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    Integration strategy of network pharmacology in Traditional Chinese Medicine:a narrative review

    2022-07-20 15:54:14WUJiashuoZHANGFangqingLIZhuangzhuangJINWeiyiSHIYue

    WU Jiashuo,ZHANG Fangqing,LI Zhuangzhuang,JIN Weiyi,SHI Yue

    WU Jiashuo,ZHANG Fangqing,LI Zhuangzhuang,SHI Yue,Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing 100193,China

    JIN Weiyi,Hebei Medical University,Shijiazhuang 050017,China

    Abstract Traditional Chinese Medicine (TCM) has been extensively used as a mainstay for treating various pathologies.Combing the pharmacology and systems biology approaches,the network pharmacology (NP)approach was developed to predict the probable mechanism underlying the therapeutic effect of TCM.However,approaches solely based on NP cannot effectively elucidate the curative mechanism in a holistic and reliable manner due to limitations in NP-based methods and complexity of TCM components.Thus,integration strategies combining NP with other approaches are increasingly being used.Since the interdisciplinary research in TCM has received much attention in the advent of the big data era of which the NPbased integration strategy is broadly used,the strategy is clearly elaborated in the present review.We summarized several NP-based integration strategies and their applications in TCM studies,including multi-omics approach,gut microbiota study,chemical information analysis,data-mining,and network toxicology study.

    Keywords:network pharmacology;toxicology;medicine,Chinese traditional;integration strategy;review

    1.INTRODUCTION

    Traditional Chinese Medicine (TCM) has been used to treat diseases in China for thousands of years.1,2However,considering the paucity of a comprehensive understanding of the mechanisms underlying the therapeutic effects of TCM and its herbal formulas,TCM is considered only as an alternative treatment strategy.3Unlike synthetic drugs,TCM drugs possess“multicomponent”,“multi-target”,and“multi-pathway”characteristics.Therefore,a complex network of herbcomponent-target-pathway-disease,metabolites,and gut microbiota must be comprehensively explored to elucidate mechanisms of TCM.

    In the advent of the big data era,comprehensive studies of TCM can be achieved in a new modality.The concept of NP was conceived by Hopkins.4NP integrates systematic data to analyze the holistic process of interactions between compounds and the human body.The application of NP in TCM was developed subsequently by Li.5The term "TCM Systems Bioinformatics (TCMSB)" was proposed and the experimental paradigms of TCM network pharmacology were established gradually.6,7The systems pharmacology-based framework of TCM was introduced systematically by Wanget al.8The construction of"component-target-disease (CTD)" network was put forward and the application of CTD in TCM was attempted.9,10The conception of "Integrative pharmacology" was put forward by Xuet al.11The association between the parameters of absorption,distribution,metabolism,excretion (ADME) and pharmacologic actions was constructed.The utility of NP in studying various TCM formulae was analyzed.12

    The narrow conception of NP refers processes including screening of active ingredients,fishing of targets,founding of disease targets database and enrichment analysis.These processes constitute a bottom?up approach from ingredients in TCM to their probable curative mechanisms.We regard NP as a pilot research to propose hypotheses of mechanisms to be validated.Therefore,studies reporting evaluation of putative mechanisms using NP-based approaches usually involved evaluation using NP-based methods.

    However,NP has several limitations if it is used alone:(a) NP is a pilot prediction with massive hypotheses to confirm,and thus the probable false-positive results cannot be avoided.For example,the similarity of the structures between ligand and protein were matched to output probable targets,of which the result varies dramatically across different platforms.It is clear that many false-positive results exist,and experimental validation plays a role.7,13(b) The NP prediction methods are too simple to holistically evaluate the effects and toxicity profile of TCM.TCM has massive ingredients,and some of them undergo changes in decoction procedures;14,15thus,the combined therapeutic effect of TCM is not equivalent to the combined therapeutic effects of constituent compounds.(c) The dose of the TCM drug decides if it is therapeutically beneficial or poisonous.16The relative abundance of compounds in TCM varies.Some compounds can hardly reach the effective concentration in the human body,and they cannot be precisely excluded from NP-based analysis.(d)The reliability of ADME-based screening is still debatable.For instance,we screened the confirmed active ingredients (Atractylenolide Ⅰ,Ⅱ,and Ⅲ) ofAtractylodes macrocephalaKoidz.by setting oral bioavailability (OB) and drug-likeness (DL) thresholds as OB ≥ 30% and DL ≥ 0.18 in TCMSP,17but all the three active ingredients were excluded.

    Thus,relying merely on the NP approach will not aid in a reliable way.The concept of“Integration Strategy”is put forward,which refers to a systematic comprehensive strategy that assembles methods for multi-domain investigation.Thus,the broad conception of NP is put forward.18Considering the limitations of NP,integration strategies based on NP are frequently being applied in TCM research,and NP-related tools and platforms are increasingly being used.

    In the present review,systematic searching of recent publications of NP-based integration strategy in the deciphering of mechanisms of TCM was conducted in databases,which will help in the subsequent exploration of TCM (Figure 1).

    Figure 1 Integration strategy of network pharmacologyThe Venn diagram reflects the interdisciplinary approach based on network pharmacology.

