal medicinerdquo Drug Metabolism and Disposition vol 36no 8 pp 1578ndash1586 2008

[56] S Gunaltay ldquoDifferential expression of interleukin-1toll-like receptor signaling regulators in microscopic and ul-cerative colitisrdquo World Journal of Gastroenterology vol 20no 34 pp 12249ndash12259 2014

[57] G S Krushna V L Shivaranjani J Umamaheswari et al ldquoInvivo and molecular docking studies using whole extract andphytocompounds of Aegle marmelos fruit protective effectsagainst isoproterenol-induced myocardial infarction in ratsrdquoBiomedicine amp Pharmacotherapy vol 91 pp 880ndash889 2017

[58] S Sultana A Alam N Khan and S Sharma ldquoInhibition ofbenzoyl peroxide and ultraviolet-B radiation induced oxi-dative stress and tumor promotion markers by cycloartenolin murine skinrdquo Redox Report vol 8 no 2 pp 105ndash1122003

[59] F S Senol K Skalicka Wozniak M T H Khan I ErdoganOrhan B Sener and K Głowniak ldquoAn in vitro and in silicoapproach to cholinesterase inhibitory and antioxidant effectsof the methanol extract furanocoumarin fraction and majorcoumarins of Angelica officinalis L fruitsrdquo PhytochemistryLetters vol 4 no 4 pp 462ndash467 2011

[60] K Y Lam ldquoAsarone from acori tatarinowii rhizoma po-tentiates the nerve growth factor-induced neuronal differ-entiation in cultured PC12 cells a signaling mediated byprotein kinase Ardquo PLoS One vol 11 no 9 Article IDe0163337 2016

[61] J-H Yoon K Youn C-T Ho M V Karwe W-S Jeongand M Jun ldquop-Coumaric acid and ursolic acid from cornifructus attenuated β-amyloid25-35-induced toxicity throughregulation of the NF-κB signaling pathway in PC12 cellsrdquoJournal of Agricultural and Food Chemistry vol 62 no 21pp 4911ndash4916 2014

[62] L Panzella T Eidenberger and A Napolitano ldquoAnti-am-yloid aggregation activity of black sesame pigment toward anovel Alzheimerrsquos disease preventive agentrdquo Moleculesvol 23 no 3 2018

[63] S Adisakwattana S Roengsamran W H Hsu andS Yibchok-anun ldquoMechanisms of antihyperglycemic effectof p-methoxycinnamic acid in normal and streptozotocin-induced diabetic ratsrdquo Life Sciences vol 78 no 4pp 406ndash412 2005

[64] S R Kim S H Sung Y P Jang G J Markelonis T H Ohand Y C Kim ldquoE-p-methoxycinnamic acid protects cul-tured neuronal cells against neurotoxicity induced by glu-tamaterdquo British Journal of Pharmacology vol 135 no 5pp 1281ndash1291 2002

[65] R N A R Mazlan ldquoSolvent extraction and identification ofactive anticariogenic metabolites in piper cubeba L through

H-1-NMR-Based metabolomics approachrdquo Moleculesvol 23 no 7 2018

[66] B Wolozin and M M Bednar ldquoInterventions for heartdisease and their effects on Alzheimerrsquos diseaserdquo Neuro-logical Research vol 28 no 6 pp 630ndash636 2006

[67] M Sato K Shibata R Nomura D Kawamoto R Nagamineand K Imaizumi ldquoLinoleic acid-rich fats reduce athero-sclerosis development beyond its oxidative and inflamma-tory stress-increasing effect in apolipoprotein E-deficientmice in comparison with saturated fatty acid-rich fatsrdquoBritish Journal of Nutrition vol 94 no 6 pp 896ndash901 2005

[68] Y T Liang W T Wong L Guan et al ldquoEffect of phy-tosterols and their oxidation products on lipoprotein profilesand vascular function in hamster fed a high cholesterol dietrdquoAtherosclerosis vol 219 no 1 pp 124ndash133 2011

[69] D Huang Z Hu and Z Yu ldquoEleutheroside B or E enhanceslearning and memory in experimentally aged ratsrdquo NeuralRegeneration Research vol 8 no 12 pp 1103ndash1112 2013

[70] N Kordjazy A Haj-Mirzaian A Haj-Mirzaian et al ldquoRoleof toll-like receptors in inflammatory bowel diseaserdquoPharmacological Research vol 129 pp 204ndash215 2018

[71] Y Lee Q Gao E Kim et al ldquoPretreatment with 5-hydroxymethyl-2-furaldehyde blocks scopolamine-inducedlearning deficit in contextual and spatial memory in malemicerdquo Pharmacology Biochemistry and Behavior vol 134pp 57ndash64 2015

[72] L Zhao J-L Wang R Liu X-X Li J-F Li and L ZhangldquoNeuroprotective anti-amyloidogenic and neurotrophiceffects of apigenin in an Alzheimerrsquos disease mouse modelrdquoMolecules vol 18 no 8 pp 9949ndash9965 2013

[73] A K Singh M P Kashyap V K Tripathi S Singh G Gargand S I Rizvi ldquoNeuroprotection through rapamycin-inducedactivation of autophagy and PI3KAkt1mTORCREB sig-naling against amyloid-β-induced oxidative stress synapticneurotransmission dysfunction and neurodegeneration inadult ratsrdquo Molecular Neurobiology vol 54 no 8 pp 5815ndash5828 2017

[74] B C F Guzman ldquoe GABAergic system as a therapeutictarget for Alzheimerrsquos diseaserdquo Journal of Neurochemistryvol 146 no 6 pp 649ndash669 2018

[75] R J Fontana D K Turgeon T F Woolf M J KnappN L Foster and P B Watkins ldquoe caffeine breath test doesnot identify patients susceptible to tacrine hepatotoxicityrdquoHepatology vol 23 no 6 pp 1429ndash1435 1996

