Research ArticleIdentification of the Active Constituents and SignificantPathways of Cangfu Daotan Decoction for the Treatment of PCOSBased on Network Pharmacology

Wenting Xu , Mengyu Tang , Jiahui Wang , and Lihong Wang

Department of Reproduction, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang,Suzhou, Jiangsu, China

Correspondence should be addressed to Lihong Wang; zjgzywlh@njucm.edu.cn

Received 18 December 2019; Accepted 27 January 2020; Published 22 February 2020

Academic Editor: Deborah A. Kennedy

Copyright © 2020 Wenting Xu et al. ,is is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Background. Polycystic ovary syndrome (PCOS) is the most common female endocrine disease. Cangfu Daotan Decoction (CDD)can effectively relieve the clinical symptoms of PCOS patients.Methods. To explore the active ingredients and related pathways ofCDD for treating PCOS, a network pharmacology-based analysis was carried out. ,e active ingredients of CDD and theirpotential targets were obtained from the TCM system pharmacology analysis platform. ,e obtained PCOS-related genes fromOMIM and GeneCards were imported to establish protein-protein interaction networks in STRING. Finally, GO analysis andsignificant pathway analysis were conducted with the RStudio (Bioconductor) database. Results. A total of 111 active compoundswere obtained from 1433 ingredients present in the CDD, related to 118 protein targets. In addition, 736 genes were found to beclosely related to PCOS, of which 44 overlapped with CDD and were thus considered therapeutically relevant. Pathway en-richment analysis identified the AGE-RAGE signalling pathway in diabetic complications, endocrine resistance, the IL-17signalling pathway, the prolactin signalling pathway, and the HIF-1 signalling pathway. Moreover, PI3K-Akt, insulin resistance,Toll-like receptor, MAPK, and AGE-RAGE were related to PCOS and treatment. Conclusions. CDD can effectively improve thesymptoms of PCOS, and our network pharmacological analysis lays the foundation for future clinical research.

1. Background

Polycystic ovary syndrome (PCOS) is the most commonendocrine disease in women and is characterized by ab-normal adrenal and ovarian androgen secretion, ovulatorydysfunction, menstrual irregularity, acne [1], and polycysticovarian morphological features, and in a significant pro-portion of patients, insulin resistance, with a prevalencebetween 5% and 15% [2, 3]. Although for a long period,studies on PCOS have focused on reproductive disorders [4],recent evidence suggests that PCOS is a heterogeneousdisorder associated with a large number of severe metabolicimplications as well as cardiovascular disease for affectedwomen [5], which brings a heavy burden to the patient’sfamily and to society. However, there is a generally poor

understanding of its aetiology [6]. Genome-wide and mo-lecular mechanism studies have identified certain candidategene targets, although their role in the development of PCOSis still largely unknown; thus, early diagnosis, effectivetreatment, and the elucidation of underlying mechanismsare necessary [7, 8].

In the past few decades, oral contraceptive pills (OCPs)have been widely used in PCOS patients to regulate theirmenstrual cycles and reduce hyperandrogenism [4]. Clo-miphene citrate and letrozole have both been used to induceovulation in PCOS patients with fertility problems [9–11].However, reports have been coming in regarding the sideeffects of OCPs in increasing the risk of venous thrombo-embolism (VTE) [12, 13]. Moreover, some experts havecalled attention to the unclear long-term risk-benefit ratio

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2020, Article ID 4086864, 15 pageshttps://doi.org/10.1155/2020/4086864

[11, 14, 15]. Due to the limitations of current treatments,traditional Chinese medicine (TCM) treatment for PCOShas become an important alternative therapy.

,ere is no specific Chinese medical term referring to“PCOS” in the ancient books of Chinese medicine.According to the clinical characteristics of PCOS, it is at-tributed to the category of irregular menstruation, infertility,obesity, etc. For thousands of years, TCM has been used totreat menstrual disorders, infertility, and obesity. ,ere are anumber of herbal formulas in treating the above diseases. Astudy showed that herbal medicine administration signifi-cantly relieved some of the symptoms of PCOS [16]. Spe-cifically, the CDD consists of nine herbs: Atractylodes lancea('unb.) Dc (Cangzhu), Cyperi Rhizoma (Xiangfu), Ari-saematis Rhizoma (Dannanxing), Arum ternatum 'unb(Banxia), Zingiber officinale Roscoe (Shengjiang), Citrusreticulata (Chenpi), Aurantii Fructus (Zhike), Poria cocos(Schw.) Wolf (Fuling), and Licorice (Gancao) and is one ofthe most common prescriptions for phlegm and dampness-type PCOS patients [17]. Another study showed that theCDD can significantly improve the pregnancy rate of in-fertile patients with PCOS, which might be associated withreduced insulin resistance, improved endometrial bloodflow, and finally improved endometrial receptivity [18].Although the CDD has been used clinically for gynaeco-logical diseases for a long time, its mechanism of action isunclear because of its complex composition.

,erefore, it is necessary to clarify the biological basisand molecular nature of the TCM decoction. Networkpharmacology has recently been developed as a new strategyand technique for elucidating complex pharmacologicalproblems for new drug discovery [19]. In recent years, theTCM Systems Pharmacology (TCMSP) database and anal-ysis platform has emerged as an ideal information con-vergence of the absorption, distribution, metabolism, andexcretion (ADME) properties, drug-likeness, drug targets,associated diseases, and interaction networks of traditionalmedicines [20].

TCM decoctions have complex ingredients and multipletargets, and network pharmacology can predict novelcompound targets and the potential pathways of actionbased on existing TCM decoctions and has helped clarify themechanism of several TCM decoctions so far [21–23].

In this study, we used the network pharmacology ap-proach to explore the potential mechanism of action of CDDin treating PCOS. We first filtered the TCMSP database foractive compounds of CDD and identified the targets, fol-lowed by mining for disease-related genes and networkanalysis of those genes (Figure 1).

2. Methods

2.1. Chemical Components of Each Herb in CDD. To screenthe active ingredients of CDD, we used the TCMSP database(http://tcmspw.com/tcmsp.php) [20]. TCMSP is a uniquesystems pharmacology platform specifically designed forChinese medicine that contains information on their ADMEcharacteristics and captures the relationships between dis-ease, targets, ingredients, and drugs [24].

2.2. Pharmacokinetic Prediction of CDD. CDD active in-gredients were filtered mainly on the basis of oralbioavailability (OB), Caco-2 permeability (Caco-2), anddrug-likeness (DL). OB, Caco-2, and DL are the three mostkey indicators of pharmacology. Specifically, the ingredientscontained in the CDD meeting the criteria of OB≥ 30%,Caco-2≥ 0.4, and DL≥ 0.18 were chosen as candidate in-gredients for further analysis.

OB refers to the percentage and rate of the release andabsorption of active ingredients into the systemic bloodcirculation and is an important pharmacokinetic index oforal drugs [25]. It is also an important index to objectivelyevaluate the intrinsic quality of oral drugs [26], which isparticularly important in the drug administration of mostoral Chinese herbal formulas [27]. DL is defined as acomplex balance of structural features and variousmolecularproperties, which determine whether the particular moleculeis similar to the known drugs [26].,ese parameters, such ashydrogen bonding characteristics and hydrophobicity,mainly influence the behaviour of molecules in living or-ganisms, which ultimately affects their transport properties,affinity for proteins, metabolic stability, and many otherproperties. Caco-2 permeability is widely used as a standardpermeability screening assay for oral drug absorption relatedto drug permeability, which can predict the intestinal ab-sorption of the ingredients and the fraction of the oral doseabsorbed in humans [28].

In this study, OB≥ 30%, DL≥ 0.18, and Caco-2≥ 0.4 wereregarded as a threshold for filtering possible candidate drugs.

2.3. Potential Targets of the Chemical Components of CDD.We chose the TCMSP database as the main source ofcomponent-target data and obtained the target proteinnames of each herb in CDD. Only the proteins that hadinteractions with the bioactive components in CDD we hadalready obtained were selected. ,en, we converted thetarget protein names of the bioactive components of CDDinto gene names with the species limited into “Homo sa-piens” with the UniProt Knowledgebase (UniProtKB, http://www.uniprot.org).

2.4. Known 'erapeutic Targets for PCOS. We collectedPCOS targets from two sources. One is the GeneCardsdatabase (https://www.genecards.org/), which is a search-able, integrative database that predicts human genes. ,eknowledgebase automatically integrates gene-centric datafrom ∼150 web sources, including genomic, transcriptomic,proteomic, genetic, clinical, and functional information [29].Another resource was the genemap in the OnlineMendelianInheritance in Man (OMIM) database [30] (https://omim.org/, updated on November 15, 2019), which is a compre-hensive, authoritative, and timely knowledgebase of humangenes and genetic disorders in the human genome. Wesearched the OMIM database with the keyword “PCOS.”