    2.MULTI-OMICS APPROACH

    2.1.Proteomics

    Protein is the fundamental constituent of all cells of the body.Millions of proteins play vital roles in life activities.The proteomic approaches aim to analyze cells holistically by detecting the inner dynamic processes of proteins.Besides,the potential disease targets can also be predicted by screening differential protein expression levels using techniques such as iTRAQ labeling quantitative proteomics.19,20

    Generally,the protein-protein interaction (PPI) analysis is conducted to select the hub proteins for biological enrichment analysis-Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis-to predict related pathways,molecular functions,biological processes,and cellular components of specific species.PPI analysis is a systems biology method to analyze the topological structure of a protein-protein network,widely used in both proteomics and NP.21,22

    Liuet al23used a novel integration strategy based on NP and proteomics approaches.After detection of differential protein expression using proteomic approaches,molecular docking-a NP technology-was conducted to evaluate the binding affinity between proteins and ligands.Docking evaluation gave probable key ligands and hub proteins for validation in the case of sheer number of differential proteins and probable ligands in TCM.Liu while screening ligands from the literature,could also have utilized NP databases to find more active ingredients for docking studies.The further pharmacological validation of monomers was conducted including but not limited to the screened ligands (some reported active ingredients might have been ignored by purely manual screening).This line of thinking was used when the NP databases were utilized to find potentially active ingredients.24However,since the reliability of ADME filtering results of compounds using NP-related platforms is debatable,NP prediction ought to be combined with the reported data.

    Moreover,the Cytoscape software was used to develop the network of the differential proteins25or ligands in TCM26and calculate the topological parameters like degree centrality using the network analyzer.Cytoscape network analysis is similar to the docking approach,with the difference that Cytoscape network analysis is based on topological configuration between objects and the docking analysis is based on the molecular structure of pharmacophores.

    2.2.Metabolomics

    As a major approach of systems biology,metabolomics is aimed at analyzing the metabolites with a relative molecular mass of less than 1000.27Metabolomics has been widely used to study TCM.28,29

    With the aim to develop an integration strategy to make the metabolomics approach more targeted,Wang identified 595 differential metabolites inAstragalus membranaceus(Fisch.) Bunge extract while evaluating its anti-liver fibrosis properties.Six of these metabolites were analyzed by NP-based methods,and the potential metabolite-target-component interaction network was developed by MBROLE 2.0 platform.The topological analysis that followed indicated the probable hub targets and key metabolites.30

    The multi-omics approach has a problem of too much data,which poses difficulty in collecting effective data.Besides conducting PPI analysis between differential proteins and selecting the hub proteins for biological enrichment analysis,the key differential metabolites can also be identified by carting out network analysis before metabolism pathway analysis.Therefore,the NP-based tools provide a promising approach to narrow down the selected scope for more efficient validation.

    Besides,NP-based methods can build bridges between the extract and monomers to some degree.Huaet al31utilized the NP-based method after the analysis of differential metabolites of a TCM formula and predicted the active components and pathways.Wanget al32developed a workflow combining molecular docking,affinity MS,and metabolomics to determine potential ligands from TCM.

    An important aim of metabolomics is to identify the diagnostic bio-marks.Integration strategy can also be used combining network toxicology (NT) and metabolomics to relate the toxicity bio-marks with TCM components and explore its toxicity mechanisms.24,33Zhanget al35developed an integrated strategy for accurately screening the bio-marks using NP and metabolomics.

    2.3.Transcriptomics

    The transcriptomics approach is targeted at all transcripts of genes and used to investigate the transcribed RNA.The main technologies based on transcriptomics are high-throughput sequencing and gene chip analysis.36The differential gene expression profile obtained by transcriptomics can be utilized to uncover the deeplayered mechanisms underlying the treatment of diseases.37,38Currently,the transcriptomics approach has wide-ranging applications in TCM research.39,40Xinget al41collected the known transcriptomics data in Gene Expression Omnibus (GEO) database to analyze the differential gene expression profile and obtain the differentially expressed genes (DEGs).The DEGs can be compared with the target-fishing results of active components in TCM.A similar report is recently published.42

    If DEGs cannot be screened in public databases,RNA sequencing (RNA-seq) or gene chip analysis should be adopted.Heet al43utilized the RNA-seq approach to analyze the DEGs for enrichment analysis,followed by PPI analysis.Zhouet al44utilized mRNA microarray and NP-based analysis to find DEGs.Besides,the RNA-seq approach can also be used to validate the results obtained by NP-based analysis.45Screening of differential genes by transcriptomics approach and identification of probable hub targets by NP-based analysis are aimed to obtain the targets playing a role for further validation;these methods are complementary.

    Furthermore,multi-omics24,46and NP combined with transcriptomics,proteomics,and metabolomics approaches were used to uncover the mechanismof TCM in a stereoscopic and holistic manner.

