Exploring the Possible Mechanism and Drug Targets of Huang-Qi-Gui

Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2020, Article ID 2363262, 12 pages https://doi.org/10.1155/2020/2363262

Research Article Exploring the Possible Mechanism and Drug Targets of Huang-Qi-Gui-Zhi-Wu-Wu Decoction for the Treatment of Chemotherapy-Induced Peripheral Neuropathy on Network Pharmacology

Jia-lin Gu ,1,2 Guo-li Wei,1,3 Yu-zhu Ma,1,2 Jin-zhi Zhang,1,2 Yi Ji,1,2 Ling-chang Li,1,3 Jia-lin Yu,1,3 Can-hong Hu,1,3 and Jie-ge Huo 1,3

1Department of Oncology, Aﬃliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, China 2Graduate School, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, China 3Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu 210028, China

Correspondence should be addressed to Jie-ge Huo; [email protected]

Received 14 April 2020; Revised 7 November 2020; Accepted 12 November 2020; Published 23 November 2020

Academic Editor: Adolfo Andrade-Cetto

Copyright © 2020 Jia-lin Gu et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment, which may influence its successful completion. )e Huang-Qi-Gui-Zhi-Wu-Wu decoction (HQGZWWD) has been widely used to treat CIPN in China although the pharmacological mechanisms involved have not been clarified. Using the network pharmacology approach, this study investigated the potential pathogenesis of CIPN and the therapeutic mechanisms exerted by the HQGZWWD herbal formula in CIPN. )e targets of HQGZWWD were identified using traditional Chinese medicine (TCM) databases (TCMSP and ETCM) and prediction platforms (PharmMapper and TargetNet), and the genes of CIPN were collected by DisGeNET, GeneCards, and literature search. )e common target interaction network between herbal formula and diseases was constructed by using Cytoscape. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to reveal the mechanism and efficacy of HQGZWWD in the treatment of CIPN. A total of 153 CIPN-related genes were screened, and a protein-protein interaction (PPI) network with 96 nodes and 424 edges was constructed. Sixty-three active components were retrieved from HQGZWWD, with a herb-composite compound-target network including 748 nodes and 5448 edges. Forty-one targets belong to the above two networks. )e analysis of network results and literature review shows that the main pathological processes of CIPN may be the inflammatory response and nerve injury, and HQGZWWD plays a therapeutic role in CIPN by regulating inflammatory response and repairing nerve injury, thus verifying the reliable efficacy of this herbal formula. In addition, we found two new potential therapeutic targets (CDK7 and GSTM2) warranting further investigation. )is study fully illustrates that TCM has the characteristics of a multicompound, multitarget, and multipathway treatment, which is of great significance to study the curative effect of herbal formulations.