[76] R J Fontana T M deVries T F Woolf et al ldquoCaffeinebased measures of CYP1A2 activity correlate with oralclearance of tacrine in patients with Alzheimerrsquos diseaserdquoBritish Journal of Clinical Pharmacology vol 46 no 3pp 221ndash228 1998

[77] M Fan B Liu T Jiang X Jiang H Zhao and J ZhangldquoMeta-analysis of the association between the monoamineoxidase-A gene and mood disordersrdquo Psychiatric Geneticsvol 20 no 1 pp 1ndash7 2010

[78] S Chakrabarti C K Chan Y Jiang and S T DavidgeldquoNeuronal nitric oxide synthase regulates endothelial in-flammationrdquo Journal of Leukocyte Biology vol 91 no 6pp 947ndash956 2012

[79] X-j Zhao D-m Gong Y-r Jiang D Guo Y Zhu andY-c Deng ldquoMultipotent AChE and BACE-1 inhibitors forthe treatment of Alzheimerrsquos disease design synthesis andbio-analysis of 7-amino-14-dihydro-2 H -isoquilin-3-onederivatesrdquo European Journal of Medicinal Chemistryvol 138 pp 738ndash747 2017


[80] S Darvesh ldquoButyrylcholinesterase as a diagnostic andtherapeutic target for Alzheimerrsquos diseaserdquo Current Alz-heimer Research vol 13 no 10 pp 1173ndash1177 2016

[81] T Jonsson J K Atwal S Steinberg et al ldquoA mutation inAPP protects against Alzheimerrsquos disease and age-relatedcognitive declinerdquo Nature vol 488 no 7409 pp 96ndash992012

[82] F Liu K Xu Z Xu et al ldquoe small molecule luteolininhibits N-acetyl-α-galactosaminyltransferases and reducesmucin-type O-glycosylation of amyloid precursor proteinrdquoJournal of Biological Chemistry vol 292 no 52pp 21304ndash21319 2017

[83] A Gutierrez-Zepeda ldquoSoy isoflavone glycitein protectsagainst beta amyloid-induced toxicity and oxidative stress intransgenic Caenorhabditis elegansrdquo BMC Neurosciencevol 6 p 54 2005

[84] H Y Hu ldquoEffect of Qingxinkaiqiao compound on corticalmRNA expression of the apoptosis-related genes Bcl-2 BAXcaspase-3 and A beta in an Alzheimerrsquos disease rat modelrdquoJournal of Traditional Chinese Medicine vol 36 no 5pp 654ndash662 2016

[85] X L Zhang ldquoA rare missense variant of CASP7 is associatedwith familial late-onset Alzheimerrsquos diseaserdquo Alzheimers ampDementia vol 15 no 3 pp 441ndash452 2019

[86] S G Snowden A A Ebshiana A Hye et al ldquoNeuro-transmitter imbalance in the brain and Alzheimerrsquos diseasepathologyrdquo Journal of Alzheimerrsquos Disease vol 72 no 1pp 35ndash43 2019

[87] J Coyle D Price and M DeLong ldquoAlzheimerrsquos disease adisorder of cortical cholinergic innervationrdquo Sciencevol 219 no 4589 pp 1184ndash1190 1983

[88] P Whitehouse D Price R Struble A Clark J Coyle andM Delon ldquoAlzheimerrsquos disease and senile dementia loss ofneurons in the basal forebrainrdquo Science vol 215 no 4537pp 1237ndash1239 1982

[89] X Wang W Wang L Li G Perry H-g Lee and X ZhuldquoOxidative stress and mitochondrial dysfunction in Alz-heimerrsquos diseaserdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis of Disease vol 1842 no 8 pp 1240ndash12472014

[90] J B Owen R Sultana C D Aluise et al ldquoOxidativemodification to LDL receptor-related protein 1 in hippo-campus from subjects with Alzheimer disease implicationsfor Aβ accumulation in AD brainrdquo Free Radical Biology andMedicine vol 49 no 11 pp 1798ndash1803 2010

[91] S Love and J S Miners ldquoCerebrovascular disease in ageingand Alzheimerrsquos diseaserdquo Acta Neuropathologica vol 131no 5 pp 645ndash658 2016

[92] R E Bennett A B Robbins M Hu et al ldquoTau induces bloodvessel abnormalities and angiogenesis-related gene expres-sion in P301L transgenic mice and human Alzheimerrsquosdiseaserdquo Proceedings of the National Academy of Sciencesvol 115 no 6 pp E1289ndashE1298 2018

[93] S Fanning ldquoLipidomic analysis of alpha-synuclein neuro-toxicity identifies stearoyl CoA desaturase as a target forParkinson treatmentrdquo Molecular Cell vol 73 no 5pp 1001ndash1014 2018

[94] J C M Zijlmans S E Daniel A J Hughes T Revesz andA J Lees ldquoClinicopathological investigation of vascularparkinsonism including clinical criteria for diagnosisrdquoMovement Disorders vol 19 no 6 pp 630ndash640 2004

[95] M R Benedictus M A A Binnewijzend J P A Kuijer et alldquoBrain volume and white matter hyperintensities as

determinants of cerebral blood flow in Alzheimerrsquos diseaserdquoNeurobiology of Aging vol 35 no 12 pp 2665ndash2670 2014

[96] S Kouhestani A Jafari and P Babaei ldquoKaempferol atten-uates cognitive deficit via regulating oxidative stress andneuroinflammation in an ovariectomized rat model ofsporadic dementiardquo Neural Regeneration Research vol 13no 10 pp 1827ndash1832 2018

[97] R Balez ldquoNeuroprotective effects of apigenin against in-flammation neuronal excitability and apoptosis in an in-duced pluripotent stem cell model of Alzheimerrsquos diseaserdquoScientific Reports vol 6 p 31450 2016