    3.GUT MICROBIOTA STUDY

    The gut microbiota in the human body constitutes a microecological system and the balance of which can affect the normal physiological functions and susceptibility to several diseases since the gut microbiota acts on biochemical processes like catabolism and anabolism of proteins.47,48The gut microbiota study is becoming a research hotspot nowadays,and emerging theories including the gut-liver axis49and gut-lung axis50are proposed.This technique is broadly used in mechanism studies of TCM.51

    Zhanget al52reviewed the role of NP and suggested that the database recording relation between TCM and gut microbiota should be further refined.Herein,a novel database of gut microbiota,the gutMEGA database,53will be introduced.This database has a collection of metagenomics data of 59 132 quantification events for 6 457 taxa at seven different levels.A similar database is GMrepo54that holds a great quantity of meta-data of gut samples and the associated human phenotypes.The gut microbiota database was used in various individual studies,55but no TCM studies utilized them to this day.These databases were believed to provide a promising prediction to decipher the probable mechanism of TCM related to microecology.

    Gaoet al56explored the systematic relationship between proteins,metabolites,and gut microbiota using NP,metabolomics,and gut microbiota sequencing to investigate the potential mechanism underlying the curative effect of Qi-Jian Mixture in type-2 diabetes.Dinget al57confirmed the activity of the TCM formula Ge-Gen-Qin-Lian decoction against LPS-induced acute injury and predicted the potential targets using NP-based methods.The mechanism of the lung-gut axis was further elucidated through transcriptomics and metabolomics approaches.

    4.CHEMICAL INFORMATION ANALYSIS

    4.1.Quali-quantitative analysis

    For the NP-based methods have limited capacity in excluding the ingredients that are present in extremely low concentrations,the quali-quantitative analysis of TCM with the NP method has been utilized.Thus,the credibility of NP prediction increases remarkably.Banerjeeet al58identified thirteen components by LCMS based metabolite screening,and the components were further conducted NP-based analysis.The Mahuang Fuzi Xixin decoction was conducted qualitative analysis to identify the ingredients.Twenty-four ingredients were identified to match the ingredients recorded in databases.These ingredients were further analyzed by NP-based methods and the toll-like receptor and T-cell receptor pathways were highlighted.59

    4.2.Pharmacokinetic study and ADME screening

    The high content of ingredients in the TCM does not always mean a high therapeutic concentration in the body due to the complex nonlinear process of drug metabolism.60Therefore,the pharmacokinetic study is considered.An investigation was performed over the type II diabetes mellitus based on the pharmacokinetic target components of Sanye Tangzhi formula.61Five components were absorbed and eliminated efficiently.These components were further conducted NP-based analysis.A qualitative and pharmacokinetic based integration NP strategy was performed to investigate the curative mechanisms ofPhlomis brevidentata H.W.Li Radixfor the treating pharyngitis and pneumonia.62As a result,twenty-three chemical compounds were identified,three of which were found exhibiting similar ADME characteristics and further anlyzed through NP-based methods and five targets were highlighted.

    Besides pharmacokinetic study,the ADME properties of TCM compounds can also be evaluated by NP tools.63,64For example,the simplified molecular input line entry specification (SMILES) sequence of compounds can be entered into the SwissADME platform65to predict the ADME parameters.However,as described above,the reliability of ADME-based screening is debatable.Thus,the details of several platforms that can provide ADME properties are summarized to motivate further related researches (Table 1).

    Table 1 Platforms that can provide ADME properties

    4.3.Spectrum-effect relationship approach

    The spectrum-effect relationship approach is viable in TCM research.72,73The spectrum-effect relationships were utilized to investigate the correlation between the curative effect of TCM and their fingerprints.The fingerprints of the TCM exact and drug-containing serum are collected and profiles,including a spectrum of high performance liquid chromatography (HPLC),gas chromatography (GC),were built.By comparing the spectra using analytical methods such as gray relational,cluster,and principal component analysis,the differential chromatographic peaks are screened and identified to predict the potential active compounds.74However,reports on the integration strategy of NP and the spectrum-effect relationship approach are scarce,which can be due to the high workload and time consumption.As an effective approach to screen the probable bioactive ingredients in TCM,spectrum-effect relationship approach may play a role in further research.Conclusively,the chemical information analysis of TCM is believed to provide stronger support for the follow-up NP-based analysis.The methods of NP and chemical information analysis are mutually potentiating and the integration strategy can help to increase the reliability of NP.

    5.DATA-MINING AND THE INNOVATIVE APPLICATIONS OF NP

    It is known that selecting TCM from tens of thousands of studies is difficult.75To avoid the omission of valuable information,data-mining of TCM is utilized recently.76,77Data mining approaches can find TCM combinations of significant therapeutic value using methods78,79such as frequency analysis,correlation rule mining,and recurrent neural network.

    The modular characteristics of TCM that have curative effect in endometriosis were explored.80The search of modern and ancient literatures was conducted to prepare for data mining.After screening,551 literatures were performed analysis including descriptive analysis,frequent itemset mining and recurrent neural network analysis.The herbs with therapeutic benefits were further analyzed by NP.A natural product library was developed by data mining and screened it for ADME properties using NP.81Other studies combining NP and data mining are also published.82-84

    Taking the NP and data mining as a whole,an optimized strategy is formed.Furthermore,this kind of optimization is not merely limited to the NP-based analysis,but exists throughout the investigation,namely the innovative application of NP.