1. Introduction oxaliplatin and taxanes, rates may be as high as 90% [1]. )e occurrence of CIPN is dose dependent and may be relieved Chemotherapy-induced peripheral neuropathy (CIPN) is by dose reduction or drug withdrawal. )e emergence of one of the most common side effects of chemotherapy with CIPN seriously affects the efficacy of chemotherapy and the platinum drugs, taxanes, Catharanthus roseus alkaloids, quality of life of patients [2]. CIPN usually occurs in the early thalidomide, and bortezomib. It has been reported that the stages of chemotherapy; its typical clinical manifestations total incidence of CIPN is more than 60%, while for include sensations of symmetrical burning or tingling, loss 2 Evidence-Based Complementary and Alternative Medicine of sensation, and numbness at the ends of the extremities. 2. Methods of Data Preparation Physical examination reveals fine motor impairment and sensory ataxia, as well as motor neuropathy and proprio- 2.1. Composite Compounds of HQGZWWD. ADME refers to ceptive impairment, such as myasthenia and muscle bundle the process of absorption, distribution, metabolism, and tremor [3, 4]. Further, autonomic neuropathy such as ab- excretion of exogenous compounds, which can reflect the dominal pain, diarrhea, constipation, postural hypotension, dynamic changes of drug activity in animals or humans. It is and laryngospasm are often accompanying symptoms. an important guide to the development of new drugs and to Neurogenic pain is also a clinical symptom, which is more the design of compounds [17]. We searched the Traditional likely to have more of a physical and mental impact on Chinese Medicine Systems Pharmacology Database and patients, and often needs auxiliary pain relief and antide- Analysis Platform (TCMSP, http://tcmspw.com/tcmsp.php), pressant therapy [5]. )e emergence of CIPN will lead to which is the most widely used information query platform tension in patients, affect their quality of life, reduce the for TCM, to identify the composite compounds and targets treatment dose, prolong chemotherapy treatment, or even of HQGZWWD [18]. A total of 790 compounds were stop treatment, thus interfering with the achievement of the identified: 87 in Hedysarum Multijugum Maxim, 220 in desired effect. Cinnamomi Ramulus, 85 in Paeoniae Radix Alba, 265 in )e management of CIPN has entered a stage of com- Zingiber Officinale Roscoe, and 133 in Jujubae Fructus. All prehensive treatment. Traditional Chinese Medicine (TCM), molecules were screened according to the ADME criteria as an important part of the Complementary and Alternative (oral bioavailability ＞30% and drug likeness ＞0.18) rec- Medicine (CAM) approach, plays a key role. Increasing data ommended by TCMSP [19, 20]. A total of 63 compounds show that TCM has an obvious efficacy in the prevention were selected. Notably, 14 of these effective compounds were and treatment of cancer and its complications, including verified by ultraperformance liquid chromatography- radiotherapy, chemotherapy, and postoperative recovery quadrupole-time-of-flight mass spectrometry (UPLC-Q- [6–8]. TOF-MS) technology in our previous study, and several )e Huang-Qi-Gui-Zhi-Wu-Wu decoction compounds are included: jaranol, isorhamnetin, for- (HQGZWWD) was first published in the Synopsis of Golden mononetin, calycosin, kaempferol,(3R)-3-(2-hydroxy-3,4- Chamber written by Zhang Zhongjing, a medical scientist in dimethoxyphenyl)chroman-7-ol, quercetin, sitosterol, the Han Dynasty (25 AD), and represents one of the more (+)-catechin, paeoniflorin, benzoyl paeoniflorin, and por- commonly used clinical herbal formulations. It consists of iferast-5-en-3beta-ol (Supplementary Tables S1 and S2). five herbs: Hedysarum Multijugum Maxim (Huang Qi), Cinnamomi Ramulus (Gui Zhi), Paeoniae Radix Alba (Bai 2.2.CompoundTargetsofHQGZWWD. In order to make the Shao), Zingiber Officinale Roscoe (Sheng Jiang), and Jujubae targets of HQGZWWD more comprehensive, we have Fructus (Da Zao). Its main function is to supplement qi, the added descriptions of target information from the Ency- warming meridian, and to ease pain. HQGZWWD is mainly clopedia of Traditional Chinese Medicine (ETCM, http:// used for the hand-foot syndrome, CIPN, diabetic peripheral www.nrc.ac.cn:9090/ETCM/). )e ETCM was updated in neuropathy, and rheumatoid arthritis. Previously, we have 2018 and provides a more professional ADME evaluation confirmed the efficacy of HQGZWWD in the prevention and enhanced information on compounds and targets [21]. and treatment of CIPN without reducing antitumor activity Based on the limitations of the database, we also used of chemotherapeutic drugs in the animal model and cancer PharmMapper (http://lilab-ecust.cn/pharmmapper/) and patients [9]. However, the potential therapeutic mechanism TargetNet (http://targetnet.scbdd.com/), both of which are involved has not been fully elucidated. target prediction platforms. )e former predicts the target Network pharmacology is based on the similarity of the using a pharmacophore model, which models the molecular structure and efficacy of drugs to construct a drug-target docking of compounds through characteristic features and network to explore the mechanisms of action of different the spatial arrangement of pharmacologically active mole- agents. It emphasizes the multichannel regulation of sig- cules [22]. TargetNet builds a large number of quantitative naling pathways to improve the therapeutic effects of drugs structure activity relationship (QSAR) models based on the and to reduce their toxicity and adverse effects, so as to input compounds to predict targets [23]. Next, UniProt improve the success rate of new drug clinical trials and save (https://www.uniprot.org/) was used to standardize all target on the costs involved in drug research. Network pharma- names. Some compounds for which the target information cology is a current research hotspot applied to clarify the could not be identified were excluded. In total, 48 com- effective components and treatment activity of TCM [10]. It pounds were selected (Supplementary Table S3). has been widely used to explore the therapeutic mechanisms of TCM in diseases involving the cardiovascular and nervous systems, respiratory diseases, diabetes, cancer, and osteo- 2.3. Targets of CIPN arthropathy and has achieved significant results [11–16]. )e purpose of this study was to analyze the pathogenesis of 2.3.1. Targets from Known Databases. )e molecular targets CIPN and the potential therapeutic mechanisms of for CIPN were obtained from GeneCard (https://www. HQGZWWD through network pharmacology, so as to genecards.org/) and DisGeNET (https://www.disgenet.org/). provide a theoretical basis for the clinical application of GeneCard is an authoritative platform for human gene an- herbal formulations. notation information that integrates human gene information Evidence-Based Complementary and Alternative Medicine 3 from other databases [24]. DisGeNET integrates a large CSF2). )is suggests that these genes may be the key genes or number of data about disease-associated genes and variants central genes affecting the development of CIPN (Figure 1). from multiple sources, covering almost all areas of human diseases [25]. In addition, we searched the PubMed database (https://www.ncbi.nlm.nih.gov/pubmed/) to supplement in- 3.2. GO Functional Analysis of the CIPN Network. formation on the disease gene. )rough the modular analysis of the CIPN network using the Mcode cluster, the entire network was divided into three clusters (Figure 2). 2.3.2. Target Supplement. GeneMANIA (http://genemania. )ese clusters were then interpreted using GO biological org/), developed by the University of Toronto, was used to process (GO-BP) analysis. )e top 10 most significantly analyze and identify dominant genes and provided genomic enriched BP terms in each group were selected for analysis. and proteomic data to discover functionally similar genes )e results showed that cluster 1 included the immune [26]. We uploaded the disease targets downloaded from response, cellular response to lipopolysaccharide, positive GeneCard and DisGeNET to the database and output a list of regulation of nitric oxide biosynthesis, positive regulation of 20 resultant genes. chemokine biosynthesis, and inflammatory response. )rough database screening, literature search, and Cluster 2 included mechanisms involving transcription- prediction target supplements, a total of 153 disease genes coupled nucleotide-excision repair, transcription elongation were selected (Supplementary Table S4). from the RNA polymerase I promoter, nucleotide-excision repair, and DNA incision. Cluster 3 included processes 2.4. Protein-Protein Interaction Network. )e protein-pro- involved in glutathione derivative biosynthesis, cellular tein interaction (PPI) networks in this article were all derived detoxification of nitrogen compounds, glutathione meta- from String V11.0 (https://string-db.org/), which was bolism, and xenobiotic metabolism (Figure 3). updated in November 2018, to search for functional inter- actions between proteins and help to mine core regulatory 3.3. KEGG Pathway Enrichment Analysis of CIPN Targets. genes in the network [27]. All disease genes were uploaded to DAVID, and 13 pathways were obtained, of which four pathways contained more 2.5. Network Construction. We constructed three networks: enriched genes (i.e., 20 in pathways in cancer, 18 in the (i) the CIPN network, (ii) the herbal-compounds-targets PI3K-Akt signaling pathway, 13 in the Jak-STAT signaling network for HQGZWWD, and (iii) the HQGZWWD-CIPN pathway, and 10 in the MAPK signaling pathway) (Figure 4). overlapping targets network. All networks were built through the network visualization software Cytoscape (V3.7.2 https://cytoscape.org/), an open source network that 3.4. Herbal-Compounds-Targets Network of HQGZWWD. focuses on data visualization and analysis. Its core function is )is network consisted of 728 nodes (5 herbal nodes, 48 to provide a basic functional visual layout and query network compound nodes, and 675 compound-target nodes) and based on the combination of basic data [28]. In addition, we 5448 edges, of which 6 compounds (mairin, beta-sitosterol, modularized the CIPN network through the Mcode cluster (+)-catechin, quercetin, stigmasterol, and kaempferol) function in Cytoscape, which is conducive to better mining appeared in more than two herbs, and many targets (such as the core functions of the network. GSTM1, GSTM2, ACHE, and ESR2) that were targets of multiple compounds. In addition, 41 overlapping targets (peripheral nodes, such as CYP2C8, GSTM1, AGXT, 2.6. Gene Ontology Functional and Kyoto Encyclopedia of GSK3B, and ABCC4) were identified after comparing herbal Genesand GenomesPathway EnrichmentAnalysis. )e Gene formula targets with CIPN targets, of which three targets Ontology (GO) function and Kyoto Encyclopedia of Genes (AGXT, ABCC4, and PPARD) were not identified in the and Genomes (KEGG) pathway enrichment analyses of all previously constructed disease network, and two targets targets were obtained from the Database for Annotation, (CDK7 and GSTM2) were obtained from the predictive Visualization and Integrated Discovery (DAVID, V6.8, platform. Finally, using the DAVID platform, we found that https://david.ncifcrf.gov/), which integrates biological data the targets in herbal formulations were enriched in a variety and analysis tools to provide comprehensive biological of diseases such as lung cancer, type 2 diabetes, bladder function annotation information for the large-scale gene or cancer, chronic obstructive pulmonary disease, colorectal protein lists [29]. cancer, and chronic renal failure (Figure 5).