[98] V K Burg H S Grimm T L Rothhaar et al ldquoPlant sterolsthe better cholesterol in Alzheimerrsquos disease A mechanis-tical studyrdquo Journal of Neuroscience vol 33 no 41pp 16072ndash16087 2013

[99] Y Kwon ldquoLuteolin as a potential preventive and therapeuticcandidate for Alzheimerrsquos diseaserdquo Experimental Gerontol-ogy vol 95 pp 39ndash43 2017

[100] H Jiancheng andWWenwu ldquoEffect of TianmaGouteng Yinon apoptosis of dopaminergic neurons in Parkinsonrsquos diseasemodel ratsrdquo Journal of Traditional Chinese Medicine vol 51no 11 pp 1024ndash1027 2010

[101] L F Liu ldquoTianma Gouteng Yin a traditional Chinesemedicine decoction exerts neuroprotective effects in animaland cellular models of Parkinsonrsquos diseaserdquo Scientific Re-ports vol 5 no 1 2015

[102] G Yuchi J Zhaochen and L Jingbo ldquoPrescription regularityof traditional Chinese medicine treatment for Parkinsondisease based on complex network analysisrdquo Journal ofTraditional Chinese Medicine vol 59 no 24 pp 2142ndash21472018

[103] L Munoz and A J Ammit ldquoTargeting p38 MAPK pathwayfor the treatment of Alzheimerrsquos diseaserdquo Neuropharma-cology vol 58 no 3 pp 561ndash568 2010

[104] J Gao ldquoHDAC3 but not HDAC2 mediates visual experi-ence-dependent radial glia proliferation in the developingXenopus tectumrdquo Frontiers in Cellular Neuroscience vol 102016

[105] Y Kong X Liang L Liu et al ldquoHigh throughput sequencingidentifies microRNAs mediating alpha-synuclein toxicity bytargeting neuroactive-ligand receptor interaction pathway inearly stage of drosophila Parkinsonrsquos disease modelrdquo PLoSOne vol 10 no 9 Article ID e0137432 2015

[106] Y Zhu X Duan X Cheng et al ldquoKai-Xin-San a stan-dardized traditional Chinese medicine formula up-regulatesthe expressions of synaptic proteins on hippocampus ofchronic mild stress induced depressive rats and primarycultured rat hippocampal neuronrdquo Journal of Ethno-pharmacology vol 193 pp 423ndash432 2016

[107] D E Adkins ldquoSNP-based analysis of neuroactive ligand-receptor interaction pathways implicates PGE2 as a novelmediator of antipsychotic treatment response data from theCATIE studyrdquo Schizophrenia Research vol 135 no 1ndash3pp 200-201 2012

[108] X J Li K-W Kim H Oh X-Q Liu and Y-C KimldquoChemical constituents and an antineuroinflammatorylignan savinin from the roots of acanthopanax henryirdquoEvidence-Based Complementary and Alternative Medicinevol 2019 Article ID 1856294 10 pages 2019

[109] A Liu X Zhao H Li et al ldquo5-Hydroxymethylfurfural anantioxidant agent from Alpinia oxyphylla miq improvescognitive impairment in Aβ1-42 mouse model of Alz-heimerrsquos diseaserdquo International Immunopharmacologyvol 23 no 2 pp 719ndash725 2014


[110] B B Booij T Lindahl P Wetterberg et al ldquoA gene ex-pression pattern in blood for the early detection of Alz-heimerrsquos diseaserdquo Journal of Alzheimerrsquos Disease vol 23no 1 pp 109ndash119 2011

[111] P Fehlbaum-Beurdeley A C Jarrige-Le Prado D Pallareset al ldquoToward an Alzheimerrsquos disease diagnosis via high-resolution blood gene expressionrdquo Alzheimerrsquos amp Dementiavol 6 no 1 pp 25ndash38 2010

[112] T L Spires-Jones and B T Hyman ldquoe intersection ofamyloid beta and tau at synapses in Alzheimerrsquos diseaserdquoNeuron vol 82 no 4 pp 756ndash771 2014

[113] C Ballard S Gauthier A Corbett C Brayne D Aarslandand E Jones ldquoAlzheimerrsquos diseaserdquo 5e Lancet vol 377no 9770 pp 1019ndash1031 2011

[114] B Dejanovic M A Huntley and A D Maziere ldquoChanges inthe synaptic proteome in tauopathy and rescue of tau-in-duced synapse loss by C1q antibodiesrdquo Neuron vol 100no 6 pp 1322ndash1336 2018

[115] A Palotas H J Reis G Bogats et al ldquoCoronary arterybypass surgery provokes Alzheimerrsquos disease-like changes inthe cerebrospinal fluidrdquo Journal of Alzheimerrsquos Diseasevol 21 no 4 pp 1153ndash1164 2010

[116] T A Lee B Wolozin K B Weiss and M M BednarldquoAssessment of the emergence of Alzheimerrsquos disease fol-lowing coronary artery bypass graft surgery or percutaneoustransluminal coronary angioplastyrdquo Journal of AlzheimerrsquosDisease vol 7 no 4 pp 319ndash324 2005

[117] R B Horenstein B D Mitchell W S Post et al ldquoe ABCG8G574R variant serum plant sterol levels and cardiovasculardisease risk in the old order amishrdquo Arteriosclerosis 5rom-bosis and Vascular Biology vol 33 no 2 pp 413ndash419 2013

[118] S I Jeong K J KimM K Choi et al ldquoα-Spinasterol isolatedfrom the root of Phytolacca americana and its pharmaco-logical property on diabetic nephropathyrdquo Planta Medicavol 70 no 8 pp 736ndash739 2004