    Generally,the NP method links TCM ingredients with the disease targets,but the probable curative effects of TCM cannot be explored for lack of pharmacologyrelated data.A new model of“targets-(pathway)-targets”(TPT) was proposedto overcome these concerns by utilizing the concept of“module”.85Exemplified by the study of Zuoet al86.After the processes of targetfishing and enrichment analysis,the miscellaneous targets were divided into eight modules by the Louvain algorithm87,88according to the molecular function and biological process;different modules share different functional propensities and correspond to different pathways.The contribution scores of modules toward diseases were calculated by the contribution-scoring algorithm to evaluate the relationship between modules and diseases.Therefore,diseases related to the module with the highest score were further analyzed,and the hub targets were screened from the key module.

    Anin silicodrug repurposing model for coronary disease was developed.89Specifically,the drug,target and the PPI interaction networks of the coronary disease genes were developed.The permutation testing was then performed to evaluate the natural products and drugs to be prioritized for association with the disease.The calculated values were corrected by the Benjamini-Hochberg approach90and the level of association was characterized by Z-score.After analysis,the drugs and natural products that showed a novel action mechanism against coronary disease were selected.Similarly,Huet al91used the Prince algorithm92to infer new associations betweenHedyotis diffusa Willd.and various genes using an iterative network propagation method.After the analysis of gene families,the relevant genes and pathways were identified.

    6.NT

    The efficacy and safety profiles of synthetic drugs,as well as TCM,are of utmost importance.93For instance,aristolochic acid causes nephrotoxicity.94,95Aristolochia manshuriensis Kom.of the Aristolochiaceae family was previously used in a TCM formula.Despite the processing of TCM,the potential safety issues cannot be neglected.Therefore,the toxicological studies of TCM and its formulas are crucial.With the modernization of TCM development,more experimental toxicology studies were conducted recently.96.97

    Similar to network pharmacology,toxicology also has a prediction method NT.NT was conceptualized in 2011.98NT entails the prediction and pilot analysis of TCM toxicity using the network model.Further,approaches such as NP are used to conduct the enrichment analysis.Similar to NP,the NT method can also be integrated with several research approaches.Exemplified by the study of Liuet al.99It was reported that an active ingredient inTripterygium wilfordii Hook.f.named celastrol triggered cardiotoxicity in zebrafish embryo;100however,the underlying mechanisms were unclear.NT-based method combining the metabolomics study was taken.The palmitic acid and TNF pathway were selected for experimental toxicology validation through analysis of differential metabolites,potential hub targets and pathways.Houet al101combined the spectrum-toxicity relationship with the NT-based method to determine the probable hepatotoxic ingredients in TCM.

    TCM is the coordination of efficacy and toxicity,102these targets that did not associate with the therapeutic effect were regarded to be harmful,and thus the NT method is like that in NP.Numerous integration strategies were reported recently.33,34,103

    7.CONCLUSIONS

    The rapid development of systems biology has derivatized NP as well as several algorithms,tools,platforms,and software.These NP-based approaches have been broadly utilized in TCM-related research.There are many difficulties in the comprehensively investigation of bioactive ingredients and systematically explanation of curative mechanisms of TCM due to the characteristics of“multi-component”,“multi-target”,and“multi-pathway”.The NP-based methods can provide ideas for addressing the issues involved in TCMrelated researches.Essentially,NP is a pilot research that provides valuable references for the follow-up pharmacodynamics and mechanism study,but the analysis solely based on NP can cause the absence of experimental evidence and probable false-positive results.With the aim of overcoming these limitations,integration strategies have emerged.

    In perspective,the integration strategy of NP should focus on its irreplaceable advantages.NP is convenient and timesaving with large amount of information.Moreover,many methods of NP-based analysis are indispensable,such as PPI,GO and KEGG analysis,which is closely linked with most multi-omics approaches to analyze the data.

    Conclusively,TCM studies are still in infancy,and more TCM-related basic research is essential.NP-based methods and the integration strategies can preliminarily predict the potential material basis of TCM and its probable mechanism,which can build a bridge between Chinese and Western medicine.Using the integration strategies,we explored many possibilities in this review that are expected to be helpful for subsequent studies.We believe that more integration studies will be conducted in the future to advance the TCM research.

    8.ACKNOWLEDGMENTS

    The authors would like to thank all the reviewers who participated in the review and MJEditor (www.mjeditor.com) for its linguistic assistance during the preparation of this manuscript.

    9.REFERENCES

    1.Lin HS,Jie L,Zhang Y.Developments in cancer prevention and treatment using Traditional Chinese Medicine.Front Med 2011;5:127-33.

    2.Fan H,Lu F,Yang A,et al.A review on the nonpharmacological therapy of Traditional Chinese Medicine with antihypertensive effects.Evid-based Complement Altern Med 2019;2019:1-7.

    3.Barnes MA,Barbara M.Complementary and alternative medicine use among adults:United States.National health statistics reports 2008;12:1-23.

    4.Andrew L Hopkins.Network pharmacology.Nat Biotechnol 2007;25:1110-11.