3. Results 3.5. HQGZWWD-CIPN Overlapping Targets Network. 3.1. =e CIPN Network. Information relative to 150 targets )e above 41 overlapping targets were inserted into the PPI was extracted from String, and 96 nodes and 424 edges were network and denominated the HQGZWWD-CIPN com- constructed under the condition of high conﬁdence. In this mon target network. A total of 40 nodes and 247 edges were network, targets with a higher degree are regarded as the constructed, in which 7 targets had a higher degree in the core targets (32 in STAT3, 31 in IL6, 28 in TNF, 24 in IL10, network (29 in TP53, 27 in ALB, 23 in IL6, 23 in VEGFA, 22 24 in VEGFA, 23 in TP53, 22 in IL2, 22 in IL4, and 21 in in CASP3, 21 in TNF, and 20 in CYP3A4). )ese nodes were 4 Evidence-Based Complementary and Alternative Medicine

BCR FGD4 ARHGEF10

TGFB1 RRM1 RHOBTB2 DES GTF2H1 GTF2H3 FANCD2 IL17RD OPRM1 IGF1R CXCL8 ITGB3 CDK7 ERCC3 IL4R XPA TAC4 EDN1 CTSS ERCC5 TAC1 CSF3 CTLA4 HTR3A ERCC2 ERCC4 IL4 IL10RA CCNH CXCR4 STAT3 IFNG NDRG1 F2 NTRK1 ERCC1 MNAT1 BDNF EPO VEGFA XRCC1 ABCB1 IL6 IL10 SERPINB2 CYP1B1 ICAM1 FASLG TP53 IL2RA GSTP1 ITGA1 CYP3A5 ALB FAS IL2 CSF2 DCC THBS4 CYP3A4 HSPB1 TNF TLR4 CYP2C8 CD40LG ALOX12 IL1B MTHFR SOD2 BCL2 CASP3 CSF3R CYP17A1 GSTM1 DPYD GSK3B MKI67 TNFRSF1B PSMB1 GSTM3 GSTM2 TYMP APOE MBL2 AURKA BTRC AIFM1 SLCO1B1 ABCA1 ABCG2 GPX7 CEP72 ABCC1

Figure 1: CIPN target protein-protein interaction network. Nodes with a darker color have a higher degree in the network.

ICAM1 XRCC1 ALB GSTM1 ERCC1 GSTM2 IL2RA IL4 CCNH CYP3A5 IL2 STAT3 ERCC3 IFNG GTF2H1 MNAT1 CSF2 IL6 XPA CDK7 VEGFA CXCL8 CYP3A4 GTF2H3 GSTP1 IL10 TNF ERCC2 TLR4 ERCC5 ERCC4 IL1B GSTM3 CSF3 FANCD2 CYP2C8

(a) (b) (c)

Figure 2: Mcode clustering of CIPN targets in the protein-protein interaction network. (a–c) represent clusters 1, 2, and 3, respectively. predicted to play a core role in the treatment of CIPN with region; and (iii) “molecular functions (MF)” involving cy- HQGZWWD (Figure 6). tokine activity, oxygen binding, growth factor activity, and glutathione binding. KEGG pathway enrichment analysis 3.6. GO Functional and KEGG Pathway Enrichment Analysis showed that the overlapping targets were mainly involved in ofOverlapping Targets. To study the biological functions and cytokine and inﬂammatory responses as well as the T-cell metabolic pathways of these key targets, DAVID analysis receptor, NF-kappa B, HIF-1, TNF, and Jak-STAT signaling was employed to analyze overlapping targets. GO functional pathways (Figures 7(a) and 7(b)). analysis revealed the following target-associated terms: (i) “biological processes (BP)” involving negative regulation of 4. Discussion apoptosis mechanisms, immune responses, positive regulation of chemokine biosynthetic processes, and positive At present, the mechanisms involved in CIPN have not been fully regulation of nitric oxide biosynthetic processes; (ii) “cell elucidated and may include disruption of neuronal axonal trans- components (CC)” comprising the extracellular space, ex- port, mitochondrial dysfunction, inﬂammatory stimulation, oxi- ternal side of the plasma membrane, and extracellular dative stress, nerve injury, and changes in ion channel activity. )e Evidence-Based Complementary and Alternative Medicine 5

Immune response Cellular response to lipopolysaccharide Positive regulation of gene expression Positive regulation of MHC class II biosynthetic process Positive regulation of chemokine biosynthetic process Inﬂammatory response Defense response to protozoan Negative regulation of apoptotic process Positive regulation of cell proliferation Positive regulation of calcidiol 1-monooxygenase activity

Transcription-coupled nucleotide-excision repair Nucleotide-excision repair, preincision complex assembly Nucleotide-excision repair, preincision complex stabilization Nucleotide-excision repair, DNA incision, 3'-to lesion Nucleotide-excision repair, DNA incision, 5'-to lesion Nucleotide-excision repair, DNA incision Transcription elongation from RNA polymerase I promoter Termination of RNA polymerase I transcription Global genome nucleotide-excision repair Transcription initiation from RNA polymerase I promoter

Glutathione derivative biosynthetic process Cellular detoxiﬁcation of nitrogen compound Nitrobenzene metabolic process Glutathione metabolic process Lipid hydroxylation Xenobiotic metabolic process Xenobiotic catabolic process Oxidative demethylation Metabolic process Steroid metabolic process

0 5 10152025 –Log10 (P value)

Cluster 1 2 3 Figure 3: GO biological process analysis of CIPN clusters. pathogenesis of CIPN is mainly associated with injury to sensory antidepressants, and antiepileptic agents are commonly used in neurons in the dorsal root ganglion caused by chemotherapeutic clinical treatment [32, 33]. )e only agent currently recommended drugs. )e incidence and severity are not only related to individual for the treatment of neuralgia caused by CIPN is duloxetine [34, 35]. factors but also include the type of agent, cumulative dose, treat- A “stop-and-go” strategy is generally adopted, which involves ment schedule, and treatment time [30]. )e classic treatment stopping treatment with the drug immediately, reducing the drug strategy is still prevention and management of symptoms [31]. Ion dose, or prolonging the time of chemotherapy and then resuming channel modulators, neuroprotective agents, antioxidants, tricyclic treatment after the symptoms are relieved [36]. 6 Evidence-Based Complementary and Alternative Medicine

EDN1 TNF THBS4 CD40LG ITGB3 CTLA4 TLR4 ICAM1

ITGA1 TNFRSF1B

GSTP1 IL1B

FAS SOD2 NOD-like receptor Neurotrophin signaling signaling pathway VEGFA BDNF pathway Wnt signaling pathway

GSK3B HSPB1 MAPK signaling pathway

NTRK1 Toll-like receptor BTRC signaling pathway

BCL2 NFATC4 FoxO signaling pathway

CXCR4 Jak-STAT signaling IL4 pathway

CASP3 NF-kappa B signaling CSF3 pathway

IGF1R CSF2 Pathways in cancer

TGFB1 IL6 TNF signaling pathway

PI3K-Akt signaling FZD3 pathway IL2RA T-cell receptor signaling pathway HIF-1 signaling pathway FASLG STAT3

CXCL8 IL10

TP53 IL10RA

BCR IL4R PPARD IFNG DCC CSF3R EPO IL2

Figure 4: KEGG pathways of CIPN targets.