[119] L Zhu P Wang W Yuan and G Zhu ldquoKaempferolinhibited bovine herpesvirus 1 replication and LPS-inducedinflammatory responserdquo Acta Virologica vol 62 no 2pp 220ndash225 2018

[120] D Deliorman ldquoStudies on the vascular effects of the fractionsand phenolic compounds isolated from Viscum album sspalbumrdquo Journal for Ethnopharmacology vol 72 no 1-2pp 323ndash329 2000

[121] T Nagatsu MMogi H Ichinose and A Togari ldquoChanges incytokines and neurotrophins in Parkinsonrsquos diseaserdquo Ad-vances in Research on Neurodegeneration Springer BerlinGermany pp 277ndash290 2000

[122] I Peter M Dubinsky S Bressman et al ldquoAnti-tumor ne-crosis factor therapy and incidence of Parkinson diseaseamong patients with inflammatory bowel diseaserdquo JAMANeurology vol 75 no 8 p 939 2018

[123] A Steinert I Linas B Kaya et al ldquoe stimulation ofmacrophages with TLR ligands supports increased IL-19expression in inflammatory bowel disease patients and incolitis modelsrdquo 5e Journal of Immunology vol 199 no 7pp 2570ndash2584 2017

[124] T I Kam ldquoPoly (ADP-ribose) drives pathologic alpha-synuclein neurodegeneration in Parkinsonrsquos diseaserdquo Sci-ence vol 362 no 6414 2018

[125] M R Cookson ldquoe role of leucine-rich repeat kinase 2(LRRK2) in Parkinsonrsquos diseaserdquo Nature Reviewslsquo Neuro-science vol 11 no 12 pp 791ndash797 2010

[126] D G Healy M Falchi S S OrsquoSullivan et al ldquoPhenotypegenotype and worldwide genetic penetrance of LRRK2-

associated Parkinsonrsquos disease a case-control studyrdquo 5eLancet Neurology vol 7 no 7 pp 583ndash590 2008

[127] S R Subramaniam and M-F Chesselet ldquoMitochondrialdysfunction and oxidative stress in Parkinsonrsquos diseaserdquoProgress in Neurobiology vol 106-107 pp 17ndash32 2013

[128] T Jiang Q Sun and S Chen ldquoOxidative stress a majorpathogenesis and potential therapeutic target of anti-oxidative agents in Parkinsonrsquos disease and Alzheimerrsquosdiseaserdquo Progress in Neurobiology vol 147 pp 1ndash19 2016

[129] A D Korczyn ldquoVascular parkinsonism-characteristicspathogenesis and treatmentrdquo Nature Reviews Neurologyvol 11 no 6 pp 319ndash326 2015


clinical features of AD are diverse and that the pathologicalfactors are complicated erefore current pharmacologyfocusing on acetylcholine esterase inhibitors and an N-methyl-D-aspartic acid receptor (NMDAR) modulator isunsatisfactory for ameliorating the symptoms of AD [9] Forexample donepezil the most effective drug for the treatmentof AD can only temporarily relieve the symptoms andcannot inhibit the progression of AD [10] Development ofLY450139 which has been investigated in a phase III trial ofanti-Aβ drug candidates has been halted due to its inhi-bition of the NOTCH protein even though it can signifi-cantly reduce Aβ levels in patients [5] Currently approveddrugs for the treatment of AD such as rivastigmine andmemantine result in various side effects such as bradycardiaor hepatotoxicity [11ndash13] Hence it is critical to exploremore systemic effective and harmless anti-AD agents

Traditional Chinese medicine (TCM) has a long historyin the treatment of dementia [3 14] For example Kai-Xin-San the representative prescription written by Sun Simiao inBeiji Qianjin Yaofang during the Tang Dynasty is a TCMformula with antidementia effects [15] Modern pharma-cological research also verified that active ingredientsextracted from Chinese herbs such as apigenin β-asaroneand huperzine A exert curative effects against AD in vivoand in vitro indeed some of them have been used in clinicaltrials [15] Notably Acori Tatarinowii Rhizoma (ATR therhizome of A calamus also named Acorus calamus varangustatus Shi Chang Pu in Chinese) is widely used to treatmemory and cognitive dysfunction due to its anti-inflam-matory antifibrillar amyloid plaque and anti-tau phos-phorylation activities [16ndash19] In TCM Codonopsis Radix(CR the roots of C pilosula also named Codonopsis pilosula(Franch) Nannf Dang Shen in Chinese) functions byreinforcing qi (vital energy) improving the immune systemand reducing blood pressure and also has an antidiabeticeffect by reducing the blood glucose level and inhibitingreactive oxygen species (ROS)-induced damage [20 21]Injection of CR has neuroprotective effects based onblockade of brain Ca2+ accumulation and improvement insuperoxide dismutase activity [22] For enhanced efficiencyCR is usually combined with ATR such as Tiaoxin Recipe[23] and Shen-Zhi-Ling oral liquid [24] and it is known as amonarch minister assistant and guide in TCM Howeverconsidering the complexity of traditional experimentalmethods it is difficult to explore the detailed synergisticmechanism of ATR and CR