2.5. Protein-Protein Interactions. To illustrate the possibleinteraction between PCOS-related targets and the potential

2 Evidence-Based Complementary and Alternative Medicine

targets of CDD, we intersected the potential targets of CDDand PCOS-related drug targets and obtained the intersectingtargets with RStudio 3.6.1 (Venn Diagram). ,e overlappingtarget proteins of PCOS and CDD were used to construct aprotein-protein interaction (PPI) network with multipleprotein patterns on the Search Tool for the Retrieval of

Interacting Genes/Proteins (STRING) platform (https://string-db.org/, version 11.0). We set the organism type to“Homo sapiens” and left the default settings in place for theother parameters. ,en, we exported the downloaded“string_interactions.tsv” file and imported it into Cytoscape3.7.2 to obtain the PPI network and perform network

Cangfu Daotan

Decoction

Ingredients ofcompounds in

CDD

TCMSP

Candidatecompounds

OB, DL, Caco-2

Candidatetargets

PCOS-related genes

OMIM GeneCards

PCOS

Overlap genes

PPI string platform Cytoscape 3.7.2

PPI network of therapeutic

targets from CDD for treating PCOS

CDD-PCOS compound-

candidate target network

RStudio

KEGG pathway analysis

GO enrichment analysis

Figure 1: A schematic of the network pharmacology-based analysis of CDD for the treatment of PCOS.

Evidence-Based Complementary and Alternative Medicine 3

analysis. In the network, nodes represent the target proteins,and edges represent the interaction between proteins.

2.6. GO and KEGG Pathway Enrichment Analysis. GeneOntology (GO) and Kyoto Encyclopedia of Genes andGenomes (KEGG) pathway enrichment analysis are im-portant methods used to describe the characteristics ofcandidate targets. We selected the standard p value cutoff of0.05 and the q value of 0.05 and performed the enrichmentanalysis with RStudio 3.6.1 (Bioconductor, clusterProfiler).

3. Results

3.1. Composite Ingredients of CDD. A total of 1051 chemicalingredients of the nine herb medicines in CFDT were re-trieved from TCMSP, including 49 ingredients in Atrac-tylodes lancea ('unb.) Dc, 104 ingredients in CyperiRhizoma, 123 ingredients in Arisaematis Rhizoma, 116 in-gredients in Arum ternatum 'unb., 265 ingredients inZingiber officinale Roscoe, 63 ingredients in Citrus reticulata,17 ingredients in Aurantii Fructus, 34 ingredients in Poriacocos (Schw.) Wolf, and 280 ingredients in Licorice. 122ingredients passed the filters of OB≥ 30%, DL≥ 0.18, andCaco-2≥ 0.4. ,e pharmacokinetic properties of the com-pounds are shown in Table 1.

3.2. Target Gene Prediction of CDD. A total of 1433 potentialtargets from the 111 ingredients were retrieved from theTCMSP database (Figure 2). After eliminating the over-lapping proteins, 118 related proteins were obtained andconverted into gene names with the species limited into“Homo sapiens” based on the UniProtKB.

3.3. PCOS-Related Target Network. Research has shown thatPCOS is a genetic predisposing, complex polygenic, mul-tifactorial disorder [7, 31]. In this study, we obtained 736targets related to PCOS through the GeneCards database(https://www.genecards.org/) and the OMIM database(https://omim.org/).

3.4. PPI Network Analysis. Among the above 736 PCOS-related targets, CDD shared 44 common targets with PCOS(Figure 3).,e 44 putative therapeutic targets were importedinto the STRING database to establish the putative thera-peutic target PPI network. ,e “string_interaction.tsv” filewas then imported into Cytoscape 3.7.2 to perform networkanalysis. ,e network had 44 nodes, which interacted with361 edges. ,e average node degree is 16.4, and the averagelocal clustering coefficient is 0.698. From yellow to green, thedegrees of freedom increase, and the thicker edges suggeststronger interactions (Figure 4). Our results indicated thatthe top mutual target proteins have various beneficialfunctions for treating PCOS at the molecular level.

In our network, the degree of the greenness of the nodesis high, and the numbers of edges of the nodes are 37 forAKT1; 32 for IL-6; 29 for VEGFA; 28 for CCND1, STAT3,MAPK1, and MAPK8; 27 for ESR1; 26 for FN1; 25 for

MMP9, CXCL8, and MAPK14; 23 for AR; and 22 forPPARG and HIF1A. ,ese results demonstrate that thesetargets are closely related to others in the network andconsequently may play key roles in PCOS.

AKTs have been confirmed to play an important role ingranulosa-lutein cell (GC) proliferation, and there is re-ciprocal feedback between AKT and androgen. ,is studyshowed that the high expression of AKT1 and AKT2 maycause GC dysfunction in PCOS patients through a possiblerelation with androgen [32]. Elevated serum levels of IL-6 inPCOS patients reflect low-grade chronic inflammation,which has been attributed to insulin resistance in PCOS [33].In a PCOS rat model, increased expression of IL-6 and IL-11was found to be associated with the AKT/STAT3 pathway.Increased levels of IL-6 and IL-11 stimulated adipocytesfrom adipose tissue of the PCOS rat model, which mayactivate AKT/STAT3 signalling and promote cell prolifer-ation. Vascular endothelial growth factor (VEGF) plays animportant role in the pathogenesis of many diseases. PCOSwas also considered to be associated with high expressionlevels of VEGF. It was found that VEGF was a pivotalmediator of other factors to control ovary angiogenesis inwomen who underwent assisted reproductive technology(ART) procedures [34].

,e MAPK signalling pathway is one of the most im-portant signal transduction pathways in organisms andmediates physiological and pathological processes, such asthe growth, development, and differentiation of organisms.Studies have shown that the MAPK signalling pathway playsan important role in the proliferation of ovarian granulosacells [35, 36].

Research confirmed that PPARG rs709154 and ESR1rs1999805 are significantly associated with PCOS risk in aChinese population [37]. MMP9 may also be involved in thepathogenesis of PCOS [38]. HIF1A can induce glycolysisgene expression and promote anaerobic metabolism [39].HIF-1a signalling was confirmed to be inhibited in a ratmodel with PCOS by increasing PHD activity [40].

3.5. Putative 'erapeutic Compound-Putative 'erapeuticTarget Network Construction. ,e Merge function ofCytoscape 3.7.2 software was used to combine the Drug-Mol-Gene target network and the PCOS-Drug-Gene in-teraction network. ,e results showed that 111 compoundsall together play a role in treating PCOS in the composite(Figure 5). ,e targets of 111 putative therapeutic targets inthe treatment of PCOS include AKT1, IL-6, VEGFA,CCND1, STAT3, MAPK1, MAPK8, ESR1, FN1, MMP9,CXCL8, MAPK14, AR, PPARG, and HIF1A.

3.6. GO Functional Enrichment Analysis. To further illu-minate the biological effects involved in the treatment ofPCOS with CDD, we performed GO analysis of the 44PCOS-related putative potential therapeutic target genes.GO annotation and enrichment of the genes encoding CDDwere conducted from three aspects: molecular function(MF), biological process (BP), and cellular composition

4 Evidence-Based Complementary and Alternative Medicine

Table 1: A list of the active compounds in CDD.

Mol ID Molecule name 0B (%) Caco-2 DLMOL001484 Inermine 75.18 0.89 0.54MOL001792 DFV 32.76 0.51 0.51MOL000211 Mairin 55.38 0.73 0.78MOL002311 Glycyrol 90.78 0.71 0.67MOL000239 Jaranol 50.83 0.61 0.29MOL002565 Medicarpin 49.22 1 0.34MOL000359 Sitosterol 36.91 1.32 0.75MOL003656 Lupiwighteone 51.64 0.68 0.37MOL003896 7-Methoxy-2-methyl isoflavone 42.56 1.16 0.2MOL000392 Formononetin 69.67 0.78 0.21MOL000417 Calycosin 47.75 0.52 0.25

MOL004805 (2S)-2-[4-Hydroxy-3-(3-methylbut-2-enyl)phenyl]-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4-one 31.79 1 0.72