)rough previous animal studies, we determined that First, we constructed and analyzed the core network of HQGZWWD could reduce the intake of platinum in the CIPN, in which regulatory genes including STAT3, IL6, dorsal root ganglion of the oxaliplatin rat model and could TNF, IL10, VEGFA, TP53, IL2, IL4, and CSF2 were iden- promote platinum pumping, so as to reduce accumulation of tified. Among these was STAT3, which not only participates platinum and prevent chronic peripheral neurotoxicity in- in the signal transduction pathways of many cytokines induced by exposure to oxaliplatin [37]. A meta-analysis cluding interferon, interleukins, and growth factors but also showed that HQGZWWD could effectively prevent and regulates important functional activities such as cell growth, reduce oxaliplatin-related peripheral neurotoxicity [38]. differentiation, migration, apoptosis, autophagy, immunity, )erefore, we propose that HQGZWWD can effectively and metabolism. Studies have shown that STAT3 is not only reduce and alleviate the incidence and severity of CIPN. involved in the inflammatory response but also mediates )rough network pharmacology, we constructed the core tumorigenesis and stages of carcinogenesis [39, 40]. Fur- networks involved in CIPN and mechanisms of action of thermore, STAT3 also has an effect on peripheral nerve cell herbal formulations to explore the underlying pathogenesis regeneration and participates in nerve repair [41]. )e cy- of CIPN and to explore any molecular therapeutic mech- tokines IL6, TNF, IL10, IL2, and IL4 are all immunomod- anisms and/or pathways potentially associated with ulatory factors, among which TNF and IL-6 have been HQGZWWD. confirmed to be involved in the pathological process of Evidence-Based Complementary and Alternative Medicine 7

AGXT MTHFR PPARD GSTM1 ABCC4

ICAM1 Berberine (S)-Coclaurine (-)-Taxifolin Coumestrol Malkangunin IL6

CASP3 Jujuboside A Stepholidine MLNR DRD3 BCHE MAPK9 DRD4 FGFR2 PDE10A CTRB1 Spiradine A PTON1 FDPS Nuciferin TP53 CACNA1H IL8 PTGER3 WARS GJA1 CCL2 BIRC5 DUOX2 TNF HTR5A F3 ABCA2 PPIA MYC NFE2L2 Stepharine CA9 Protoporphyrin CDC37 CAV1 SIRT1 APP PTGES CA14 PARP1 SLC18A2 ACACA PKIA HCAR2 CHEK2 IL1B BCAT2 ATP5F1B S1PR4 HTR1D RAF1 CLDN4 CTSG PNMT PCK1 EIF4E DCPS PADI4 SHMT1 VEGFA CCR2 GCK SLC5A2 HRH2 Dihydrocapsaicin CASP8 DDX6 MET SLC5A1 ALDH2 IGFBP3 Fumarine CHRNA4 TGFB2 OAT CLEC4E ABL1 CRHR1 KIT HTR1F MMP2 MTAP RXRG IGF2 PAH HNF4G ADRA2B BLVRB CNR1 CHRFAM7A PLAU HPRT1 PLA2G2A ADAM17 GART IRF1 NOS1 LTB4R IGF1 PIK3R1 PTAFR HSPB1 Poriferast-5-en-3beta-ol FGG LCK PTPN7CTDSP1MCL1 RBP4 CA1 Ceanothic acid UGE1 BCL2L1 APOBEC3G NR2E3 RORA ALK ERBB3 BRS3 PRKACA PTPN1 DNMT1 COMT IL4 APAF1 MTNR1A CNR2 PRKCB CCND1 PPP1CC AKR1B1 MAPK10 PPARG PON1 DDP4 TUBA1A CTSB PROCRADK IMPDH2 TBXAS1 ATIC MTNR1B MMP13 SEC14L2 TNKS PYGM OPRK1 CA3 6-Methylgingediacetate2 SULT1E1 EPHX2 TTPA GTSM2 BCL2A1 CHEK1 ITGAL XDH Moupinamide FLT4 DRD2 HDAC8 F7 KCNA5 SDS TGFB1 HAGH GABRG3 PRKCA DUSP3 LCN2 SIGMAR1 GABRQ MAPK14 RAC1 PGF MAPK1 ESR2 CYP27B1 NOS3 RHEB OPRL1 HTR1A CA2 MMP12 MAPKAPK2 PLEKHA4 SOD2 SPR ALOX5 GRIN3A VDR THRA SYK PLA2G10 REN FKBP1A SLCO1A2 SLC22A8 CDK6 NCF1 GSTT2B Benzoyl paeoniflorin KCNMA1 PTGDR GABRG1 CYP2B6 GC CYP24A1 FABP5 Beta-carotene AVPR1A GPI RARB PTPN22 HMGCR ESRRB S1PR1 OLR1 SQLE PDE4D AMY2 RXRB CYP19A1 HOXA10 TYK2 GABRA6 NOS2 IFNG WAS CYP3A43 TTR P2RX7 TPI1 SORD SCN5A SLC22A4 ABCC3 RELA ALPL KIAA1310 CACNA1S PPO2 SHBG ABCB11 SLC6A3 NR1I3 ACHE OXTR RAB11A NR1H2 BACE1 SLC10A6 ADH1C CYP1A2 HSPA8 Albiflorin HDAC2 PRSS1 MAOB PLG (-)-Catechin AURKA DTYMK NCOA1 ABCC2 TOP2 RAB9A HTR2A CYP2A13 PLA2G1B PLK1 JAK3 MME KIF11 GRIN2C RIPK2 TOP2A CTSF HSP90AB1 CA12 HDAC6 ISG20 IKBKB RNASE4 CMA1 OPRD1 Zingiber Officinale PDE4B CHRNA2 ADH5 ABO UGT1A4 NCOA2 NR3C1 SULT2B1 ESRRA HEXB GRIN2B Roscoe NR2F2 CD40LG PTGS2 MIF Paeoniflorin HDAC1 FKBP1B BTK F10 GSTA1 AKT1 PLIN1 BAX MAP2 MMP10 MAP2K1 Jujubae Fructus UMPS (3S,6R,8S,9S,10R,13R,14S,17R) CYP2R1 AKR1C1 CYP2E1 GABRP BCL2 DPP4 GRIN2A CHRM4 CA7 S100A9 CCL5 CLK1 KCNH2TRAPPC3 RARG PTK2B UAP1 SERPINE1JUN NR1H3 COA7 Hedysarum PTPN2 CALM3 DHODH PPARA CYP27A1 CYP2J2 Multijugum Maxim LSS SERPINA6 SRD5A2 GPER RPS6KA3 RNASE3 GABRD GMPR MDM2 AHSA1 Lactiflorin DUSP1 TADA3 HPGDS CAT CYP2C8 Peroxyergosterol SLC6A2 MTTP FABP3 S1PR2 EIF3F CA13 CLEC4A ADAM33 SULT2A1 GSTT2 MAPK8 FABP7 CASP9 HSD11B1 CYP2C19 Paeoniae Radix Alba PRLR CES1 GRIN2D PDE4A CACNA1B IGF1R PDE3A MMP3 CHRM1 TERT HNMT SOAT1 SLC16A7 CASP1 TOP1 HTR4 Cinnamomi Ramulus FYN MMP1 PTPN11 GRIN1 MAOA SLC22A1 GRIN3B GRM2 LYZ CDK2 HSD11B2 FABP6 CDC25B DYRK1A Jaranol (3S,5R,8R,9R,10S,14S)-3,17-Dihydroxy AMD1 SOAT2 STK17B EPHA2 PTGIR STAT1 CYP3A5 PTK2 IGHG1 CA4 DHFR HDAC3 METAP2 GABRE CYP2C9 SLC22A3 NR1I2 CHRM2 PTGER4 THRB RXRA AKR1C2 TYMS MMP8 RUVBL2 SLCO2B1 HMOX1 PTPRC GRIA2 CYP2D6 CYP1A1 CA6 SERPINA1 TRPV1 MTHFD1 GABRA4 ESR1 CA5A PTGER2 OPRM1 Paeoniflorgenone MMP9 MPO NR3C2 CYP11A1 ESRRG FABP4 Hederagenin NQO1 ADRA1B HIBCH PGR ATP5B HSD17B2 VCAM1 PTGER1 CA5B TUBB2B GNPDA1 FAAH GABRB2 SLC22A7 SLC10A1 AR GM2A CTNNA1 NCOA6 UGT3A1 HSP90AA1 HSD17B3 APRT YARS GALR3 CES2 HAS2 CYP1B1 CFD GABRA2 SLCO1B3 FECH HSD17B1 B3GAT1 NR1H4 EFTUD1 MGLL GLO1 CYP11B2 SF3B3 GPR35 S1PR5 HCK NT5M CD209 GRB2 NME2 GABRA3 GABRA1 PSMD3 Mairin EPHB4 CYP11B1 PTGS1 CHRM5 ANG KAT2B (3S,8S,9S,10R,13R,14S,17R) HTR3A MSD1 CSNK2A1 GABRA5 GABRB1 PIM1 GSR CASR PREP GABRB3CYP3A7GABRG2 TLR9 BRAF PTN HSD3B1 SRC SLC2A4 EGFR SLC6A4 CSNK2B ADRA2C STS NQO2 RAB5A PYGL HDAC4 CYP4A11 HTR1E APOBEC3A FGFR1 TNNC1 ME2 ACTB FDFT1 SRD5A1 CBR1 INSR PNP FFAR1 ALOX15 ACE CHRM3 ELANE HK1 ABCG2 (+)-Catechin NR0B1 HSPA2 CEBPB F11 Isorhamnetin PTGFR PSPH HTR7 NOS2A SLC16A1 UBA1 DCK PDPK1 DIO1 ERBB4 TGFBR1 PIK3CG JAK1 BST1 CYP2A6 ATP5C1 AHR ATP5A1 BHMT CTSS GSTZ1 DRD1 ARHGAP1 PPP3CA TAAR1 CTSD ANXA1 UCK2 GP1BA TEK HTR6 SLC22A11 AKR1C3 CTSK Beta-sitosterol KIF5A SLC22A6 CCNA2 SLPI 3,9-Di-O-methylnissolin PRKAA1 CASP7 HTR2C KDR GMPR2FKBP3SELE HRAS GSTA3 CHIT1 LTA4H ITPKA BIRC7 HTR1B NMNAT1 HADH SLCO4C1 IL10 RARA ADRA2A ADRB1 CD1A HPN DRD5 ADRB2 IMPA1 RHOA ADRA1A ADRA1D SLCO1C1 Stigmasterol EDNRBHRH1EDNRA XIAP CDK7 RAC2 TK1 CDA SETD7 MTHFD2 7-O-Methylisomucronulatol CHRNA7 GALK1 CCNT1 PMS2 ACPP MAN1B1 MTFMT AMY1A MAPK12 AMY2ATGM3 TNK2 ACADM MTR ABCB1 GCKR GBA SLC22A5 Quercetin ARL5A ITGAV DPEP1 TPSB2 HCRTR1 IGHG2 9,10-Dimethoxypterocarpan-3-O--D-glucoside GSTM2 PAPSS1 JAK2 CDK5R1 RAN CDC42ITGA2BFOLH1 NPS2 ATP1A2 GPBAR1 GSTP1 Kaempferol ATP1A3 CRABP2 (6aR,11aR)- ATP1A1 ITK CTSL FNTA PRKCQ ZAP70 9,10-Dimethoxy-6a, 11a-dihydro-6H-benzofurano[3,2-c]chromen-3-ol F2 Isomucronulatol-7,2'-di-O-glucosiole Bifendate (3R)-3-(2-Hydroxy-3, 4-dimethoxyphenyl)chroman-7-ol Formononetin ABCC1 Calycosin GSK3B FA 1, 7-Dihydroxy-3, 9-dimethoxy pterocarpene SLCO1B1 IL2 ALB CYP17A1 CYP3A4