    5.Li S.Network systems underlying Traditional Chinese Medicine syndrome and herb formula.Curr Bioinform 2009;4:110-20.

    6.Li S.Network target for screening synergistic drug combinations with application to Traditional Chinese Medicine.BMC Syst Biol 2011;5:188-96.

    7.Li S,Zhang B.Traditional Chinese Medicine network pharmacology:theory,methodology and application.Chin J Nat Med 2013;11:110-20.

    8.Wang YH,Yang L.Systems pharmacology-based research framework of Traditional Chinese Medicine.Shi Jie Zhong Yi Yao 2013;7:103-10.

    9.Li X,Xu X,Wang J,et al.A system-level investigation into the mechanisms of Chinese traditional medicine:compound Danshen formula for cardiovascular disease treatment.PLoS One 2012;7:e43918.

    10.Tao W,Xu X,Wang J,et al.Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease.J Ethnopharmacol 2013;145:1-10.

    11.Xu HY,Yan,HJ.Integrative pharmacology:new paradigm of modernization of Chinese medicine.Zhong Guo Zhong Yao Za Zhi 2014;39:357-62.

    12.Huang T,Zhong LLD,Lin CY,et al.Approaches in studying the pharmacology of Chinese Medicine formulas:bottom-up,topdown-and meeting in the middle.Chin Med 2018;13:15.

    13.Park SY,Park JH,Kim HS,et al.Systems-level mechanisms of action of Panax ginseng:a network pharmacological approach.Ginseng Res 2018;42:98-106.

    14.Sun D,Yan Q,Xu X,et al.LC-MS/MS analysis and evaluation of the anti-inflammatory activity of components from Bushen Huoxue decoction.Pharm Biol 2017;55:937-45.

    15.Xiang L,Fan Y,Hang F,et al.Intraconversion of Polar Ginsenosides,their transformation into less-polar ginsenosides,and Ginsenoside acetylation in Ginseng flowers upon baking and steaming.Molecules 2018;23:759.

    16.Stumpf WE.The dose makes the medicine.Drug Discov Today 2006;11:550-55.

    17.Ru JL,Li P,Wang JN,et al.TCMSP:a database of systems pharmacology for drug discovery from herbal medicines.J Cheminformatics 2014;6:13.

    18.Chen WB,Zhuang J,Gong L,et al.Investigating the dysfunctional pathogenesis of Wilms’ tumor through a multidimensional integration strategy.J Transl Med 2019;9:266-73.

    19.Pan L,Zhang J,Wang J,et al.ITRAQ-based quantitative proteomic analysis reveals proteomic changes in three fenoxaprop-P-ethyl-resistant Beckmannia syzigachne biotypes with differing ACCase mutations.J Proteomics 2017;160:47-54.

    20.Zhu HG,Cheng WH,Tian WG,et al.iTRAQ-based comparative proteomic analysis provides insights into somatic embryogenesis in Gossypium hirsutum L.Plant Mol Biol 2018;96:89-102.

    21.Zhao J,Xie M,Liu JN,et al.Investigation of the therapy targets of Yi-Qi-Yang-Yin-Hua-Tan-Qu-Yu recipe on type 2 diabetes by serum proteome labeled with iTRAQ.J Ethnopharmacol 2018;224:1-14.

    22.Liu CN,Chen J,Yang S,et al.The Chinese herbal formula Zhibai Dihuang Granule treat Yin-deficiency-heat syndrome rats by regulating the immune responses.J Ethnopharmacol 2018;225:271-78.

    23.Liu XJ,Shi Y,Hu YH,et al.Bupleurum marginatum Wall.ex DC in liver fibrosis:pharmacological evaluation,differential proteomics,and network pharmacology.Front Pharmacol 2018;9:524.

    24.Zhao P,Li J,Yang L,et al.Integration of transcriptomics,proteomics,metabolomics and systems pharmacology data to reveal the therapeutic mechanism underlying Chinese herbal Bufei Yishen formula for the treatment of chronic obstructive pulmonary disease.Mol Med Rep 2018;17:5247-57.

    25.Lima-Leite A,Gualiume Vaz Madureira Lobo J,Barbosa da Silva Pereira,et al.Proteomic analysis of gastrocnemius muscle in rats with streptozotocin-induced diabetes and chronically exposed to fluoride.PloS one 2014;9:e106646.

    26.Wang Z,Linghu KG,Hu Y,et al.Deciphering the pharmacological mechanisms of the Huayu-Qiangshen-Tongbi formula through integrating network pharmacology and in vitro pharmacological investigation.Front Pharmacol 2019;10:1065.

    27.Misra BB,Mohapatra S.Tools and resources for metabolomics research community:a 2017-2018 update.Electrophoresis 2019;40,227-246.

    28.Luo H,Sun SJ,Wang Y,et al.Revealing the sedative-hypnotic effect of the extracts of herb pair Semen Ziziphi spinosae and Radix Polygalae and related mechanisms through experiments and metabolomics approach.BMC Complement Med Ther 2020;20,206.

    29.Wang XM,Xu WJ,Xu LK,et al.Antipyretic effect of herba Ephedrae-Ramulus Cinnamomi herb pair on yeast-induced pyrexia rats:a metabolomics study.Chin J Integr Med 2018;24:676-82.