A single formula of TCM usually comprises many herbsand exerts its curative effect by additive and complementaryeffects of multiple herbs [25] erefore treating AD withTCM shows the following advantages (1) TCM includesmultiple active ingredients that may activate various kinds ofbiological targets and pathways to provide synergistic andoradditive effects to benefit patients with AD (2) TCM isderived from natural products so it may have low toxicityand few side effects [26] However owing to themultiple andcomplex characteristics of these formulas their exactmechanisms of action are still unclear and difficult to de-termine by traditional experimental assays For example thefamous formula Shi-Quan-Da-Bu-Tang in TCM improves

the intestinal immune system but its ten single herbs showno such activity indicating certain synergistic effects amongmultiple herbs [25] is result again demonstrated that it isdifficult to explore the mechanisms of action of TCM Inrecent years based on chemical pharmacokinetic andpharmacological data the methodology of systems phar-macology has helped us to interpret the details of thesynergistic mechanisms in Chinese formulas [27ndash29] Sys-tems pharmacology integrates pharmacokinetics synthesisdata target screening pathway interaction and networkanalysis to elucidate the therapeutic mechanisms of drugsfrom the molecular and cellular levels to the tissueand organism levels [26 30] Following a systems phar-macology-based strategy many reports explain the poly-pharmacological and synergistic mechanisms and predictthe principal ingredients and signaling pathways of herbpairs for various diseases [31ndash34] Using this model Lu et alrevealed that Huangqi and Huanglian exert synergistictherapeutic effects on diabetes mellitus based on five pivotalingredients [35] Zhi-Zhu-Wan has efficacious therapeuticeffects on functional dyspepsia due to 29 major activecomponents [16] Based on systems pharmacology the in-gredients from the herb Cistanche tubulosa show synergisticeffects on neuroinflammation [36] and the compoundsrutin and amentoflavone exert synergistic effects on relievingdepression [37]

Consequently we constructed a systems pharmacologymodel to explore the therapeutic mechanism of ATR and CRfor treating AD First the active ingredients selected fromthe database were screened by two ADME parameters toensure comprehensiveness Second a large-scale analysis oftargets was performed by target identification to establish thenetwork Finally network construction including com-pound-target (C-T) target-pathway (T-P) and compound-target-organ (C-T-O) networks was applied to reveal theunderlying mechanism of the combination of ATR and CRon AD in our study (Figure 1)

2 Materials and Methods

21 Chemical Ingredients Database Construction All of theconstituent data of ATR and CR were retrieved from theTCM Systems Pharmacology Database and Analysis Plat-form (TCMSP httplspnwueducn) [38] Subsequentlythe initial structures of all ingredients were depicted in TIFformat using ChemDraw (version 160) Additionally thepharmacology-related properties including oral bioavail-ability (OB) drug-likeness (DL) molecular weight (MW)octanol-water partition coefficient predicted by ACDPhysChem Suite (AlogP) number of acceptor atoms forH-bonds (nHAcc) and number of donor atoms for H-bonds(nHDon) were obtained from TCMSP

22 Active Ingredient Screening by ADME An early phar-macokinetic evaluation is important due to the failurescaused by limited pharmacokinetic profiles in modern drugdiscovery [39] However identifying the pharmacokineticproperties by traditional biological experiments is expensive
















CR ATR

AD

ME

scre

enin

g

OB DL

TCM

SP

sear

chin

g

Target fishing


Active ingredients

AD-related targets





Aij ωei +CAi + CBi

CAi minus CBi

11138681113868111386811138681113868111386811138681113868

11138681113868111386811138681113868111386811138681113868

ωei Cedge

Tedge

CS(i) 1113944n

ij


(1)


3 Results







200300400500600

20

40

60

80

Val

ue

02468

10


CRATR

lowast

lowast

lowast

lowast

lowast

lowast






H

HHO

H

H

4298 076


OO

5358 013

CR5 EIC

OH

O

H

HH

H

419 014


O

O

H

HH

H

4193 017


OH

H

8698 005

CR21 Perlolyrine HN

N

O

OH

6595 027

CR28 DIOP

O

O O O4359 039


Table 1 Continued


CR32 ZINC03978781

HOH

H

HH H

H

4383 076

CR37 Stigmasterol

HOHH

HH H

H

4383 076

CR38 Syringin

OH

OH

OH

HO

HO

HH

O O

O O1464 032

CR43 Tectorigenin

OHOH

O

O

O

HO

2841 027


O

O

O

4256 02

CR48 Spinasterol

HOH

HH H

H

H

4298 076


H

O

O

H

475 015


H

H OH

O

O 6811 017


Table 1 Continued


CR61 Frutinone A

O

OO

O

659 034

CR63 Luteolin O

O

OH

OH

OH

HO

3616 025

CR67 Taraxerol

H

H

HO

H 384 077


HOH

HH

H

3742 075

CR70 Norharman

NHN

1888 008


O

O

O

HO

3216 041

CR75 HMFHO

O

O4507 002


H H OO 3967 023


Table 1 Continued


CR77 ApigeninO

O

OH

OH

HO

2306 021


NH2+

Ondash

OHN

529 013


OO

3312 079


O

HN

HO

OH

HOO

OO

OO

O

O

O

O3833 029

CR101 Codonopsine

O

O

OH

OHHN

4583 013

CR103 DaturilinO O

O

O

5037 077

CR106 Glycitein

HO

OH

O

O

O 5048 024


Table 1 Continued


CR112 Spinoside A

HO

HO OH

OH

O

OO

O O

O

O

3997 04



HO

H

HH

H

H 454 076


O

O

O

HN

N

40 066


OO

OO

O

3384 015




Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004


HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013


O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References



























































































































































CR ATR

AD

ME

scre

enin

g

OB DL

TCM

SP

sear

chin

g

Target fishing


Active ingredients

AD-related targets





Aij ωei +CAi + CBi

CAi minus CBi

11138681113868111386811138681113868111386811138681113868

11138681113868111386811138681113868111386811138681113868

ωei Cedge

Tedge

CS(i) 1113944n

ij


(1)