Figure 5: Herbs-compounds-targets network of HQGZWWD. Red triangle nodes represent herbs, diamond nodes represent compounds, green diamond nodes represent repeated compounds in herbs, peripheral nodes represent overlapping targets between HQGZWWD and CIPN, gray round nodes were not identified in the previously constructed CIPN targets network, and blue rounds represent targets derived from predictive data. peripheral nerve injury [42, 43]. )e core biological pro- pathways, including the Jak-STAT, NF-kappa B, MAPK, and cesses of CIPN include the immune response, positive Toll-like receptor signaling pathways. )e Jak-STAT sig- regulation of nitric oxide biosynthesis, inflammatory re- naling pathway is widely involved in cell proliferation, sponse, and positive regulation of chemokine biosynthesis. differentiation, and apoptosis, which can promote the oc- Nitric oxide exerts both anti-inflammatory and proin- currence and development of inflammation and tumors. flammatory regulatory effects. Its proinflammatory activity Dominguez et al. [45] found that this pathway can be ac- is mainly manifested in the promotion of the proliferation of tivated in the spinal cord microglia of rats with peripheral inflammatory cells and tissue injury. An imbalance in nitric nerve injury and leads to neuropathic pain. Essentially, we oxide levels is the key factor causing neuropathic pain [44]. found that the main pathological processes of CIPN may )rough pathway enrichment analysis, we found that most involve the inflammatory response and nerve injury, and our genes we identified were enriched in inflammation-related results also indirectly explain the complexity of CIPN 8 Evidence-Based Complementary and Alternative Medicine

ABCC4 CYP3A5 CYP17A1 SLCO1B1

GSTP1 GSTM1 CYP2C8 ABCC1

CYP3A4 ABCG2

MTHFR CYP1B1

ABCB1 GSTM2 HTR3A CDK7 SOD2

OPRM1 TP53 IGF1R ALB BCL2

VEGFA IL2 HSPB1 IL6 CTSS CASP3 ICAM1 F2 TNF AGXT IL10 GSK3B IL1B

TGFB1 IL4 AURKA IFNG CD40LG

Figure 6: Overlapping targets network. )e node having a darker color has a higher degree in the network. pathogenesis, and these key pathways provide a direction for mapped to the endocrine system and to respiratory system the future development of new drugs. diseases, which are especially enriched in cancer. In recent years, Secondly, we explored the herbal compounds and their TCM has attracted much attention in improving cancer and its targets. Our results showed that HQGZWWD comprises a side effects, which is consistent with our results suggesting that variety of active compounds. For example, quercetin is a fla- HQGZWWD exerts pharmacological effect on many diseases, vonoid widely found in herbs, which exerts antioxidative, anti- including CIPN, through the synergistic action of many inflammatory, antiallergic, and analgesic effects [46]. Recent compounds and different targets. )is may define this herbal studies have shown that quercetin can reduce the growth and formula as having multitarget and multifunction characteristics. invasion of tumor cells [47, 48]. Quercetin has anti-inflam- Finally, we targeted HQGZWWD and CIPN, as a key matory activity by inhibiting the production of cyclooxygenase approach in excavating the core treatment mechanism of the (COX) and lipoxygenase (LOX), which are considered to be TCM. We found that TP53, ALB, IL6, VEGFA, CASP3, TNF, closely related to inflammation [49, 50]. In addition, this and CYP3A4 may play core regulatory roles in treatment. compound shows remarkable antinociceptive and neuro- Among these, TP53 is a highly tumor-related gene. Mutant protective effects in animal models and inhibits light edema TP53 promotes the proliferation, migration, survival, and information [51, 52]. Another molecule identified was catechin, vasion of tumor cells, enhances drug resistance, and promotes which has anti-inflammatory and antioxidant activities and can the metabolism of tumor cells [58]. Both CASP3 and CASP4 reduce abnormal sensation after chemotherapy [53, 54]. Other belong to the caspase family, which can maintain homeostasis active compounds identified, such as formononetin [55], iso- by regulating apoptosis and inflammation [59, 60]. VEGFA can rhamnetin [56], and kaempferol [57], have been shown to be protect neurons by promoting neovascularization and vascular effective in inhibiting inflammation and analgesia. It is worth permeability. Vencappa et al. [61] demonstrated that VEGFA noting that we found that the targets of HQGZWWD can be could prevent cisplatin-induced sensory neuronal damage. In Evidence-Based Complementary and Alternative Medicine 9