MOL004806 Euchrenone 30.29 1.09 0.57MOL004808 Glyasperin B 65.22 0.47 0.44MOL004810 Glyasperin F 75.84 0.43 0.54MOL004811 Glyasperin C 45.56 0.71 0.4MOL004814 Isotrifoliol 31.94 0.53 0.42MOL004815 (E)-1-(2,4-Dihydroxyphenyl)-3-(2,2-dimethylchromen-6-yl)prop-2-en-l-one 39.62 0.66 0.35MOL004820 Kanzonol W 50.48 0.63 0.52MOL004827 Semilicoisoflavone B 48.78 0.45 0.55MOL004828 Glepidotin A 44.72 0.79 0.35MOL004829 Glepidotin B 64.46 0.46 0.34MOL004833 Phaseolinisoflavan 32.01 1.01 0.45MOL004835 Glypallichalcone 61.6 0.76 0.19MOL004838 8-(6-Hydroxy-2-benzofuranyl)-2,2-dimethyl-5-chromenol 58.44 1 0.38MOL004841 Licochalcone B 76.76 0.47 0.19MOL004848 Licochalcone G 49.25 0.64 0.32MOL004849 3-(2,4-Dihydroxyphenyl)-8-(1,1-dimethylprop-2-enyl)-7-hydroxy-5-methoxy-coumarin 59.62 0.4 0.43MOL004855 Licoricone 63.58 0.53 0.47MOL004856 Gancaconin A 51.08 0.8 0.4MOL004857 Gancaconin B 48.79 0.58 0.45MOL004863 3-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-8-(3-methylbut-2-enyl)chromone 66.37 0.52 0.41MOL004864 5,7-Dihydroxy-3-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)chromone 30.49 0.9 0.41MOL004866 2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)chromone 44.15 0.48 0.41MOL004879 Glycyrin 52.61 0.59 0.47MOL004882 Licocoumarone 33.21 0.84 0.36MOL004884 Licoisoflavone B 38.93 0.46 0.55MOL004891 Shinpterocarpin 80.3 1.1 0.73MOL004898 (E)-3-[3,4-Dihydroxy-5-(3-methylbut-2-enyl)phenyl]-1-(2,4-dihydroxyphenyl)prop-2-en-l-one 46.27 0.41 0.31MOL004910 Glabridin 53.25 0.97 0.47MOL004911 Glabridin 52.9 0.97 0.31MOL004912 Glabrone 52.51 0.59 0.5MOL004913 1,3-Dihydroxy-9-methoxy-6-benzofurano[3,2-c]chromone 48.14 0.48 0.43MOL004915 Eurycarpin A 43.28 0.43 0.37MOL004935 Sigmoidin B 34.88 0.42 0.41MOL004941 (2R)-7-Hydroxy-2-(4-hydroxyphenyl)chroman-4-one 71.12 0.41 0.18MOL004945 (2S)-7-Hydroxy-2-(4-hydroxyphenyl)-8-(3-methylbut-2-enyl)chromen-4-one 36.57 0.72 0.32MOL004948 Isoglycyrol 44.7 0.91 0.84MOL004949 Isolicoflavonol 45.17 0.54 0.42MOL004957 HMO 38.37 0.79 0.21MOL004959 1-Methoxyphaseollidin 69.98 1.01 0.64MOL004966 3′-Hydroxy-4′-0-methylglabridin 43.71 1 0.57MOL000497 Licochalcone A 40.79 0.82 0.29MOL004974 3′-Methylglabridin 46.16 0.94 0.57MOL004978 2-[(3R)-8,8-Dimethyl-3,4-dihydro-2H-pyrano[6,5-f]chromen-3-yl]-5-methoxyphenol 36.21 1.12 0.52MOL004980 Inflacoumarin A 39.71 0.73 0.33MOL004985 Icso-5-enoic acid 30.7 1.22 0.2MOL004988 Kanzonol F 32.47 1.18 0.89MOL004991 7-Acetoxy-2-methylisoflavone 38.92 0.74 0.26

Evidence-Based Complementary and Alternative Medicine 5

(CC). ,e most enriched terms in GO analysis are shown inFigures 6–8.

In detail, the top 18 terms in the GO BP category weremainly enriched in the regulation of developmental growth,reproductive system development, response to steroidhormone, epithelial cell proliferation, gland development,

regulation of epithelial cell proliferation, transcriptioninitiation from RNA polymerase II promoter, femalepregnancy, multi-multicellular organism process, DNA-templated transcription, initiation, muscle cell proliferation,ossification, regulation of DNA-binding transcription factoractivity, response to radiation, ameboidal-type cell

Table 1: Continued.

Mol ID Molecule name 0B (%) Caco-2 DLMOL004993 8-Prenylated eriodictyol 53.79 0.43 0.4MOL004996 Gadelaidic acid 30.7 1.2 0.2MOL000500 Vestitol 74.66 0.86 0.21MOL005000 Gancaonin G 60.44 0.78 0.39MOL005001 Gancaonin H 50.1 0.6 0.78MOL005003 Licoagrocarpin 58.81 1.23 0.58MOL005007 Glyasperin M 72.67 0.49 0.59MOL005012 Licoagroiosoflavone 57.28 0.71 0.49MOL005016 Odoratin 49.95 0.42 0.3MOL005017 Phaseol 78.77 0.76 0.58MOL005018 Xambioona 54.85 1.09 0.87MOL005020 Dehydroglyasperin C 53.82 0.68 0.37MOL000173 Wogonin 30.68 0.79 0.23MOL000184 NSC63551 30.25 1.42 0.76MOL000186 Stigmasterol 3-0-beta-D-glucopyranoside_qt 43.83 1.31 0.76MOL000188 3β-Acetoxyatractylone 40.57 1.22 0.22MOL000085 Beta-daucosterol_qt 36.91 1.3 0.75MOL000088 Beta-sitosterol 3-0-glucoside_qt 36.91 1.3 0.75MOL000092 Daucosterin_qt 36.91 1.42 0.76MOL000094 Daucosterol_qt 36.91 1.3 0.76MOL003542 8-Isopentenyl-kaempferol 38.04 0.53 0.39MOL000358 Beta-sitosterol 36.91 1.32 0.75MOL004027 1,4-Epoxy-16-hydroxypheneicos-1,3,12,14,18-pentaene 45.1 1.28 0.24MOL004053 Isodalbergin 35.45 0.8 0.2MOL004058 Khell 33.19 1.12 0.19MOL004068 Rosenonolactone 79.84 0.72 0.37MOL004071 Hyndarin 73.94 1 0.64MOL004074 Stigmasterol glucoside_qt 43.83 1.31 0.76MOL004077 Sugeonyl acetate 45.08 0.72 0.2MOL000449 Stigmasterol 43.83 1.44 0.76MOL013146 8,11,14-Docosatrienoic acid, methyl ester 43.23 1.53 0.3MOL001510 24-Epicampesterol 37.58 1.43 0.71MOL000953 CLR 37.87 1.43 0.68MOL001755 24-Ethylcholest-4-en-3-one 36.08 1.46 0.76MOL002670 Cavidine 35.64 1.08 0.81MOL002714 Baicalein 33.52 0.63 0.21MOL005030 Gondoic acid 30.7 1.2 0.2MOL000519 Coniferin 31.11 0.42 0.32MOL006936 10,13-Eicosadienoic 39.99 1.22 0.2MOL006957 (3S,6S)-3-(Benzyl)-6-(4-hydroxybenzyl)piperazine-2,5-quinone 46.89 0.41 0.27MOL003578 Cycloartenol 38.69 1.53 0.78MOL006129 6-Methylgingediacetate2 48.73 0.55 0.32MOL001771 Poriferast-5-en-3beta-ol 36.91 1.45 0.75MOL008698 Dihydrocapsaicin 47.07 0.98 0.19MOL005815 Citromitin 86.9 0.88 0.51MOL005828 Nobiletin 61.67 1.05 0.52MOL000275 Trametenolic acid 38.71 0.52 0.8MOL000282 Ergosta-7,22E-dien-3beta-ol 43.51 1.32 0.72MOL000283 Ergosterol peroxide 40.36 0.84 0.81MOL000287 3beta-Hydroxy-24-methylene-8-lanostene-21-oic acid 38.7 0.61 0.81MOL000296 Hederagenin 36.91 1.32 0.75

6 Evidence-Based Complementary and Alternative Medicine

ADRB2

AKT1

AR

PPARG

RXRAMAPK14GSK3B

wogonin

ESR1

ACHE

PGR

NOS2

SLC6A2

KDR

IL6

CASP9

MMP1 CCL2

FN1

CXCL8

3beta-acetoxyatractylone

CDKN1A

BCL2

BAX

CCND1

beta-daucosterol_qtCangzhuNSC63551

PCOS

(a)

CASP9

MAPK14

GSK3B

ADRB2 BCL2BAX

Isodalbergin sitosterol

Hyndarin

rosenonolactone

NOS2

ESR1

AR

PPARG

RXRA Khell

NCOA2DRD3

sugeonyl acetate

Xiangfu

stigmasterol glucoside_qt

NR3C2PON1

PCOS

8-Isopentenyl-kaempferol

PLAU

KDR

PGR

Stigmasterol

beta-sitosterol

SLC6A2

AKR1B1

DRD2

(b)