3 Results







200300400500600

20

40

60

80

Val

ue

02468

10


CRATR

lowast

lowast

lowast

lowast

lowast

lowast






H

HHO

H

H

4298 076


OO

5358 013

CR5 EIC

OH

O

H

HH

H

419 014


O

O

H

HH

H

4193 017


OH

H

8698 005

CR21 Perlolyrine HN

N

O

OH

6595 027

CR28 DIOP

O

O O O4359 039


Table 1 Continued


CR32 ZINC03978781

HOH

H

HH H

H

4383 076

CR37 Stigmasterol

HOHH

HH H

H

4383 076

CR38 Syringin

OH

OH

OH

HO

HO

HH

O O

O O1464 032

CR43 Tectorigenin

OHOH

O

O

O

HO

2841 027


O

O

O

4256 02

CR48 Spinasterol

HOH

HH H

H

H

4298 076


H

O

O

H

475 015


H

H OH

O

O 6811 017


Table 1 Continued


CR61 Frutinone A

O

OO

O

659 034

CR63 Luteolin O

O

OH

OH

OH

HO

3616 025

CR67 Taraxerol

H

H

HO

H 384 077


HOH

HH

H

3742 075

CR70 Norharman

NHN

1888 008


O

O

O

HO

3216 041

CR75 HMFHO

O

O4507 002


H H OO 3967 023


Table 1 Continued


CR77 ApigeninO

O

OH

OH

HO

2306 021


NH2+

Ondash

OHN

529 013


OO

3312 079


O

HN

HO

OH

HOO

OO

OO

O

O

O

O3833 029

CR101 Codonopsine

O

O

OH

OHHN

4583 013

CR103 DaturilinO O

O

O

5037 077

CR106 Glycitein

HO

OH

O

O

O 5048 024


Table 1 Continued


CR112 Spinoside A

HO

HO OH

OH

O

OO

O O

O

O

3997 04



HO

H

HH

H

H 454 076


O

O

O

HN

N

40 066


OO

OO

O

3384 015




Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004


HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013


O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References















































































































































Aij ωei +CAi + CBi

CAi minus CBi

11138681113868111386811138681113868111386811138681113868

11138681113868111386811138681113868111386811138681113868

ωei Cedge

Tedge

CS(i) 1113944n

ij


(1)