Negative regulation of apoptotic process –Log10 (P value) Response to drug Positive regulation of nitric oxide biosynthetic process Extrinsic apoptotic signaling pathway in absence of ligand

Cellular response to lipopolysaccharide BP Response to glucocorticoid Immune response Positive regulation of peptidyl-serine phosphorylation Response to amino acid Positive regulation of chemokine biosynthetic process

Extracellular space External side of plasma membrane 10 Extracellular region Organelle membrane

Cell surface CC Platelet alpha granule lumen Plasma membrane Membrane ra Mitochondrion Neuronal cell body Cytokine activity Oxygen binding 5 Growth factor activity Aromatase activity

ATPase activity MF Glutathione binding Heme binding Oxidoreductase activity Monooxygenase activity Iron ion binding

015 10 5 –Log10 (P value) (a)

Cytokines and inflammatory response –Log10 (P value) Cytokine network 5.5 T-cell receptor signaling pathway Pathways in cancer

NF-kappa B signaling pathway 4.5 HIF-1 signaling pathway PI3K-Akt signaling pathway TNF signaling pathway 3.5 FoxO signaling pathway Jak-STAT signaling pathway IL 5 signaling pathway MAPK signaling pathway 2.5 IL-10 anti-inflammatory signaling pathway Sphingolipid signaling pathway Chaperones modulate interferon signaling pathway 1.5

0 24 –Log10 (P value) (b)

Figure 7: (a) GO functional analysis of overlapping targets. (b) KEGG pathway enrichment analysis of overlapping targets. addition, inflammation-related targets such as IL6 and TNF are these targets were the positive regulation of nitric oxide bio- also core targets of CIPN. )e GO function analysis of over- synthesis, immune responses, and responses to glucocorticoids, lapping targets showed that the main biological processes of which are similar to CIPN. While KEGG pathway enrichment 10 Evidence-Based Complementary and Alternative Medicine analysis showed that the targets that were mainly enriched Authors’ Contributions included cytokines and inflammatory response, elements of the cytokine network, and the T-cell receptor, NF-kappa B, HIF-1, Jialin Gu and Guoli Wei contributed equally to this work. and PI3K-Akt signaling pathways, which were mostly associated with the inflammatory response. For example, the HIF-1 Supplementary Materials signaling pathway participates in many biological processes such as hypoxia adaptation, inflammatory development, and Supplementary 1. Table S1: compounds identified in the tumor growth and plays a key role in inflammation and me- HQGZWWD formula. Supplementary 2. Table S2: effective diates tumorigenesis [62, 63]. We found that these pathways compounds identified in the HQGZWWD formula. Sup- intersect with the disease pathway of CIPN, indicating that plementary 3. Table S3: targets of the HQGZWWD formula. HQGZWWD has a certain pertinence in the treatment of Supplementary 4. Table S4: targets of CIPN. (Supplementary CIPN. Materials) Overall, our results show that HQGZWWD plays a therapeutic role in CIPN by regulating the inflammatory Acknowledgments response and repairing nerve injury, thus providing support for the reliable efficacy of this herbal formula. In addition, in )is study was supported by grants from the Project of the overlapping targets network, we identified two potential Provincial TCM Leading Talent of Jiangsu (no. SLJ0211) and targets (CDK7 and GSTM2) from the prediction platform, the Project of National Clinical Research Base of TCM in which have not been verified by experiments, and represent a Jiangsu Province (no. JD2019SZXYB04). clear direction for future research as novel targets for the treatment of CIPN. References Our innovation in this study lies in our integration of [1] L. A. Colvin, “Chemotherapy-induced peripheral neuropathy: multiple TCM databases, which may compensate for the de- where are we now?” Pain, vol. 160, no. Suppl 1, pp. S1–S10, ficiency of incomplete data. Further, our supplementary analysis 2019. of the targets for CIPN treatment through a prediction model [2] J. Ma, A. Kavelaars, P. M. Dougherty, and C. J. Heijnen, provides new information for the future study of pathological “Beyond symptomatic relief for chemotherapy-induced pe- processes and therapeutic targets. Finally, this study fully il- ripheral neuropathy: targeting the source,” Cancer, vol. 124, lustrates that TCM possesses the characteristic of an active no. 11, pp. 2289–2298, 2018. multicompound, multitarget, and multipathway formula, which [3] P. Zis, A. Paladini, A. Piroli, P. C. McHugh, G. Varrassi, and is of great significance in the study of the curative effect of herbal M. Hadjivassiliou, “Pain as a first manifestation of para- formulations. However, there are some issues that cannot be neoplastic neuropathies: a systematic review and meta- overlooked; although the selection of effective compounds is analysis,” Pain and =erapy, vol. 6, no. 2, pp. 143–151, 2017. [4] V. Brozou, A. Vadalouca, and P. Zis, “Pain in platin-induced well founded (mainly recommended by databases), they are neuropathies: a systematic review and meta-analysis,” Pain mostly reported in a single plant, which does not mean that they and =erapy, vol. 7, no. 1, pp. 105–119, 2018. are still present and play a therapeutic role in the traditional [5] R. Avan, G. Janbabaei, N. Hendouei et al., “)e effect of preparation. As mentioned above, we found only about 30% of pregabalin and duloxetine treatment on quality of life of the effective compounds in a mass spectrometric analysis of breast cancer patients with taxane-induced sensory neurop- HQGZWWD. )erefore, more mass spectrometric analysis athy: a randomized clinical trial,” Journal of Research in needs to be carried out to determine the effective compounds of Medical Sciences, vol. 23, p. 52, 2018. traditional preparations. [6] L. Ye, Y. Jia, K. Ji et al., “Traditional Chinese medicine in the prevention and treatment of cancer and cancer metastasis,” 5. Conclusion Oncology Letters, vol. 10, no. 3, pp. 1240–1250, 2015. [7] J. Nie, C. Zhao, L. Deng et al., “Efficacy of traditional Chinese )rough network pharmacology, we found that HQGZWWD medicine in treating cancer,” Biomedical Reports, vol. 4, no. 1, has a significant advantage in the treatment of CIPN. At the pp. 3–14, 2016. same time, the underlying molecular biological mechanisms [8] F. Qi, L. Zhao, A. Zhou et al., “)e advantages of using have been revealed by analyzing the potential core targets, traditional Chinese medicine as an adjunctive therapy in the biological functions, and signal pathways involved. Our study whole course of cancer treatment instead of only terminal provides a theoretical basis for the clinical application of stage of cancer,” Bioscience Trends, vol. 9, no. 1, pp. 16–34, HQGZWWD for the treatment of CIPN. 2015. [9] X. Cheng, J. G. Huo, D. Wang et al., “Herbal medicine AC591 prevents oxaliplatin-induced peripheral neuropathy in animal Data Availability model and cancer patients,” Frontiers in Pharmacology, vol. 8, no. 11, p. 344, 2017. )e data used to support the findings of this study are [10] A. L. Hopkins, “Network pharmacology: the next paradigm in available from the corresponding author upon request. drug discovery,” Nature Chemical Biology, vol. 4, no. 11, pp. 682–690, 2008. Conflicts of Interest [11] H. Y. Fang, H. W. Zeng, L. M. Lin et al., “A network-based method for mechanistic investigation of Shexiang Baoxin )e authors declare that there are no conflicts of interest Pill’s treatment of cardiovascular diseases,” Scientific Reports, regarding the publication of this paper. vol. 7, no. 1, Article ID 43632, 2017. Evidence-Based Complementary and Alternative Medicine 11