    30.Wang D,Li R,Wei S,et al.Metabolomics combined with network pharmacology exploration reveals the modulatory properties of Astragali Radix extract in the treatment of liver fibrosis.Chin Med 2019;14:30.

    31.Hua YL,Ma Q,Yuan ZW,et al.A novel approach based on metabolomics coupled with network pharmacology to explain the effect mechanisms of Danggui Buxue Tang in anaemia.Chin J Nat Med 2019;17:275-90.

    32.Wang Z,Liang H,Cao H,et al.Efficient ligand discovery from natural herbs by integrating virtual screening,affinity mass spectrometry and targeted metabolomics.Analyst 2019;144:2881-90.

    33.Bai JP,Abernethy DR.Systems pharmacology to predict drug toxicity:integration across levels of biological organization.Annu Rev Pharmacol Toxicol 2013;53:451-73.

    34.Li XY,Jin X,Li YZ,et al.Network toxicology and LC-MS-based metabolomics:new approaches for mechanism of action of toxic components in traditional Chinese medicines.Chin Herb Med 2019;11:357-63.

    35.Zhang W,Chen Y,Jiang H,et al.Integrated strategy for accurately screening biomarkers based on metabolomics coupled with network pharmacology.Talanta 2020;211:120710.

    36.Sultan M,Schulz MH,Richard H,et al.A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome.Science 2008;321:956-60.

    37.Banchereau R,Cepika AM,Banchereau J,et al.Understanding human autoimmunity and autoinflammation through transcriptomics.Annu Rev Immunol 2017;35:337-70.

    38.Wang Z,Gerstei M,Snyder M.RNA-Seq:a revolutionary tool for transcriptomics.Nat Rev Genet 2009;10:57-63.

    39.Yang Q,Gao L,Tao M,et al.Transcriptomics analysis of Candida albicans treated with Huanglian Jiedu decoction using RNA-seq.Evid Based Complement Alternat Med 2016;2016,3198249.

    40.Chen F,Wei Y,Zhang J,et al.Transcriptomics analysis investigates sesquiterpenoids accumulation pattern in different tissues of Atractylodes lancea (Thunb.) DC.plantlet.Plant Cell Tiss Organ Cult 2017;130:73-90.

    41.Xing X,Chen S,Li L,et al.The active components of Fuzheng Huayu formula and their potential mechanism of action in inhibiting the hepatic stellate cells viability-a network pharmacology and transcriptomics approach.Front Pharmacol 2018;9:525.

    42.Li AP,He SS,Zhang WN,et al.Exploration the active compounds of Astragali Radix in treatment of adriamycin nephropathy by network pharmacology combined with transcriptomic approach.J Ethnopharmacol 2020;258:112537.

    43.He S,Li A,Zhang W,et al.An integrated transcriptomics and network pharmacology approach to exploring the mechanism of adriamycin-induced kidney injury.Chem Biol Interact 2020;325:109096.

    44.Zhou Y,Wu R,Cai FF,et al.Xiaoyaosan decoction alleviated rat liver fibrosisviathe TGFβ/Smad and Akt/FoxO3 signaling pathways based on network pharmacology and transcriptomic analysis.J Ethnopharmacol 2020;2020:113021.

    45.Li D,Liu D,Yue D,et al.Network pharmacology and RNA sequencing studies on triterpenoid saponins from Bupleurum chinense for the treatment of breast cancer.RSC Adv 2019;9:41088-98.

    46.Zhao P,Yang L,Li J,et al.Combining systems pharmacology,transcriptomics,proteomics,and metabolomics to dissect the therapeutic mechanism of Chinese herbal Bufei Jianpi formula for application to COPD.Int J Chron Obstruct Pulmon Dis 2016;11:553-66.

    47.Zhou B,Yuan Y,Zhang S,et al.Intestinal flora and disease mutually shape the regional immune system in the intestinal tract.Front Immunol 2020;11:575.

    48.Ma Y,Peng X,Yang J,et al.Impacts of functional oligosaccharide on intestinal immune modulation in immunosuppressive mice.Saudi J Biol Sci 2020;27:233-41.

    49.Szabo G.Gut-liver axis in alcoholic liver disease.Gastroenterology 2015;148:30-6.

    50.Krzyzaniak MJ,Peterson CY,Cheadle G,et al.Efferent vagal nerve stimulation attenuates acute lung injury following burn:the importance of the gut-lung axis.Surgery 2011;150:379-89.

    51.Wang Y,Meng SN,Zhang X,et al.Review of the intestinal flora alteration treated with Chinese medicine.Huan Qiu Zhong Yi Yao 2015;8:620-23.

    52.Zhang R,Zhu X,Bai H,et al.Network pharmacology databases for Traditional Chinese Medicine:review and assessment.Front Pharmacol 2019;10:123.

    53.Zhang Q,Yu K,Li S,et al.gutMEGA:a database of the human gut MEtaGenome Atlas.Brief Bioinform 2020;bbaa082.