NR3C2

PON1

CLR

PLAU

Nanxing

SLC6A2

beta-sitosterol

AKR1B1

24-epicampesterol

NCOA2

ADRB2Stigmasterol

Sitosterol

PGR

RXRA

PCOS

BCL2

BAX

CASP9

(c)

gondoic acid

PPARG

baicalein

RXRA

ESR1

AR

NCOA2

CycloartenolBanxia

MMP9

(3S,6S)-3-(benzyl)-6-(4-hydroxybenzyl)piperazine-2,5-quinone

VEGFAPLAU

24-Ethylcholest-4-en-3-one

PCOS

Cavidine

ADRB2AKT1

BCL2

NR3C2

AKR1B1

10,13-eicosadienoic

coniferin

PON1

CASP9

SLC6A2

BAX

PGR

HIF1A

Stigmasterol

IGF2

beta-sitosterol

(d)

NR3C2PON1

ESR1

poriferast-5-en-3beta-ol

PLAU

Shengjiang

SLC6A2beta-sitosterol

AKR1B1

6-methylgingediacetate2

NCOA2

ADRB2 Stigmasterol

PGR

RXRA PCOS

BCL2BAX

CASP9

(e)

NR3C2

ESR1 Citromitin

PPARG

NOS2

AR

NCOA2nobiletin

MAPK8

TIMP1

MMP9 ESR2

GSK3B

sitosterol

PCOS

PGRChenpi

BAX

BCL2

CASP9

(f)

PPARG

AR Zhike

ESR1

GSK3BADRB2

TIMP1nobiletin

ESR2MMP9

MAPK8

NOS2beta-sitosterol

PON1

NCOA2

BCL2

PCOS

PGR

BAX

CASP9

(g)

ergosta-7,22E-dien-3beta-ol

trametenolic acid

NR3C2

PCOS

Fuling

RXRA

Ergosterol peroxide

hederagenin

SLC6A2

PGR

NCOA2

(h)

Figure 2: Continued.

Evidence-Based Complementary and Alternative Medicine 7

Xambioona

euchrenone

icos-5-enoic acid

Jaranol

Gancaonin AGlypallichalcone3-(3,4-dihydroxyphenyl)-5,7-dihydroxy-8-(3-methylbut-2-enyl)chromoneGancaonin B Glepidotin B gadelaidic acid dehydroglyasperins C

glyasperin BIsoglycyrol shinpterocarpin8-(6-hydroxy-2-benzofuranyl)-2,2-dimethyl-5-chromenolKanzonol F Vestitol

3'-MethoxyglabridinIsotrifoliol 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)chromone(E)-1-(2,4-dihydroxyphenyl)-3-(2,2-dimethylchromen-6-yl)prop-2-en-1-onekanzonols W 8-prenylated eriodictyol

licochalcone G Gancaonin G

GlabroneEurycarpin A

Calycosin

Licoagrocarpin

GSK3B ADRB2MAPK14

RXRA

PPARG

BCL2

AR

CCND1

KDR

Inermine

PCOSPGR

7-Methoxy-2-methyl isoflavoneGlabrene1,3-dihydroxy-9-methoxy-6-benzofurano[3,2-c]chromenone

Lupiwighteone Phaseol

Glycyrol

(2S)-7-hydroxy-2-(4-hydroxyphenyl)-8-(3-methylbut-2-enyl)chroman-4-one

DFV

3-(2,4-dihydroxyphenyl)-8-(1,1-dimethylprop-2-enyl)-7-hydroxy-5-methoxy-coumarin

Licoagroisoflavone

STAT3HSD3B1

HSD3B2

PPARD

ATP5F1B

ESR2

MAPK1

NR3C2

Phaseolinisoflavan IsolicoflavonolLicochalcone B Licoriconeformononetin HMO licochalcone a7-Acetoxy-2-methylisoflavone

Glabridin (2R)-7-hydroxy-2-(4-hydroxyphenyl)chroman-4-oneglyasperin F Glyasperin C(E)-3-[3,4-dihydroxy-5-(3-methylbut-2-enyl)phenyl]-1-(2,4-dihydroxyphenyl)prop-2-en-1-oneGancaonin HSigmoidin-B Odoratin

NOS2

IL4

ESR1

Gancao

ACHE

NCOA2

Medicarpin 1-Methoxyphaseollidin5,7-dihydroxy-3-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)chromoneGlyasperins M Licocoumarone3'-Hydroxy-4'-O-Methylglabridin 2-[(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano[6,5-f]chromen-3-yl]-5-methoxyphenolsitosterol

Licoisoflavone BGlycyrinSemilicoisoflavone BMairinGlabranin(2S)-2-[4-hydroxy-3-(3-methylbut-2-enyl)phenyl]-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4-oneGlepidotin AInflacoumarin A

(i)

Figure 2: ,e potential targets from the ingredients of the herbs in CDD in the treatment of PCOS. ,e yellow triangle, red diamond, blueoctagon, and the light pink ellipse nodes represent the herbs, targets, disease, and the molecules, respectively.