[12] J. Fang, L. Wang, T. Wu et al., “Network pharmacology-based interaction networks,” Genome Research, vol. 13, no. 11, study on the mechanism of action for herbal medicines in pp. 2498–2504, 2003. Alzheimer treatment,” Journal of Ethnopharmacology, [29] D. W. Huang, B. T. Sherman, and R. A. Lempicki, “Systematic vol. 196, pp. 281–292, 2017. and integrative analysis of large gene lists using DAVID [13] Q. Ge, L. Chen, M. Tang et al., “Analysis of mulberry leaf bioinformatics resources,” Nature Protocols, vol. 4, no. 1, components in the treatment of diabetes using network pp. 44–57, 2009. pharmacology,” European Journal of Pharmacology, vol. 833, [30] V. A. Carozzi, A. Canta, and A. Chiorazzi, “Chemotherapy- pp. 50–62, 2018. induced peripheral neuropathy: what do we know about [14] L. Zeng and K. Yang, “Exploring the pharmacological mechanisms?” Neuroscience Letters, vol. 596, pp. 90–107, mechanism of Yanghe decoction on HER2-positive breast 2015. cancer by a network pharmacology approach,” Journal of [31] T. J. Kaley and L. M. Deangelis, “)erapy of chemotherapy- Ethnopharmacology, vol. 199, pp. 68–85, 2017. induced peripheral neuropathy,” British Journal of Haema- [15] G. Yu, Y. Zhang, W. Ren et al., “Network pharmacology-based tology, vol. 145, no. 1, pp. 3–14, 2009. identification of key pharmacological pathways of Yin- [32] D. R. Pachman, D. L. Barton, J. C. Watson, and C. L. Loprinzi, Huang-Qing-Fei capsule acting on chronic bronchitis,” In- “Chemotherapy-induced peripheral neuropathy: prevention ternational Journal of COPD, vol. 12, pp. 85–94, 2017. and treatment,” Clinical Pharmacology & =erapeutics, [16] N. Wang, G. Zhao, Y. Zhang et al., “A network pharmacology vol. 90, no. 3, pp. 377–387, 2011. approach to determine the active components and potential [33] S. Hou, B. Huh, H. K. Kim, K. H Kim, and S Abdi, “Treatment targets of Curculigo Orchioides in the treatment of osteo- of chemotherapy-induced peripheral neuropathy: systematic porosis,” Medical Science Monitor, vol. 23, pp. 5113–5122, review and recommendations,” Pain Physician, vol. 21, no. 6, 2017. pp. 571–592, 2018. [17] P. J. Eddershaw, A. P. Beresford, and M. K. Bayliss, “ADME/ [34] E. M. L. Smith, H. Pang, C. Cirrincione et al., “Effect of PK as part of a rational approach to drug discovery,” Drug duloxetine on pain, function, and quality of life among pa- Discovery Today, vol. 5, no. 9, pp. 409–414, 2000. tients with chemotherapy-induced painful peripheral neu- [18] J. Ru, P. Li, J. Wang et al., “TCMSP: a database of systems ropathy,” JAMA, vol. 309, no. 13, pp. 1359–1367, 2013. [35] M. Takenaka, H. Iida, S. Matsumoto, S. Yamaguchi, pharmacology for drug discovery from herbal medicines,” N. Yoshimura, and M. Miyamoto, “Successful treatment by Journal of Cheminformatics, vol. 6, no. 13, 2014. adding duloxetine to pregabalin for peripheral neuropathy [19] X. Xu, W. Zhang, C. Huang et al., “A novel chemometric induced by paclitaxel,” American Journal of Hospice and method for the prediction of human oral bioavailability,” Palliative Medicine, vol. 30, no. 7, pp. 734–736, 2013. International Journal of Molecular Sciences, vol. 13, no. 6, [36] C. Brami, T. Bao, and G. Deng, “Natural products and pp. 6964–6982, 2012. complementary therapies for chemotherapy-induced pe- [20] W. Tao, X. Xu, X. Wang et al., “Network pharmacology-based ripheral neuropathy: a systematic review,” Critical Reviews in prediction of the active ingredients and potential targets of Oncology/hematology, vol. 98, pp. 325–334, 2016. Chinese herbal Radix Curcumae formula for application to [37] G. L. Wei, Z. C. Gu, L. C. Li et al., “Experimental study of cardiovascular disease,” Journal of Ethnopharmacology, Huangqi Guizhi Wuwu decoction to prevent oxaliplatin-in- vol. 145, no. 1, pp. 1–10, 2013. duced chronic peripheral neuropathy by reducing platinum [21] H.-Y. Xu, Y.-Q. Zhang, Z.-M. Liu et al., “ETCM: an ency- accumulation,” Modernization of Traditional Chinese Medi- clopaedia of traditional Chinese medicine,” Nucleic Acids cine and Materia Medica-World Science and Technology, Research, vol. 47, no. D1, pp. D976–D982, 2019. vol. 21, no. 07, pp. 1467–1473, 2019. [22] X. Liu, S. Ouyang, B. Yu et al., “PharmMapper server: a web [38] J. Tian, Z. Q. Yao, X. Y. Wu et al., “Systematic review and server for potential drug target identification using phar- meta-analysis on efficacy of Huangqi Guizhi Wuwu decoction macophore mapping approach,” Nucleic Acids Research, for oxaliplatin-induced peripheral neurotoxicity,” Chinese vol. 38, no. suppl_2, pp. W609–W614, 2010. Journal of Experimental Traditional Medical Formulae, vol. 19, [23] Z.-J. Yao, J. Dong, Y.-J. Che et al., “TargetNet: a web service no. 22, pp. 325–330, 2013. for predicting potential drug-target interaction profiling via [39] B. B. Aggarwal, A. B. Kunnumakkara, K. B. Harikumar et al., multi-target SAR models,” Journal of Computer-Aided Mo- “Signal transducer and activator of transcription-3, inflam- lecular Design, vol. 30, no. 5, pp. 413–424, 2016. mation, and cancer,” Annals of the New York Academy of [24] M. Safran, I. Dalah, J. Alexander et al., “GeneCards Version 3: Sciences, vol. 1171, no. 1, pp. 59–76, 2009. the human gene integrator,” Database (Oxford), vol. 2010, [40] D. Masciocchi, A. Gelain, S. Villa, F. Meneghetti, and baq020 pages, 2010. D. Barlocco, “Signal transducer and activator of transcription [25] J. Piñero, J. M. Ram´ırez-Anguita, J. Saüch-Pitarchet al., “)e 3 (STAT3): a promising target for anticancer therapy,” Future DisGeNET knowledge platform for disease genomics: 2019 Medicinal Chemistry, vol. 3, no. 5, pp. 567–597, 2011. update,” Nucleic Acids Research, vol. 48, no. D1, [41] S. Dziennis and N. J. Alkayed, “Role of signal transducer and pp. D845–D855, 2020. activator of transcription 3 in neuronal survival and regen- [26] M. Franz, H. Rodriguez, C. Lopes et al., “GeneMANIA update eration,” Reviews in the Neurosciences, vol. 19, no. 4–5, 2018,” Nucleic Acids Research, vol. 46, pp. W60–W64, 2018. pp. 341–361, 2008. [27] D. Szklarczyk, A. L. Gable, D. Lyon et al., “STRING v11: [42] Y. Q. Zhou, Z. Liu, Z. H. Liu et al., “Interleukin-6: an emerging protein-protein association networks with increased coverage, regulator of pathological pain,” Journal of Neuro- supporting functional discovery in genome-wide experi- inflammation, vol. 13, no. 1, p. 141, 2016. mental datasets,” Nucleic Acids Research, vol. 47, no. D1, [43] X.-M. Wang, T. J. Lehky, J. M. Brell, and S. G. Dorsey, pp. D607–D613, 2019. “Discovering cytokines as targets for chemotherapy-induced [28] P. Shannon, A. Markiel, O. Ozier et al., “Cytoscape: a software painful peripheral neuropathy,” Cytokine, vol. 59, no. 1, environment for integrated models of biomolecular pp. 3–9, 2012. 12 Evidence-Based Complementary and Alternative Medicine