    54.Wu S,Sun C,Li Y,et al.GMrepo:a database of curated and consistently annotated human gut metagenomes.Nucleic Acids Res 2020;48:D545-53.

    55.Wang W,Xiao Y,Wang X,et al.Disordered gut microbiota in children who have chronic pancreatitis and different functional gene mutations.Clin Transl Gastroenterol 2020;11:e00150.

    56.Gao K,Yang R,Zhang J,et al.Effects of Qijian mixture on type 2 diabetes assessed by metabonomics,gut microbiota and network pharmacology.Pharmacol Res 2018;130:93-109.

    57.Ding Z,Zhong R,Yang Y,et al.Systems pharmacology reveals the mechanism of activity of Ge-Gen-Qin-Lian decoction against LPS-induced acute lung injury:a novel strategy for exploring active components and effective mechanism of TCM formulae.Pharmacol Res 2020;156:104759.

    58.Banerjee S,Bhattacharjee P,Kar A,et al.LC-MS/MS analysis and network pharmacology of Trigonella foenum-graecum-a plant from Ayurveda against hyperlipidemia and hyperglycemia with combination synergy.Phytomedicine 2019;60:152944.

    59.Liang X,Liu CS,Xia T,et al.Identification of active compounds of Mahuang Fuzi Xixin decoction and their mechanisms of action by LC-MS/MS and network pharmacology.Evid Based Complement Alternat Med.2020;2020:3812180.

    60.Liang Z,Gu Y,Duan X,et al.Design of multichannel functional near-infrared spectroscopy system with application to propofol and sevoflurane anesthesia monitoring.Neurophotonics 2016;3:045001.

    61.Liu W,Chen XH,Ge YY,et al.Network pharmacology strategy for revealing the pharmacological mechanism of pharmacokinetic target components of San-Ye-Tang-Zhi-Qing formula for the treatment of type 2 diabetes mellitus.J Ethnopharmacol 2020;113044:1-42.

    62.Zhang C,Liu C,Qu Y,et al.LC-MS-based qualitative analysis and pharmacokinetic integration network pharmacology strategy reveals the mechanism of Phlomis brevidentata H.W.Li treatment of pneumonia.ACS Omega 2021;6:4495-505.

    63.Mahomoodally MF,Picot-Allain MCN,Zengin G,et al.Phytochemical analysis,network pharmacology and in silico investigations on anacamptis pyramidalis tuber extracts.Molecules 2020;25:2422.

    64.Shawky E.Prediction of potential cancer-related molecular targets of North African plants constituents using network pharmacologybased analysis.J Ethnopharmacol 2019;238:111826.

    65.Daina A,Michielin O,Zoete V.SwissADME:a free web tool to evaluate pharmacokinetics,drug-likeness and medicinal chemistry friendliness of small molecules.Sci Rep 2017;7:42717.

    66.Wishart D,Knox C,Guo A,et al.DrugBank:a comprehensive resource for in silico drug discovery and exploration.Nucleic Acids Res 2006;34:668-72.

    67.Tao W,Li B,Gao S,et al.CancerHSP:anticancer herbs database of systems pharmacology.Sci Rep 2015;5:11481.

    68.Davies M,Nowotka M,Papadatos G,et al.ChEMBL web services:streamlining access to drug discovery data and utilities.Nucleic Acids Res 2015;43:612-20.

    69.Pence HE,Williams A.ChemSpider:an online chemical information resource.J Chem Educ 2010;87:1123-4.

    70.Xu HY,Zhang YQ,Liu ZM,et al.ETCM:an encyclopaedia of Traditional Chinese Medicine.Nucleic Acids Res 2019;47:976-82.

    71.Xiong GL,Wu ZX,Yi JC,et al.ADMETlab 2.0:an integrated online platform for accurate and comprehensive predictions of ADMET properties.Nucleic Acids Res 2021;49:5-14.

    72.Chen XY,Gou SH,Shi ZQ,et al.Spectrum-effect relationship between HPLC fingerprints and bioactive components of Radix Hedysari on increasing the peak bone mass of rat.J Pharm Anal 2019;9:266-73.

    73.Chen Y,Pan G,Xu W,et al.Spectrum-effect relationship study between HPLC fingerprints and antioxidant activity of Sabia parviflora.J Chromatogr B Analyt Technol Biomed Life Sci 2020;1140:121970.

    74.Zhu CS,Lin ZJ,Xiao ML,et al.The spectrum-effect relationshipa rational approach to screening effective compounds,reflecting the internal quality of Chinese herbal medicine.Chin J Nat Med 2016;14:177-84.

    75.Zhao Y,Xie Q,He L,et al.Comparsion analysis of data mining models applied to clinical research in Traditional Chinese Medicine.J Tradit Chin Med 2014;34:627-34.

    76.Li K,Li J,Su J,et al.Identification of quality markers of Yuanhu Zhitong tablets based on integrative pharmacology and data mining.Phytomedicine 2018;44:212-9.

    77.Sun JH,Sun F,Yan B,et al.Data mining and systematic pharmacology to reveal the mechanisms of Traditional Chinese Medicine in mycoplasma pneumoniae pneumonia treatment.Biomed Pharmacother 2020;125:109900.