CYP17A1

FABP1 IL33

LTBP1MAOBMIR93PRKCASMAD1 GRB2EGFRSUMO1P1 OPRD1

HPINSIG2PRKCZ HSD17B1HECTD4 NPYPDE10A

MMP19

CYP1A2

CD40LGCARTPT

AKR1C3

APLN

PAEP MAPK14

LOC109029530

HOXA10

MEP1AACAN

PRKAA2

MIR16-1CXCL10

ICAM1

ALDH1A3

ENSG00000230704

ABCA1

LOC108783649

SGTA

WNT5A NCOA3

PCOS1 CDKN1A

HLA-A

SULT1E1FOXL2

HSP90AA1 CHRM2

CETP PTH2 MIR486-1PRSS1 SDC4 STK11 CCNA2

MIFNNTCCN5 FOXO1 ENO2WDR48 FN1

IL6ST PTH PDE11APCSK1TJP1 MEF2APLAT NR3C2

GSTM3

BAX

GSTP1

MSTN CGB5

JUN

SLC30A8

VCAM1GC

RXRB

IL1RN

NPPAIGFBP2CRH ADRB2

PON1 MIR323ANFATC1

DPP4PRDX2 SPARC LOXGORASP1 LMX1BPGR

TNC UCP2 SERPINF2 SOCS3BGLAP F3IAPP CYP11A1

NFIC PORPCSK9ATM MIR23AAQP8CCNB1

GSTT1

CZIB

IGF1R KCNH2AKT2IFNG EDNRB

HSD11B2 PIK3CGCYCS

MIR486-2 NOTCH3ADRA1BMIR106BEGLN1

PPIG PPARA APOBCYP19A1OXA1L CTRB1

GPT PPP1R3AMIR99AGAPDH BCL2HSD3B1

NFKB2 ANGPTL6ZNF217TGIF1 RELB DRD2

IL1A TNXBTIMP4HSPA5 MRO NOS3MAPK10

ACTR6 HSD17B13MIR518C MIOX IL10 NOBOX

KEAP1SMAD7CD4 HSPB1GFPT1MCF2L2PCNAMIR155ADOFGF2NDUFA6SLC17A5 VDRKRAS NPTN-IT1F5

ZFX TOR2A HDAC3ANXA5 CAT COG2DOCK1 CHRM1

PGRMC1

LOC108964933

ADAMTS1

KCNQ1

IRF3AFM

SCN5A LINC01572AHR

IGF2ARF6 INHBC APOA1CHEK1TPM1 GZMBADIPOR1 SORBS1CASP8 SMAD5 ADH1B

H6PDSET TRPV1 PRKAR2B CASP9GPER1AOPEP GATA6SH2B3 SERPINF1BBC3

MIR151AMCM2 LIF DSPPGGT1 ADMACE2MIR103A1

NPPBGLUD1 HGFFEM1A SFRP5KL INHBA

BDNFPCO1IL1B FGFR1PLIN3 NOS2 ANGPTL2NR1H2 ANGPTL8PTGS2

PRLARNTLMUC1 FSHBCHIT1APOA4 SLPIRAB5BLOC110408762 MMP9

PTEN HLA-DQB1SLC39A14 HMGCR TNFRSF11B AFA1LGALS3MAPK1

FAAHPYY HAMPPAX6 CXCL8RETN ACVR1 PBX1HTR3A

GDF9 TLR2GPC4CYB5A AVPTNFSF11 USP34 SULT2A1NCOA1

FLT1IGFBP4 PNPLA3 RUNX2LEP

PNPLA6 ALPPCAPN5 XPA HHEXCYP2R1 XIAP PDCD4SERPINA6GAS5 EIF6

DCN ACVR2BFADS1 SREBF1 CDH5BST2 MPOGNAQ PLIN1 TIMP2F2 NR1H3 CHST4BMP8ACDK2 OPRM1

NCOA4 CYBADNAH8CYP11B1VWFCSF1 CYP1A1AQP7THADA

BFSP1ADRA1D NOX5WT1SHBGSLC22A1 FOXC2 ADRB1CREB1

SLC2A4RG MIR27BPCK2NPPC TGFB1TTRGJA1PRKAB1 IRS1

STAR STS EDN2 PDE8AALOX12 AR MIR592 CTBP1-ASPKIA

HSP90B1 FNDC5 TGFAVTNPLA2G7 HCRTHBG2CHKB TIMP1

PLCB1 SFRP4AKR1B1TBC1D4 SNAI2ZNF318 SERPINA12 SLC9A1APOD

THBS1SOCS1 EPHA7GNB3 LPAABCC8 C3TGFBR3 AGA2

Chenpi

PCOS

Nanxing

ZhikeShengjiang

Cangzhu

Gancao

FBN3 NQO1HFETP53NRIP1 FAS BANCRSRA1 HIF1A

IRS4 CDKN1CGIPFOXO3 MIR222UGT2B15GRPEGF LEPQTL1

CNR1 DRD3 LHB IL18 COL27A1 AGTR1 VCAN FMR1

IFIH1HBA1 ANGPTL1CDKAL1MIR16-2 PKD1TBL1XR1TIMP3 CFLAR

XiangfuFuling

IL17A

Banxia

HLA-BGAL MIR574PTX3 SRD5A1

LINC-ROR SUOXIDE ITFG1 IL6R

EDN1 SLC22A3CD28APLNRGCG

MT-TL1CX3CL1CCK PROK1RELA

MTR C1QTNF12DENND1A LBPIL6 FGF19SLC4A2 GH1ITGAVCHRNA2

CLEC16ASAA1 SLC2A4LOC110386951 MTORMIR145 MUC16ALDH3A2 SST CD163

ILKTPM2INSL3 GAD2PRKAA1KCNK5MUC5AC FSHR

ITLN1 CELF4MCM4 FADS2 GET3 MMP26 RXRA

HNF1AALBHSD3BP4FABP4 LHFPL3 LOC109623489MAP2

RAD54B MMP2 FGF21AFPAPOC1 SRD5A2

APMAPMC4R TH VIM IGF1

FTO

LIPE

MTNR1B CDK5

KIF1B PRKAG3STON1-GTF2A1L

PNPLA2

PTGER3

FOSL2

MIR320A

SOS1

MYC KCNJ11

MAOA TDRD7 IL5 MIR23BIGFBP5 KCNJ5 MIR26BLUMINSR

HSPA1A

BMP15

TTC21A

IRS2

GLUL

PCGF1

MIR146A

CYP11B2

KLK3

IL2RA

PYGM

SLC22A2

CPB2

MIR27A

NCOA2

SCNN1G

CAV1

APOE

LEPR

GNRHR

ENHO

CHRM5

C1QL3

CGA

NOTCH1

SREBF2

TNF

IFI27

CD63

ZFP36L2

PWRN2

TNFSF12

IL4

G6PD

F13A1

CCL2

SMAD2

PLA2G4A

AMHR2

CDK4

AGA3

ESM1

MMP1

ATP5F1B ADRB3

CALCA

LIPC

MAP3K2-DT

TRIB3

GYS1

PIK3R1

NR5A1

TM4SF4

HAS2

AGER

KNG1PRPF8 ENPP1CDC27PGFYAP1

MIP IGFBP3LMNA GJA4 KISS1RGHRL

ZNF143 GYS2HBB THBDIGF2R SERPINE1

CAPN10 RAB8B HMGA2ENG C1QTNF3IGFBP1

HSD11B1-AS1 TEP1FEM1B IL11AKR1C1RB1

ESR1TAC3 PER2HSD17B6 PRKCD

SKIL MIR30C1POMCHMGB1 PTGS1

IL2

GPX3

MIR25

MIR30C2

ADA

GAB1

PPARGC1A

BMP6TXNRD2

NM

CASR

CTLA4

MMP8

SELL

SELPHAS1

MIR181A1

IGFL3

SERPINC1

PEPD

LCN2

ADRA1A

GDF15

FGF13

ADIPOR2

PPARG

COL8A1

AHSG

AKT1

SMAD3

CDH1

ITGAX

MAPK7

ATOX1

MTNR1A

LTA

GLP1R

GTF2A1L

EPHX1

GSK3B

GFPT2

PCO NGFR

GNASHAS3

CHRM3

ESR2

LDLR SORCS1

SFTPDCLOCK BRCA1

FOS

MCL1

EPB41L3LYZ

MIAT UCN3 BFSP2 SERPINA13PSMAD4GSTM1 TNFSF15

NR3C1CCN2XDH CHRM4CCL3 SLC6A4FGFR2 GRIA2

IGFBP6 TFAMFERMT3 GHR

PTK2 ANGPTL4

NUCB2

MIR223

SLC30A10 LHCGR

IL1R1AQP9 ADRA2A HOTAIR SLC18A2UTS2VEGFA

SPP1 NCOR1 NGF LINC01828XIRP1STAT3APC ERBB4 PPARD

TXNIPSLC4A3FSTADIPOQMIR19B1WNT4CHGAHSPE1 KISS1 F7

CAMK2G LOC108863620 REN TCF7L2HLA-GLTA4HCYP21A2 ADRA2CHSD3B2

SCN11A IL23A ROCK1TNFRSF1B PECAM1 BCO1LPLAGTR2MIR21 MDM2 MAPK3 SOD1 GHRHITGB3IL7INHBB CASP3

CYP1B1KRT18 ZP4 TGFB3S100BACVR2A LOC100506124CRP EPHB2

PEPCCCN1 SLC6A2TGFB2CSRNP1 COMTMGAMND6

INTS6 SERPINA4HMOX1FANK1 CYP3A7 INSL5AGT TP63

MIR200C

GREB1

CSF3

STXBP3 CP

ACE TNFRSF11A WNT3A

LPIN1

GP5

CDK6

CD36

FEM1C MTHFR

OCTN3

INHA

HSD3B7

CHI3L1

HSD11B1

GHSR

MT-ATP6MSR1

LPP

AHSA1

MIR483

PDP1

HSD17B2

NAMPT

ADH1C

KDR

FOSL1

AMHHLA-DRB1TACR3 CCND1 APPL1 SPTLC1TOX3 ACHE

INS

IRX5

PRDX4

GNRH1

GABRA1

ATHS

PAFAH1B1

MAPK8

SLC6A3 ENSG00000286145FBN1TPO

RBP4NDUFS4 RARRES2PLAU

ENSG00000234940

Figure 3: ,e CDD-PCOS-related drug targets. ,e blue octagon, yellow hexagon, green ellipse, mint green triangle, and red diamondrepresent disease, herbs, PCOS-related targets, CDD-related targets, and the common targets between CDD and PCOS, respectively.

8 Evidence-Based Complementary and Alternative Medicine

ESR1

GSK3B

MAPK1

NOS2

PPARD

IL4

TIMP1

DRD2

CCND1PON1

ACHE AKT1

MMP9

DRD3

MAPK14

HIF1A

PLAU

VEGFA

IL6

RXRA

BAX

KDR

MAPK8

AKR1B1

FN1

NR3C2

PGR

HSD3B1

MMP1STAT3

CXCL8BCL2CASP9

PPARG

SLC6A2 CDKN1A

ADRB2

IGF2NCOA2

ARHSD3B2CCL2 ESR2

Figure 4: PPI network of targets for CDD in treating PCOS (from yellow to green, the degrees of freedom increase, and the thicker edgessuggest stronger interactions).