3 Results







200300400500600

20

40

60

80

Val

ue

02468

10


CRATR

lowast

lowast

lowast

lowast

lowast

lowast






H

HHO

H

H

4298 076


OO

5358 013

CR5 EIC

OH

O

H

HH

H

419 014


O

O

H

HH

H

4193 017


OH

H

8698 005

CR21 Perlolyrine HN

N

O

OH

6595 027

CR28 DIOP

O

O O O4359 039


Table 1 Continued


CR32 ZINC03978781

HOH

H

HH H

H

4383 076

CR37 Stigmasterol

HOHH

HH H

H

4383 076

CR38 Syringin

OH

OH

OH

HO

HO

HH

O O

O O1464 032

CR43 Tectorigenin

OHOH

O

O

O

HO

2841 027


O

O

O

4256 02

CR48 Spinasterol

HOH

HH H

H

H

4298 076


H

O

O

H

475 015


H

H OH

O

O 6811 017


Table 1 Continued


CR61 Frutinone A

O

OO

O

659 034

CR63 Luteolin O

O

OH

OH

OH

HO

3616 025

CR67 Taraxerol

H

H

HO

H 384 077


HOH

HH

H

3742 075

CR70 Norharman

NHN

1888 008


O

O

O

HO

3216 041

CR75 HMFHO

O

O4507 002


H H OO 3967 023


Table 1 Continued


CR77 ApigeninO

O

OH

OH

HO

2306 021


NH2+

Ondash

OHN

529 013


OO

3312 079


O

HN

HO

OH

HOO

OO

OO

O

O

O

O3833 029

CR101 Codonopsine

O

O

OH

OHHN

4583 013

CR103 DaturilinO O

O

O

5037 077

CR106 Glycitein

HO

OH

O

O

O 5048 024


Table 1 Continued


CR112 Spinoside A

HO

HO OH

OH

O

OO

O O

O

O

3997 04



HO

H

HH

H

H 454 076


O

O

O

HN

N

40 066


OO

OO

O

3384 015




Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004


HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013


O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References
















































































































































H

HHO

H

H

4298 076


OO

5358 013

CR5 EIC

OH

O

H

HH

H

419 014


O

O

H

HH

H

4193 017


OH

H

8698 005

CR21 Perlolyrine HN

N

O

OH

6595 027

CR28 DIOP

O

O O O4359 039


Table 1 Continued


CR32 ZINC03978781

HOH

H

HH H

H

4383 076

CR37 Stigmasterol

HOHH

HH H

H

4383 076

CR38 Syringin

OH

OH

OH

HO

HO

HH

O O

O O1464 032

CR43 Tectorigenin

OHOH

O

O

O

HO

2841 027


O

O

O

4256 02

CR48 Spinasterol

HOH

HH H

H

H

4298 076


H

O

O

H

475 015


H

H OH

O

O 6811 017


Table 1 Continued


CR61 Frutinone A

O

OO

O

659 034

CR63 Luteolin O

O

OH

OH

OH

HO

3616 025

CR67 Taraxerol

H

H

HO

H 384 077


HOH

HH

H

3742 075

CR70 Norharman

NHN

1888 008


O

O

O

HO

3216 041

CR75 HMFHO

O

O4507 002


H H OO 3967 023


Table 1 Continued


CR77 ApigeninO

O

OH

OH

HO

2306 021


NH2+

Ondash

OHN

529 013


OO

3312 079


O

HN

HO

OH

HOO

OO

OO

O

O

O

O3833 029

CR101 Codonopsine

O

O

OH

OHHN

4583 013

CR103 DaturilinO O

O

O

5037 077

CR106 Glycitein

HO

OH

O

O

O 5048 024


Table 1 Continued


CR112 Spinoside A

HO

HO OH

OH

O

OO

O O

O

O

3997 04



HO

H

HH

H

H 454 076


O

O

O

HN

N

40 066


OO

OO

O

3384 015




Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004


HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013


O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References













































































































































Table 1 Continued


CR32 ZINC03978781

HOH

H

HH H

H

4383 076

CR37 Stigmasterol

HOHH

HH H

H

4383 076

CR38 Syringin

OH

OH

OH

HO

HO

HH

O O

O O1464 032

CR43 Tectorigenin

OHOH

O

O

O

HO

2841 027


O

O

O

4256 02

CR48 Spinasterol

HOH

HH H

H

H

4298 076


H

O

O

H

475 015


H

H OH

O

O 6811 017


Table 1 Continued


CR61 Frutinone A

O

OO

O

659 034

CR63 Luteolin O

O

OH

OH

OH

HO

3616 025

CR67 Taraxerol

H

H

HO

H 384 077


HOH

HH

H

3742 075

CR70 Norharman

NHN

1888 008


O

O

O

HO

3216 041

CR75 HMFHO

O

O4507 002


H H OO 3967 023


Table 1 Continued


CR77 ApigeninO

O

OH

OH

HO

2306 021


NH2+

Ondash

OHN

529 013


OO

3312 079


O

HN

HO

OH

HOO

OO

OO

O

O

O

O3833 029

CR101 Codonopsine

O

O

OH

OHHN

4583 013

CR103 DaturilinO O

O

O

5037 077

CR106 Glycitein

HO

OH

O

O

O 5048 024


Table 1 Continued


CR112 Spinoside A

HO

HO OH

OH

O

OO

O O

O

O

3997 04



HO

H

HH

H

H 454 076


O

O

O

HN

N

40 066


OO

OO

O

3384 015




Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004


HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013


O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References













































































































































Table 1 Continued


CR61 Frutinone A

O

OO

O

659 034

CR63 Luteolin O

O

OH

OH

OH

HO

3616 025

CR67 Taraxerol

H

H

HO

H 384 077


HOH

HH

H

3742 075

CR70 Norharman

NHN

1888 008


O

O

O

HO

3216 041

CR75 HMFHO

O

O4507 002


H H OO 3967 023


Table 1 Continued


CR77 ApigeninO

O

OH

OH

HO

2306 021


NH2+

Ondash

OHN

529 013


OO

3312 079


O

HN

HO

OH

HOO

OO

OO

O

O

O

O3833 029

CR101 Codonopsine

O

O

OH

OHHN

4583 013

CR103 DaturilinO O

O

O

5037 077

CR106 Glycitein

HO

OH

O

O

O 5048 024


Table 1 Continued


CR112 Spinoside A

HO

HO OH

OH

O

OO

O O

O

O

3997 04



HO

H

HH

H

H 454 076


O

O

O

HN

N

40 066


OO

OO

O

3384 015




Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004


HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013


O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References













































































































































Table 1 Continued


CR77 ApigeninO

O

OH

OH

HO

2306 021


NH2+

Ondash

OHN

529 013


OO

3312 079


O

HN

HO

OH

HOO

OO

OO

O

O

O

O3833 029

CR101 Codonopsine

O

O

OH

OHHN

4583 013

CR103 DaturilinO O

O

O

5037 077

CR106 Glycitein

HO

OH

O

O

O 5048 024


Table 1 Continued


CR112 Spinoside A

HO

HO OH

OH

O

OO

O O

O

O

3997 04



HO

H

HH

H

H 454 076


O

O

O

HN

N

40 066


OO

OO

O

3384 015




Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004


HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013


O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References













































































































































Table 1 Continued


CR112 Spinoside A

HO

HO OH

OH

O

OO

O O

O

O

3997 04



HO

H

HH

H

H 454 076


O

O

O

HN

N

40 066


OO

OO

O

3384 015




Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004


HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013


O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References













































































































































Table 1 Continued


ATR3 Vanillic acid

OH

O

O OH

3547 004


HH

H

H