    78.Sun W,Cai Z,Li Y,et al.Data processing and text mining technologies on electronic medical records:a review.J Healthc Eng 2018;2018:4302425.

    79.Guo J,Shang E,Zhao J,et al.Data mining and frequency analysis for licorice as a "Two-Face" herb in Chinese formulae based on Chinese formulae database.Phytomedicine 2014;21:1281-6.

    80.Zheng W,Wu J,Gu J,et al.Modular characteristics and mechanism of action of herbs for endometriosis treatment in Chinese medicine:a data mining and network pharmacologybased identification.Front Pharmacol 2020;11:147.

    81.Ren L,Zheng X,Liu J,et al.Network pharmacology study of traditional Chinese medicines for stroke treatment and effective constituents screening.J Ethnopharmacol 2019;242:112044.

    82.Chen SJ.Drug-target networks for Tanshinone IIA identified by data mining.Chin J Nat Med 2015;13:751-59.

    83.Yang LN,Wu ZL,Yang ZJ,et al.Exploring mechanism of key Chinese herbal medicine on breast cancer by data mining and network pharmacology methods.Chin J Integr Med 2020;27:919-26.

    84.Zheng J,Wu M,Wang H,et al.Network pharmacology to unveil the biological basis of health-strengthening herbal medicine in cancer treatment.Cancers (Basel) 2018;10:461.

    85.Liu X,Lu P,Zuo XH,et al.Prediction of network drug target based on improved model of bipartite graph valuation.Zhong Guo Zhong Yao Za Zhi 2012;37:125-29.

    86.Zuo H,Zhang Q,Su S,et al.A network pharmacology-based approach to analyse potential targets of traditional herbal formulas:an example of Yu Ping Feng decoction.Sci Rep 2018;8:11418.

    87.Blondel V,Guillaume JL,Lambiotte R,et al.Fast unfolding of communities in large networks.J Stat Mech-theory E 2008;2008:1-12.

    88.Lambiotte R,Delvenne JC,Barahona M.Laplacian dynamics and multiscale modular structure in networks.IEEE Trans Netw Sci Eng 2008;1:76-90.

    89.Fang J,Cai C,Chai Y,et al.Quantitative and systems pharmacology 4.network-based analysis of drug pleiotropy on coronary artery disease.Eur J Med Chem 2019;161:192-204.

    90.Benjamini Y,Hochberg Y.Controlling the false discovery rate:a practical and powerful approach to multiple testing.J R Stat Soc Ser C Appl Stat 1995;57:289-300.

    91.Hu CJ,He J,Li GZ,et al.Analyzing hedyotis diffusa mechanisms of action from the genomics perspective.Comput Methods Programs Biomed 2019;174:1-8.

    92.Vanunu O,Magger O,Ruppin E.,et al.Associating genes and protein complexes with diseasevianetwork propagation.PLoS Comput Biol 2010;6:e1000641.

    93.Shi YX,Lin XF,Qiong YU,et al.Clinical efficacy and safety evaluation of TCM treatment for obesity caused by psychoactive drugs.Zhong Hua Zhong Yi Yao Xue Kan 2016;34:1268-70.

    94.Arlt VM,Stiborova M,Schmeiser HH.Aristolochic acid as a probable human cancer hazard in herbal remedies:a review.Mutagenesis 2022;17:265-77.

    95.Chen M,Su M,Zhao L,et al.Metabonomic study of aristolochic acid-induced nephrotoxicity in rats.J Proteome Res 2006;5:995-1002.

    96.Balkrishna A,Manikyam HK,Sharma VK,et al.Safety evaluation of Picrorhiza kurroa Rhizome extract by bacterial reverse mutation test.Adv Stud Biol.2016;8:127-40.

    97.Park H,Hwang YH,Ma JY.Single,repeated dose toxicity and genotoxicity assessment of herb formula KIOM2012H.Integr Med Res.2017;6:361-71.

    98.Fan XH.Network toxicology and its application to Traditional Chinese Medicine.Zhong Guo Zhong Yao Za Zhi 2011;36:2920-2.

    99.Liu C,Zhang C,Wang W,et al.Integrated metabolomics and network toxicology to reveal molecular mechanism of celastrol induced cardiotoxicity.Toxicol Appl Pharmacol 2019;383:114785.

    100.Wang SF,Liu KC,Wang XM,et al.Preliminary study on cardiotoxicity of celastrol to zebrafish embryo.Zhong Guo Yao Li Xue Tong Bao 2009;25:634-6.

    101.Hou L,Wang L,Liu RP,et al.Study on basis of liver toxicity of decoction Bupleurum chinense based on integrated model of spectrum toxicity relationship and liver toxicity network.Zhong Cao Yao 2020;51:2798-806.

    102.Li YX,Peng C.The application of "Efficacy components group"in toxicity/effect material basis of Traditional Chinese Medicine.Zhong Yao Yu Lin Chuang 2018;9:53-65.

    103.Rugard M,Coumoul X,Carvaillo JC,et al.Deciphering adverse outcome pathway network linked to bisphenol F using text mining and systems toxicology approaches.Toxicol Sci 2020;173:32-40.

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