TNFRSF11BIL10

LOXNPPB

AMHR2

PBX1

IL18

SLC2A4

HLA-DRB1

SGTASST

UCP2NR5A1

EPHX1

PTH

HHEXITGB3

HSD17B2

IL2

MSTNCOMT

CD40LGVWF

CAPN5NUCB2FEM1BTP53NGFRCGB5

C1QTNF12EGFFLT1APOE

ENSG00000286145

ENSG00000230704

AMH

ENSG00000234940

AFA1

ADIPOR2

ADIPOR1THADA

IL1B

MC4RVDR

PYY

MIF

ADAMTS1

ALDH1A3ICAM1

IGFBP3GIP

PPARGC1A

SERPINA12

GH1

AKR1C3

FNDC5

PLA2G7

CHIT1

ANGPTL8

RUNX2

MIR21

PDP1

LPIN1

SERPINF1SULT2A1

VCAM1

GAL

TOR2A

BFSP1ITFG1

IRS4HAS3

CCN1AOPEPSUMO1P1

HBA1HCRT

HOXA10PNPLA6

SULT1E1

PDE8ATNFSF12

HAS1HAS2

TRPV1

IGF2R

TGFB3WNT4

SH2B3

SERPINF2

HMGA2PKD1

FMR1GPT

FGF21APOC1

SOD1ADRB3

LIFSLC30A8

SUOX

CDKAL1GYS1

IL6RSELP

LPA

AVP

FABP1NCOR1

HAMP

MCM2C3

CD36EDNRBMIR16-1

SLC18A2

SLC17A5

ARF6

SLC22A1FOXC2

GGT1KL

LTBP1

FGF2XDHMMP8ENG PGFAHSGMIR574MIR151AMIR518CATHSHDAC3CNR1EDN1CETPHNF1ASPP1

ENHOTOX3

HLA-ATIMP2C1QL3RAB5B

MIR222MUC1

MIR146A MAPK3GPER1NR1H3 MIR483ADAIAPP

SNAI2F3LIPCADMCHGACSF3MUC5AC

NOTCH3CRP FAS

SERPINE1CYP21A2

PCOS1 FGFR2

PCOS

STSH6PD

PAEPTGFB2SRD5A2

ADIPOQ

CGAPORDENND1A

NR3C1

REN

AGA2

AGA3

POMC

HSD11B1

ITLN1PCSK9

IL17AGSTM1

AKT2 MMP26

IGFL3FEM1C

HSP90AA1

GRP

MIR320A

KCNJ5

PPARA

TLR2

LEPQTL1

PWRN2

HSD11B2

GNAS INHA

PEPDWT1

DPP4MIR23B

PLAT

LHCGR

MIR23AHSD3BP4

GPX3

HP

ADOLOC108964933PTX3

ANXA5STK11

SREBF1

LCN2RARRES2INHBBHSD17B6PGRMC1GHRGNRHRCYP1A1GHRH

ZNF143UTS2

STXBP3NPY

LOC110408762IGF1R

APPL1GLP1R

MIR103A1MIR27B

CRHLMNA

VIMLIPE

KCNJ11

FEM1AMIR93MTNR1A

YAP1PTEN

IGFBP2SMAD4

MTNR1BINHBASERPINC1KLK3

GCGCG IL1RNLHBIGFBP4STARF2NGF

LGALS3IL7

INSL3

LDLR

SETPRKCZ

GJA4

MIR323A

ARNTL

MSR1

FBN3APOA1

LINC01828

AGER

GAS5

GDF9

SRD5A1

RBP4GATA6

ACEFTOAPOB ALBIRS2 FSHBNAMPT F5CDH5TNXBMTHFR

KIF1BCYP1A2

AFP

TXNRD2

CFLAR

PRL

LEP

FST

SHBG

G6PD

GSTP1

XIAP

FSHR

INS

MCM4

MUC16

NNTFOXL2

PDE11A

NOBOXHECTD4

CYP11A1CYP17A1

CYP19A1

INSRGNRH1

IGF1

GHRLIRS1

IGFBP1CAPN10

HSD11B1-AS1TCF7L2TNF

RETNOCTN3

BANCR

CCN5

LOC109029530

CTBP1-ASMIR26B

ATMNOS3

HSPB1

SLC39A14

CX3CL1

APOA4SLC22A3

EDN2

NDUFS4

IL11HSD3B7

PIK3R1

CPB2

MMP2HMOX1

LPL

FABP4

CCKACVR2A

IL1AAPLN

ENPP1

AFMIL33

ESM1GTF2A1L

IL23A

ZFP36L2SLC2A4RGAPMAP

GSTT1

PRDX4APLNR

PPP1R3AGDF15

GNAQFGFR1

SMAD3

MMP19GAD2

CP

CAV1

BDNF

TTRNCOA3HSPA5

ITGAVCD28

ACVR1CYP1B1

KCNQ1

IL2RAGJA1

CDH1

TM4SF4

PTH2PROK1

ANGPTL2BCO1

MCF2L2

ZP4MIR99AMIR592

CDC27MGAM

MIPNCOA4CCN2

ANGPTL1COL8A1

C1QTNF3MIOX

HLA-GTHBDTJP1

SLC22A2

MYC

MIR181A1MTOR

SLC9A1

MT-TL1

NOTCH1PCNA

WNT3A

CASRTACR3PRKAB1

CD4GLUD1

CYBAHBB ACTR6MROHOTAIRMIATMIR200CNFKB2

SPTLC1PLCB1ENO2GLULSOS1ROCK1

PCSK1KEAP1ILK

1,4-Epoxy-16-hydroxyheneicos-1,3,12,14,18-pentaene

Khell

sitosterol

Isodalbergin

rosenonolactoneHyndarin

sugeonyl acetatestigmasterol glucoside_qt

Stigmasterol8,11,14-Docosatrienoic acid, methyl ester

beta-sitosterol 3-O-glucoside_qt

beta-daucosterol_qt

daucosterol_qt

daucosterin_qt

3-beta-acetoxyatractylone

8-Isopentenyl-kaempferolbeta-sitosterol

24-epicampesterol

CavidineCLR24-Ethylcholest-4-en-3-one

CREB1FOSL2 PRKCAALOX12 KCNH2Xiangfu

EPHB2CASP3

PYGMBanxiaHTR3A

PKIA

ND6

CHRM5

CCNB1Nanxing

CD163

APOD AHSA1 PLA2G4A CHRM1

NFATC1

MAP2

EGLN1TNFSF15

Cycloartenol(3S,6S)-3-(benzyl)-6-(4-hydroxybenzyl)piperazine-2,5-quinone10,13-eicosadienoic6-methylgingediacetate2 coniferinbaicaleingondoic acidporiferast-5-en-3beta-olnobiletinDihydrocapsaicin

Citromitin

GSK3BESR1 IL4RXRA

CASP9 DRD3

MAPK14 NOS2LOC108863620

CDK2

IDEFOXO1

TPM1KRAS

TNFRSF1B

ESR2

PPARD BCL2

MMP1

AKT1

NR3C2

MAPK1

SLC6A2

IL6

AR

TIMP1

DRD2

BAX

HIF1A

MMP9

CXCL8

KDR

CCND1

STAT3

PPARG

IGF2 NCOA2VEGFAATP5F1B PGR ADRB2

HSD3B2

AKR1B1

CCL2

HSD3B1

ACHE

MAPK8

PON1

FN1

PLAU

CDKN1A

MIR106B

PEPCLOC110386951

PCO1PCOSRA1

STON1-GTF2A1L

MIR25MIR486-1

LOC108783649

CYP11B1EPHA7SMAD2MEF2A

SCNN1G

SPARC

GSTM3FBN1

PDCD4CXCL10SMAD1GAB1KISS1RSREBF2LPPFERMT3PRKAG3PECAM1LUM

MIR145MIR16-2MIR19B1

USP34IFI27PCGF1

PAX6TPOMAPK7GAPDHDCNMTRNPPA

NDUFA6SFRP4CSF1

TFAM

HMGB1

AQP7TRIB3

MIR486-2INSL5ANGPTL6TXNIP

THBRCA1PRKAA2ACVR2BGRB2KRT18NR1H2PTK2PIK3CG

SERPINA4XPA

PPIGKNG1PLIN3PRPF8FGF13

HLA-BCTLA4

GPC4

CYP2R1GNB3

HSP90B1

GHSRFAAHTNFRSF11APAFAH1B1TGFBR3GZMBPRKAR2BTIMP3HLA-DQB1

GP5ZFX

ZNF318

GORASP1CELF4

WDR48IRX5

DNAH8ZNF217

XIRP1

SORBS1

SLC4A3SLPI

RAB8BEPB41L3

BST2ATOX1

OXA1LKCNK5

RELB

PCK2S100B

CAMK2G

DOCK1CHKB

SFTPDLMX1B

SMAD7HBG2

CD63SCN11A

SLC4A2

UGT2B15COL27A1

NPPC

GYS2

ACAN

VCAN

ABCA1

HMGCR

APCF13A1

BMP6NRIP1

CSRNP1MT-ATP6

GET3LHFPL3

TTC21A

SERPINA13PCZIB

LINC-RORLOC100506124MEP1A

HSPA1ASOCS3

CHI3L1CYP3A7

AQP9

PNPLA2

COG2BGLAP

ITGAXMIR30C1MIR30C2

LEPRKISS1

BMP15PNPLA3INSIG2

NFIC

AGTNQO1

CATCDK5

ERBB4

IFNGTNFSF11

NM

INHBCBMP8A

SFRP5

UCN3MIR27A

MIR223

FADS2IGFBP5

AKR1C1LTA

FADS1SAA1

IGFBP6SMAD5

RAD54B

LOC109623489

CARTPTGREB1

MIR155

TGFB1

THBS1ANGPTL4

TPM2SOCS1

HSD17B1TBC1D4

FOXO3

PRDX2

IL6STABCC8

PLIN1

CYP11B2

IL1R1IL5

AQP8CCL3

MDM2WNT5A

MAP3K2-DT

LBP

NSC63551

Licoagroisoflavone

Odoratin

Phaseol

wogonin

Xambioona

Stigmasterol3-O-beta-D-glucopyranoside_qt

dehydroglyasperins C

Gancaonin GGancaonin H

Glyasperins M

Licoagrocarpin

Vestitol

PDE10A

CangzhuSLC6A4MAOB RELA CTRB1 NCOA1

BBC3 CHRM2MAPK10 PRSS1

FOSL1CYCSADH1C

AHR

F7

LTA4HADRA1A RXRBPTGER3

JUN

GlabreneGlabrone1,3-dihydroxy-9-methoxy-6-benzofurano[3,2-c]chromenoneEurycarpin ASigmoidin-B(2R)-7-hydroxy-2-(4-hydroxyphenyl)chroman-4-one(2S)-7-hydroxy-2-(4-hydroxyphenyl)-8-(3-methylbut-2-enyl)chroman-4-oneIsoglycyrol

