基于网络药理学探讨痛泻要方治疗腹泻型肠易激综合征的作用机制

Study on the Mechanism of Action of Important Formula for Painful Diarrhea in Treating Diarrhea Predominant Irritable Bowel Syndrome Based on Network Pharmacology Technology

目的:运用网络药理学探讨痛泻要方对腹泻型肠易激综合征(diarrhea predominant irritable bowel syndrome,IBS-D)的潜在作用机制。方法:通过中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)获得痛泻要方中四味中药的药物活性成分,并通过TCMSP、Swiss Target Prediction及Pharmapper数据库得到各活性成分的潜在作用靶点。使用在线人类孟德尔遗传数据库(online mendelian inheritance in man,OMIM)、Gene Cards数据库获取IBS-D疾病对应的靶点,将疾病靶点与药物靶点取交集,获得痛泻要方治疗IBS-D的潜在作用靶点,运用Cytoscape 3.7.1软件构建“中药-活性成分-潜在靶点”网络图,并进行拓扑分析筛选关键成分。利用String数据库对潜在作用靶点进行蛋白质相互作用分析,构建蛋白质相互作用(protein-protein interaction,PPI)网络,拓扑分析筛选核心靶点。使用Omicshare在线分析工具对潜在作用靶点进行基因本体(gene ontology,GO)功能富集分析及京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)信号通路富集分析,使用Cytoscape 3.7.1软件构建“代谢通路-靶标”网络图,拓扑分析筛选关键代谢通路。结果:通过TCMSP数据库筛选获得痛泻要方活性成分35个,对应潜在作用靶点370个。通过OMIM、GeneCards数据库检索得到IBS-D疾病靶标4189个,痛泻要方活性成分相关靶点与IBS-D疾病靶点的交集靶点146个,即为痛泻要方治疗IBS-D的潜在靶点。“中药-活性成分-潜在靶点”网络拓扑分析得到β-谷甾醇、山柰酚、汉黄芩素、珊瑚菜素、前胡素、川陈皮素等为痛泻要方治疗IBS-D的关键成分。潜在靶点PPI分析得到核心靶点58个,核心靶点PPI网络筛选得到关键靶点20个。GO富集分析得到GO条目3345项,其中分子功能312项,细胞组分145项,生物学过程2888项。KEGG富集分析得到相关代谢通路144条,如肿瘤坏死因子信号通路、PI3K-Akt信号通路、IL-17信号通路等。结论:痛泻要方可能通过调控PI3K-Akt、TNF等信号通路发挥治疗IBS-D的作用,具有多成分、多靶点、多通路协同作用的特点。

Objective:To explore the potential mechanism of action of Important Formula for Painful Diarrhea on diarrhea predomi nant irritable bowel syndrome(IBS-D)based on network pharmacology technology.Methods:The active ingredients of four kinds of Chinese medicinals in Important Formula for Painful Diarrhea were obtained through the traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP),and the potential targets of each active ingredient were obtained through TCMSP,Swiss Target Prediction and Pharmapper databases.The targets corresponding to IBS-D diseases were obtained by using the online Mendelian inheritance in man(OMIM)and Gene Cards databases.By intersecting disease targets with drug targets,potential therapeutic targets for treating IBS-D with Important Fonnula for Painful Diarrhe were obtained.Then,the"Chinese medici-nals-active ingredients-potential targets"network diagram was constructed by using Gytoscape 3.7.1 software,and key components were selected through topology analysis.By utilizing a String database to analyze protein interactions with potential targets,a protein protein interaction(PPI)network was constructed,and core targets were selected through topology analysis.Omicshare online analysis tool was used to carry out Gene Ontology function enrichment analysis,and Kyoto encyclopedia of genes and genomes(KEGG)signal pathway enrichment analysis on potential action targets;Cytoscape 3.7.1 software was used to build a"metabolic pathway-target"network diagram,and topology analysis was used to screen key metabolic pathways.Results:Through TCMSP database screening,35 active ingredients of Important Formula for Painful Diarrhea were obtained,corresponding to 370 potential targets of action.Through OMIM and GeneCards databases,4189 IBS-D disease targets were retrieved,and 146 intersection targets between the active ingredient related targets of Important Formula for Painful Diarrhea and IBS-D disease targets were identified,which were potential targets for the treatment of IBS-D.The network topology analysis of"Chinese medicinals-active ingredients-potential targets"showed that p-sitosterol,kaempferol,baicalin,corallin,prehussin and tangerine were the key components of Important Formula for Painful Diarrhea in the treatment of IBS-D.There were 58 core targets by PPI analysis and 20 key targets by PPI network screening.GO enrichment analysis obtained 3345 GO items,including 312 molecular functions,145 cell components and 2888 biological processes.KEGG enrichment analysis showed 144 related metabolic pathways,for example,TNF signaling pathway,PI3K-Akt signaling pathway,IL-17 signaling pathway,etc.Conclusion:Important Formula for Painful Diarrhea may play a role in the treatment of IBS-D through the regulation of PI3K-Akt,TNF and other signaling pathways,which has the characteristics of multi-component,multi-target and multi-pathway synergism.