[44] D. W. Zochodne and D. Levy, “Nitric oxide in damage, disease [59] Z.-J. Dai, J. Gao, Z.-Z. Ji et al., “Matrine induces apoptosis in and repair of the peripheral nervous system,” Cellular and gastric carcinoma cells via alteration of Fas/FasL and acti- Molecular Biology (Noisy-Le-Grand, France), vol. 51, no. 3, vation of caspase-3,” Journal of Ethnopharmacology, vol. 123, pp. 255–267, 2005. no. 1, pp. 91–96, 2009. [45] E. Dominguez, C. Rivat, B. Pommier, A. Mauborgne, and [60] G. Sollberger, G. E. Strittmatter, M. Kistowska et al., “Caspase- M. Pohl, “JAK/STAT3 pathway is activated in spinal cord 4 is required for activation of inflammasomes,” Journal of microglia after peripheral nerve injury and contributes to Immunology, vol. 188, no. 4, pp. 1992–2000, 2012. neuropathic pain development in rat,” Journal of Neuro- [61] S. Vencappa, L. F. Donaldson, and R. P. Hulse, “Cisplatin chemistry, vol. 107, no. 1, pp. 50–60, 2008. induced sensory neuropathy is prevented by vascular endo- [46] S. Kundur, A. Prayag, P. Selvakumar et al., “Synergistic anti- thelial growth factor-A,” American Journal of Translational cancer action of quercetin and curcumin against triple-negative Research, vol. 7, no. 6, pp. 1032–1044, 2015. breast cancer cell lines,” Journal of Cellular Physiology, vol. 234, [62] N. Dehne and B. Brüne,“HIF-1 in the inflammatory mi- no. 7, pp. 1103–1118, 2019. croenvironment,” Experimental Cell Research, vol. 315, no. 11, [47] S. Sun, F. Gong, P. Liu, and Q. Miao, “Metformin combined pp. 1791–1797, 2009. with quercetin synergistically repressed prostate cancer cells [63] K. Balamurugan, “HIF-1 at the crossroads of hypoxia, in- via inhibition of VEGF/PI3K/Akt signaling pathway,” Gene, flammation, and cancer,” International Journal of Cancer, vol. 664, pp. 50–57, 2018. vol. 138, no. 5, pp. 1058–1066, 2016. [48] Y.-H. Lee and P.-T. Tuyet, “Synthesis and biological evaluation of quercetin-zinc (II) complex for anti-cancer and anti- metastasis of human bladder cancer cells,” In Vitro Cellular & Developmental Biology - Animal, vol. 55, no. 6, pp. 395–404, 2019. [49] H. P. Kim, I. Mani, L. Iversen, and V. A. Ziboh, “Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from Guinea-pigs,” Pros- taglandins, Leukotrienes and Essential Fatty Acids, vol. 58, no. 1, pp. 17–24, 1998. [50] K. M. Lee, M. K. Hwang, D. E. Lee, K. W. Lee, and H. J. Lee, “Protective effect of quercetin against arsenite-induced COX- 2 expression by targeting PI3K in rat liver epithelial cells,” Journal of Agricultural and Food Chemistry, vol. 58, no. 9, pp. 5815–5820, 2010. [51] K. S. Raygude, A. D. Kandhare, P. Ghosh, A. E. Ghule, and S. L. Bodhankar, “Evaluation of ameliorative effect of quercetin in experimental model of alcoholic neuropathy in rats,” Inflammopharmacology, vol. 20, no. 6, pp. 331–341, 2012. [52] M. I. Azevedo, A. F. Pereira, R. B. Nogueira et al., “)e antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy,” Molecular Pain, vol. 9, p. 53, 2013. [53] J. S. Lee, Y. T. Kim, E. K. Jeon et al., “Effect of green tea extracts on oxaliplatin-induced peripheral neuropathy in rats,” BMC Complementary and Alternative Medicine, vol. 12, p. 124, 2012. [54] N. T. Zaveri, “Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancer applications,” Life Sciences, vol. 78, no. 18, pp. 2073–2080, 2006. [55] R. Lima Cavendish, J. de Souza Santos, R. Belo Neto et al., “Antinociceptive and anti-inflammatory effects of Brazilian red propolis extract and formononetin in rodents,” Journal of Ethnopharmacology, vol. 173, pp. 127–133, 2015. [56] K. Seo, J. H. Yang, S. C. Kim et al., “)e antioxidant effects of isorhamnetin contribute to inhibit COX-2 expression in response to inflammation: a potential role of HO-1,” Inflam- mation, vol. 37, no. 3, pp. 712–722, 2014. [57] P. Rajendran, T. Rengarajan, N. Nandakumar et al., “Kaempferol, a potential cytostatic and cure for inflammatory disorders,” European Journal of Medicinal Chemistry, vol. 86, pp. 103–112, 2014. [58] R. S. Warren, C. E. Atreya, D. Niedzwiecki et al., “Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803,” Clinical Cancer Research, vol. 19, no. 20, pp. 5777–5787, 2013.