Inflacoumarin Aicos-5-enoic acid

Kanzonol F7-Acetoxy-2-methylisoflavone

8-prenylated eriodictyolgadelaidic acid

CHRNA2

ChenpiCHRM4

FulingADH1B

GancaoSCN5A

3'-Hydroxy-4'-O-Methylglabridin1-MethoxyphaseollidinHMOIsolicoflavonol

licochalcone a3'-Methoxyglabridin

2-[(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano[6,5-f]chromen-3-yl]-5-methoxyphenol

MPO

ADRA1D

TDRD7 RB1

GRIA2TEP1

EGFRCDK4CDK6HGF

SLC30A10CYB5AALPPTAC3

HFEFGF19

CDKN1CTGFAIRF3TNCACE2PRKAA1IFIH1AGTR1 GFPT1BFSP2DSPPHSPE1TIMP4

SORCS1INTS6LINC01572NPTN-IT1

CLEC16ACHST4GFPT2CALCA

FANK1HSD17B13

SELLPER2VTNAGTR2SDC4TBL1XR1ALDH3A2TGIF1CLOCKSERPINA6SKIL

Phaseolinisoflavan

Semilicoisoflavone B

Glepidotin B

Glepidotin A

Glypallichalcone

8-(6-hydroxy-2-benzofuranyl)-2,2-dimethyl-5-chromenolLicochalcone B

licochalcone G

Gancaonin ALicoricone

3-(3,4-dihydroxyphenyl)-5,7-dihydroxy-8-(3-methylbut-2-enyl)chromone

3-(2,4-dihydroxyphenyl)-8-(1,1-dimethylprop-2-enyl)-7-hydroxy-5-methoxy-coumarin

Gancaonin B

5,7-dihydroxy-3-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)chromone

euchrenone

glyasperin B

(2S)-2-[4-hydroxy-3-(3-methylbut-2-enyl)phenyl]-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4-one

glyasperin F

Glyasperin C

Isotrifoliol

(E)-1-(2,4-dihydroxyphenyl)-3-(2,2-dimethylchromen-6-yl)prop-2-en-1-one

kanzonols W

MedicarpinLupiwighteone

7-Methoxy-2-methyl isoflavoneformononetin

Calycosin

OPRM1

LYZ

NOX5

CHRM3

CCNA2

MCL1

ADRB1

OPRD1

SLC6A3

EIF6

LicocoumaroneGlycyrin

2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)chromone

Licoisoflavone Bshinpterocarpin

(E)-3-[3,4-dihydroxy-5-(3-methylbut-2-enyl)phenyl]-1-(2,4-dihydroxyphenyl)prop-2-en-1-oneGlabridinGlabranin

ADRA2C

MAOA

FOS

ADRA2A

PRKCD

Zhike

ADRA1B

GABRA1

PTGS1

TP63

CASP8

CHEK1

ShengjiangPTGS2

InermineDFV

MairinGlycyrol

Jaranol

trametenolic acidergosta-7,22E-dien-3beta-olErgosterol peroxide

3beta-Hydroxy-24-methylene-8-lanostene-21-oicacid

hederagenin

Figure 5: Herb-compound target-PCOS target network of CDD. ,e blue octagon, mint green triangle, yellow hexagon, green paral-lelogram, pink red V, and red diamond represent disease, PCOS-related targets, herbs, CDD-related targets, molecules, and the commontargets, respectively.

Evidence-Based Complementary and Alternative Medicine 9

migration, autophagy, and process utilizing autophagicmechanism (Figure 6).

,e top 19 terms in the GO CC category were mainlyenriched in nuclear chromatin, secretory granule lumen,cytoplasmic vesicle lumen, vesicle lumen, extracellularmatrix, nuclear chromosome part, chromatin, glutamatergicsynapse, platelet alpha granule lumen, platelet alpha granule,RNA polymerase II transcription factor complex, nucleartranscription factor complex, transcription factor complex,postsynaptic density, receptor complex, asymmetric syn-apse, neuron to neuron synapse, postsynaptic specialization,and basement membrane (Figure 7).

,e top 19 terms in the GO MF category were mainlyenriched in RNA polymerase II proximal promoter se-quence-specific DNA binding, proximal promoter se-quence-specific DNA binding, nuclear receptor activity,transcription factor activity, direct ligand regulated se-quence-specific DNA binding, steroid hormone receptoractivity, protein heterodimerization activity, receptor reg-ulator activity, nuclear hormone receptor binding, hormonereceptor binding, phosphatase binding, cytokine receptorbinding, receptor ligand activity, chromatin binding, steroid

binding, protein phosphatase binding, growth factor ac-tivity, cytokine activity, protein serine/threonine kinaseactivity, DNA-binding transcription activator activity, RNApolymerase II-specific, transcription coregulator activity,and RNA polymerase II transcription factor binding(Figure 8).

3.7. Pathway Analysis. To clarify the biological actions ofthese targets, we performed KEGG analysis and pathwayenrichment analysis with the RStudio (Bioconductor) da-tabase. We listed the genes of major PCOS putative thera-peutic targets and imported them into RStudio to generaterelevant pathways that might have an important influenceon the biological process of CDD in treating PCOS. Path-ways with an adjusted p value< 0.05 were consideredsignificant.

A total of 123 signalling pathways were significantlyenriched through pathway enrichment analysis. In thehistogram and bubble diagram (Figure 9), the colour, size,and length of the nodes and bars were determined accordingto the numbers and p values of the related genes. ,e colour

BH domain bindingMAP kinase activity

Chemokine receptor bindingRNA polymerase II transcription factor bindingPotein serine/threonine/tyrosine kinase activity

Receptor regulator activityCytokine activity

Growth factor activityProtein heterodimerization activity

Protein phosphatase bindingCytokine receptor binding

Phosphatase bindingHormone receptor binding

Steroid bindingNuclear hormone receptor binding

Proximal promoter sequence-specific DNA bindingRNA polymerase II proximal promoter sequence-specific DNA binding

Steroid hormone receptor activityTranscription factor activity, direct ligand regulated sequence-specific DNA binding

Nuclear receptor activity

0.0 2.5 5.0 7.5

0.0030.0020.001

p.adjust

BH domain bindingMAP kinase activity

Chemokine receptor bindingProtein serine/threonine/tyrosine kinase activityRNA polymerase II transcription factor binding

Cytokine activityGrowth factor activity

Protein phosphatase bindingSteroid binding

Cytokine receptor bindingPhosphatase binding

Hormone receptor bindingNuclear hormone receptor binding

Receptor regulator activityProtein heterodimerization activity

Steroid hormone receptor activityTranscription factor activity, direct ligand regulated sequence-specific DNA binding

Nuclear receptor activityProximal promoter sequence-specific DNA binding

RNA polymerase II proximal promoter sequence-specific DNA binding

0.05 0.10 0.15 0.20GeneRatio

Count2468

0.0030.0020.001

p.adjust

Figure 6: GO MF enrichment analysis of therapeutic targets of CDD in treating PCOS.

10 Evidence-Based Complementary and Alternative Medicine

from blue to red reflects the adjusted p values from large tosmall, and the node size and bar length indicate the numberof related genes. ,e histogram and bubble chart wereseparately arranged according to the p value and the numberof related genes. According to the p value, the AGE-RAGEsignalling pathway in diabetic complications, Kaposi sar-coma-associated herpesvirus infection, proteoglycans incancer, endocrine resistance, hepatitis B, the IL-17 signallingpathway, prostate cancer, the prolactin signalling pathway,human cytomegalovirus infection, pancreatic cancer, theHIF-1 signalling pathway, and EGFR tyrosine kinase in-hibitor resistance were within the top 12 terms. According tothe number of related genes, Kaposi sarcoma-associatedherpesvirus infection, proteoglycans in cancer, the PI3K-Aktsignalling pathway, the AGE-RAGE signalling pathway indiabetic complications, human cytomegalovirus infection,hepatitis B, endocrine resistance, the IL-17 signallingpathway, prostate cancer, the HIF-1 signalling pathway,Epstein–Barr virus infection, and the prolactin signallingpathway were in the top 12 terms. ,e overlapping terms ofthe above lists included the AGE-RAGE signalling pathway

in diabetic complications, endocrine resistance, the IL-17signalling pathway, the prolactin signalling pathway, and theHIF-1 signalling pathway.