5404 01

ATR12 Calarene

H

5216 011

ATR15 p-MCA

O

OO

H

HH

31 005

ATR19 MarmesinO H

OHOO

5028 018

ATR20 Majudin

O

OOO

4221 013


O

3267 013


Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References













































































































































Table 1 Continued


ATR28 beta-Asarone

H

H

O

O

O

3561 006


H

HH

H5136 01



H

H

OH

O

O

OH

7586 017

ATR50 (+)-Ledene

HH

H

5184 01



Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References













































































































































Table 1 Continued



O OH

OH

HO

HO

3804 039

ATR55 Aminacrine

N

NH2

35 012

ATR57 Aristolene

H

H 522 011

ATR58 Aristolone H

H

O

4531 013

ATR59 Azaron

HH

O

O

O3839 006

ATR63 Bisasarcin

O

O

OO

O

O

1855 05

ATR65 Calamendiol

OH

OH 6113 011


Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References













































































































































Table 1 Continued



OH

HO

5763 011

ATR78 Longicyclene

HH

H

H

4607 015


OOH

3672 011


ATR84 Spathulenol

H

H H

H

HO

8161 012

ATR87 α-Gurjunene

H

H

H5257 01


H

5677 012




Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References















































































































































Table 1 Continued



OO

H

H

O O

O O

5235 062

ATR91 Cycloartenol

OH

3869 078

ATR93 KaempferolOH

OH

O

OHO

HO

4188 024



OH

OH

HH

O

4329 004



















Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References






























































































































































Cellular component






Biological process






Molecular function





IL1BCR52

CR49

CR81

CR70

CR130

RXRG

MET

CR43PTGES

CASP7

IL10

CR106CR16 CR101

CR73

CR5NOS3

CR2CALM1

CHRNA7 CR61

CR38ACHE

CR132

ABCA1 CR21

CR28CR14

CR76

MAOA

CASP3GSK3B

FLT3 CR63

CR45

SOAT1

CR117

APP

CR37

CHUK

PPARG

ESR1

BCL2

BAXINS

ADRA2C

IGF1R

MAPK10CDK5

BCHE BACE1

CR77GABRA5

INSR

F2 GABRA2

ADRB2

MAOB

ATR98

ATR65CYP2D6

ATR53

KDR ATR15NR1I2

CHRNA2ATR28CYP2A6

PLAU

ATR50

PTGS1

CHRM1

TNF

HTR2A

DIO1

ALOX5

ATR81

ATR3

ATR55

ATR102

ATR84


ATR12ATR93

ATR79

ATR20

ATR35

AHR

ATR6 ATR30

ATR19

ATR59

ATR58

CYP1A2CYP3A4

ATR40

ATR89

SLC2A4

CHRM3CR75

CHRM2 VEGFA

RXRA

ATR63

HMOX1

ABCB1

ADH1C

IKBKBF7

GABRA1PTGS2



Targets of ATR








4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References


















































































































































4 Discussion







hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References
















































































































































hsa04625CALM1

hsa04080

hsa05152

hsa00980

ALOX5

IGF1R

hsa04923hsa05167

hsa04210

hsa05222

CDK5

hsa04115

CYP1A2

PLAU

APP

hsa05210

hsa05212

GABRA5

hsa05226

hsa03320

BACE1

CHRNA2

hsa04622

hsa05033

CYP2A6

hsa04917

hsa04660

hsa04211

hsa05202

hsa04010

HMOX1

hsa04910

hsa04020FLT3

ABCB1PPARG

hsa05144

PTGS2

hsa04913

hsa04933hsa04014

hsa04520

GABRA2

ACHEhsa04370

hsa05014hsa04932

IL10

hsa04380

CYP2D6

ADH1C

HTR2A

hsa04920RXRA

hsa05160

IKBKB

INS

hsa04657

INSR

GSK3Bhsa05216

CHRNA7

hsa04215

hsa00982hsa00830

hsa05163

BAX

IL1Bhsa04722SLC2A4

hsa05010

RXRG

CASP7

PTGS1

hsa05143

hsa05204

MAOB

hsa04930hsa05134

GABRA1

hsa00350

MAOAhsa04068

hsa05161

CHRM1

ADRB2

MET

VEGFA

MAPK10

hsa04064

CHRM3

hsa04931

F2

hsa05140

CHRM2

CYP3A4hsa04620

hsa05133hsa04659

hsa04066

hsa00590

NOS3

TNF

hsa05215

hsa04668

hsa05120

hsa04725

CHUK

hsa04150

CASP3

BCL2hsa05145

KDRhsa05142

hsa04726 ESR1

AHR

ADRA2C

hsa04151

PTGES

hsa05218

hsa05418








ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References


















































































































































ADRB2

HTR2A

CHRAN7

ORAI

Gs ADCYcAMP

PKA PLN

RYRSTIM

+P


CHRM3CHRM2

GqIP3

CALM1CAMK

NOS3Vasodilatory

Anti-inflammatory

PLCDAG

PKC

IP3R


IRS1 PI3KPIP3


BRCA1NOS3

NOAngiogenesis

IKBKBCHUK MXB

Cell survival

PIP3


CHRM1CHRM2

MET

FLT3

IGF1R

KDRINSRINS

VEGFA



+P+P+P+P+P

+P

DNA TNFRTNF





IL1RIL1B




000

2000

4000

6000

8000

10000

12000

9014

4520

CR45

CR38

CR2

CR5

CR63

ATR5

9AT

R6AT

R23

ATR9

8AT

R40

CR43

CR73

CR13

0AT

R35

ATR3

0AT

R3AT

R15

ATR7

3CR

52AT

R55

ATR8

9AT

R63

ATR5

0CR

28CR

117

CR76

ATR9

3

Active ingredients

Accumulation of CS

CRATR

()

000

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

CS v

alue

s







ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References

















































































































































ATR102

ATR15CHRNA2

GABRA5ATR3

CR52

ATR55

ATR73

ATR79

CR21

CR49

CR14

ATR53

ATR84

SLC2A4

BCHE

CYP1A2F2

F7

Liver

IL10

Heart

PLAU

DIO1

CHRNA7

KDR

HMOX1

FLT3 BACE1VEGFA

MAPK10

Brain

NOS3

CDK5

RXRG

ATR81CALM1

CR81

ATR35

CR130

HTR2A

CR70ATR30

ATR58ATR98

RXRA CYP3A4

ACHEADRB2

IGF1RCHUK ATR89

ATR63

Whole blood

INSMET

TNF

CHRM1

CASP3

Other tissues

IKBKB

BCL2

BAX

CYP2A6

CR117CR45CR76

CR37

ATR93CR77

CR63

ATR20ATR12

CR28ALOX5

ATR88

ATR54ATR50

CR101CR73

CR16ATR23

ATR59

CR43

ATR19

ATR6

ATR106

ATR40

ABCB1

IL1B

INSR

PTGES

PTGS1

PTGS2

CHRM2ABCA1

CYP2D6Muscle

MAOB

GABRA1

ATR65

CHRM3

PPARG

GABRA2

GSK3B

ESR1

AHR

CR61

SOAT1 APPCR38

CR132 Kidney

CR5

MAOA NR1I2CR75

ADH1C

CR2CASP7

ADRA2C

ATR28 Intestines

Brain target

Intestines target

Kidney target

Muscle target

Molecules


Heart target Organ

Whole blood target

Liver target




Data Availability






Acknowledgments




References














































































































































Data Availability






Acknowledgments




References













































































































































EnhancingandComplementaryMechanismsofSynergistic ... · 2020. 6. 25. · CR5 EIC OH O H H H H 41.9...

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Transcript of EnhancingandComplementaryMechanismsofSynergistic ... · 2020. 6. 25. · CR5 EIC OH O H H H H 41.9...