AGE-RAGE signalling may activate multiple intra-cellular signalling pathways involving protein kinase Cand MAPKs and may influence NF-κB activity. Researchhas shown an association between PCOS and chronicinflammatory factors, proinflammatory cytokines suchas interleukin-1, interleukin-6, interleukin-17 [41–43],and tumour necrosis-α, and a variety of inflammation-related genes, including VEGF, tissue factor, and RAGE[44, 45].

Prolactin (PRL) is involved in a variety of biologicalfunctions, including osmotic regulation, reproduction, lac-tation, endocrinology and metabolism, growth and devel-opment, and immunomodulation. It is a polypeptidehormone secreted by the pituitary gland that regulates thefemale reproductive and endocrine system by activatingpathways, including the MAPK and PI3K pathways [46].Insulin resistance is a common type of endocrine resistanceand is related to PCOS by deregulating the IRS-PI3K-Akt

Mammary gland alveolus developmentCellular response to molecule of bacterial origin

Positive regulation of developmental growthCellular response to lipopolysaccharide

Cellular response to biotic stimulusRegulation of epithelial cell proliferation

Mammary gland developmentGland development

Muscle cell proliferationDNA-templated transcription, initiation

Multi-multicellular organism processMammary gland epithelium development

Maternal process involved in female pregnancyFemale pregnancy

Epithelial cell proliferationTranscription initiation from RNA polymerase II promoter

Response to steroid hormoneReproductive system development

Reproductive structure developmentRegulation of developmental growth

0 5 10 15

6e − 084e − 082e − 08

p.adjust

Mammary gland alveolus developmentMammary gland epithelium development

Maternal process involved in female pregnancyCellular response to molecule of bacterial origin

Positive regulation of developmental growthCellular response to lipopolysaccharide

Mammary gland developmentCellular response to biotic stimulus

Muscle cell proliferationDNA-templated transcription, initiation

Multi-multicellular organism processFemale pregnancy

Transcription initiation from RNA polymerase II promoterRegulation of epithelial cell proliferation

Gland developmentEpithelial cell proliferation

Response to steroid hormoneReproductive system development

Reproductive structure developmentRegulation of developmental growth

0.15 0.20 0.25 0.30 0.35GeneRatio

6e − 084e − 082e − 08

p.adjust

Count5.07.510.012.515.0

Figure 7: GO BP enrichment analysis of therapeutic targets of CDD in treating PCOS.

Evidence-Based Complementary and Alternative Medicine 11

signalling axis that integrates aberrant inflammatory re-sponses [47].

A previous study also revealed that hypoxia-induciblefactor-1a (HIF-1a) mediated endothelin-2 (ET-2) signallingand plays an important role in ovulation in rats and indi-cated that HIF-1a signalling is inhibited in a PCOS rat modelby increasing PHD activity [40].

4. Discussion

TCM plays a crucial role in the pharmaceutical industry, al-ternative medicine, and many other fields [48–50]. However,due to the complex chemical composition and unclearpharmacological mechanism of action of TCMs, it faces greatobstacles in pharmacological research, quality control andsupervision, modernization, and internationalization [51].

TCM gives priority to the concept of holism in diagnosisand pays more attention to the overall changes in function.,e treatment is based on syndrome differentiation, em-phasizing the recovery of overall function, which is similar tothe network concept of network pharmacology [52].

Traditional research methods on TCM mainly rely onpharmacochemical and pharmacological experiments,which have many problems, such as low data flux, lowprecision, long cycles, and high costs. ,e construction anddevelopment of a network pharmacology analysis platform,TCM database, and target prediction technology hasbrought new ideas and strategies for the study on the basisand mechanism of the pharmacodynamic substances ofTCM to clarify characteristics such as the good curativeeffects, high safety profile, and multicomponents andmultitargets of TCM [53]. ,ese developments also lead to anew direction for the modernization and internationaliza-tion of TCM [54].

,e combination of bioinformatics, computer technol-ogy, and experiments in the study of the pharmacodynamiccomponents and potential targets of TCM broke through thedeficiency of traditional studies is more rapid, flexible, andaccurate and has been widely used in research on the net-work pharmacology of TCM [55].

TCM has a long history in treating menstrual diseasesand infertility related to PCOS and has achieved good effects

Postsynaptic densityTranscription factor complexFicolin-1-rich granule lumen

Smooth endoplasmic reticulumCyclin-dependent protein kinase holoenzyme complex

Glutamatergic synapseBasement membrane

ChromatinPore complex

Nuclear chromosome partExtracellular matrix

Dopaminergic synapseNuclear transcription factor complex

RNA polymerase II transcription factor complexVesicle lumen

Cytoplasmic vesicle lumenSecretory granule lumen

Nuclear chromatinPlatelet alpha granule

Platelet alpha granule lumen

0 2 4 6

0.030.020.01

p.adjust

Smooth endoplasmic reticulumCyclin-dependent protein kinase holoenzyme complex

Pore complexDopaminergic synapse

Ficolin-1-rich granule lumenBasement membranePostsynaptic density

Transcription factor complexNuclear transcription factor complex

RNA polymerase II transcription factor complexPlatelet alpha granule

Platelet alpha granule lumenGlutamatergic synapse

ChromatinNuclear chromosome part

Extracellular matrixVesicle lumen

Cytoplasmic vesicle lumenSecretory granule lumen

Nuclear chromatin

0.06 0.08 0.10 0.12 0.14GeneRatio

0.030.020.01

p.adjust

Count23456

Figure 8: GO CC enrichment analysis of therapeutic targets of CDD in treating PCOS.

12 Evidence-Based Complementary and Alternative Medicine

[56]. In this study, several network pharmacology-basedmethods were used to predict potential targets. ,is ap-proach provides new clues to exploring ethnopharmacologyand herbal or even TCM formulas. ,rough the analysis ofthe putative therapeutic target network and biologicalfunctions in this study, the potential pharmacological andmolecular mechanisms of CDD in treating PCOS werepreliminary revealed.

In this study, the preliminary analysis based on networkpharmacology provided a basis for subsequent studies on thepharmacodynamic ingredients and mechanisms of CDD.However, due to the limitations of the screening conditionsand the TCM database, this study also has some short-comings. Although a large number of targets and pathwayswere obtained through network pharmacology screening,these results must be verified by subsequent pharmacologicalexperiments. In this study, the active components of CDDand their molecular mechanisms in PCOS were predictedoverall, and a variety of potential therapeutic targets wereexplored. ,us, this study lays a good theoretical foundationfor the next step of experimental verification and provides

directions for further research on the molecular mechanismof PCOS.

Data Availability

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

Disclosure

,e funders had no role in study design, data collection andanalysis, decision to publish, or preparation of themanuscript.

Conflicts of Interest

,e authors declare that they have no conflicts of interest.

Authors’ Contributions

XWT designed the study, analyzed the data, and wrote themanuscript; WLH supervised the study and revised the

Endometrial cancerYersinia infection

Thyroid hormone signaling pathwayPI3K-Akt signaling pathway

Non-small cell lung cancerBladder cancer

Small cell lung cancerColorectal cancer

EGFR tyrosine kinase inhibitor resistanceHIF-1 signaling pathway

Pancreatic cancerHuman cytomegalovirus infection

Prolactin signaling pathwayProstate cancer

IL-17 signaling pathwayHepatitis B

Endocrine resistanceProteoglycans in cancer

Kaposi sarcoma-associated herpesvirus infectionAGE-RAGE signaling pathway in diabetic complications

0 5 10

1.5e − 071.0e − 075.0e − 08

p.adjust

Endometrial cancerBladder cancer

Non-small cell lung cancerYersinia infection

Thyroid hormone signaling pathwaySmall cell lung cancer

Colorectal cancerEGFR tyrosine kinase inhibitor resistance

Pancreatic cancerProlactin signaling pathway

HIF-1 signaling pathwayProstate cancer

IL-17 signaling pathwayEndocrine resistance

Hepatitis BHuman cytomegalovirus infection

AGE-RAGE signaling pathway in diabetic complicationsPI3K-Akt signaling pathway

Proteoglycans in cancerKaposi sarcoma-associated herpesvirus infection

0.20 0.25 0.30GeneRatio

1.5e − 071.0e − 075.0e − 08

p.adjust

Count8101214

Figure 9: KEGG enrichment pathway analysis of therapeutic targets of CDD in treating PCOS.

Evidence-Based Complementary and Alternative Medicine 13

manuscript; TMY andWJH obtained and analyzed the data.All authors have read and agreed to publish this manuscript.

Acknowledgments

,is work was supported by the Science and TechnologyDevelopment Plan of SuZhou in 2018 (SYSD2018002), theScience and Technology Development Plan of SuZhou in2018 (SYSD2018195), the Projects for Science and Tech-nology of Chinese Medicine of Jiangsu Province in 2019(YB201959), and the “333” Project in Jiangsu Province in2019 (BRA2019140). ,e special funds of the Key ClinicalDisease in Diagnosis and Treatment Technology of SuZhouin 2019 (LCZX201920) also provided financial support forthis study.

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