麻黄细辛附子汤治疗类风湿关节炎作用机制的网络药理学分析

Network Pharmacological Analysis of the Mechanism of Mahuang Xixin Fuzi Decoction in the Treatment of Rheumatoid Arthritis

目的基于网络药理学方法分析麻黄细辛附子汤治疗类风湿关节炎的作用机制。方法利用中药系统药理学分析平台(TCMSP)和中药综合数据库(TCMID)筛选麻黄细辛附子汤的有效活性成分及治疗靶点;通过Cytoscape 3.2.1软件构建"中药-活性成分-靶点"可视化网络,并进行网络拓扑分析。通过TTD、DrugBank、OMIM、PharmGKB及DisGeNET等5个常用疾病基因数据库检索获得类风湿关节炎的疾病相关靶点。将筛选出的活性成分靶点与疾病相关靶点通过Genomics平台进行韦恩分析,匹配出麻黄细辛附子汤活性成分与类风湿关节炎疾病的共同靶点。将共同靶点通过STRING平台构建靶点间的蛋白相互作用(PPI)网络,并分析筛选出关键靶点作为麻黄细辛附子汤治疗类风湿关节炎的潜在靶点。通过Cytoscape软件的ClueGo插件对关键靶点进行京都基因与基因组百科全书(KEGG)通路富集分析。通过Cytoscape 3.2.1软件构建"成分-靶点-通路"网络。结果共筛选出麻黄细辛附子汤有效活性成分28个,作用靶点237个,分析得到槲皮素、山奈酚、木犀草素、β-谷甾醇、柚皮素等重要活性成分。筛选得到类风湿关节炎疾病相关基因1988个,麻黄细辛附子汤活性成分与类风湿关节炎疾病的共同靶点143个。PPI网络分析得到转录因子p65(RELA)、前列腺素G/H合成酶2(PTGS2)、AKT丝氨酸/苏氨酸激酶1(AKT1)、丝裂原活化蛋白激酶1(MAPK1)、转录因子AP-1(JUN)等关键靶点77个。KEGG通路富集分析得到TNF信号通路、IL-17信号通路、NF-κB信号通路、PI3K-Akt信号通路、HIF-1信号通路等重要信号通路39条。结论麻黄细辛附子汤通过多成分、多靶点、多通路,可能主要从调节炎症、免疫及细胞的增殖、凋亡、迁移功能等方面发挥对类风湿关节炎的治疗作用。

Objective To analyze the mechanism of action of Mahuang Xixin Fuzi decoction on rheumatoid arthritis based on network pharmacology.Methods The effective active ingredients and therapeutic targets of Mahuang Xixin Fuzi decoction were screened using the Chinese Medicine System Pharmacology Analysis Platform(TCMSP)and the Chinese Medicine Comprehensive Database(TCMID)data platform.A"Chinese medicine-active ingredient-target"visualization network was built using Cytoscape 3.2.1 software,and network topology analysis was performed.The five commonly used disease gene databases,TTD,DRUGBANK,OMIM,PharmGKB,and DisGeNET,were searched to obtain disease-related targets of rheumatoid arthritis.The screened active ingredient targets and diseaserelated targets were subjected to Wayne analysis through the Genomics platform to match the common targets of the active ingredients of Mahuang Xixin Fuzi decoction and rheumatoid arthritis diseases.The common targets were then used to construct a protein-protein interaction(PPI)network between targets through the STRING platform,and the key targets are analyzed and selected as potential targets for the treatment of rheumatoid arthritis with Mahuang Xixin Fuzi decoction.Using the ClueGo plug-in of Cytoscape software,the key targets were analyzed by Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment.The Cytoscape 3.2.1 software was then used to build a"Component-Target-Pathway"network.Results Twenty-eight important active ingredients of Mahuang Xixin Fuzi decoction were screened out,and 237 targets were analyzed.Quercetin,kaempferol,luteolin,β-sitosterol,naringenin and other important active ingredients were analyzed.1988 genes related to rheumatoid arthritis were screened,and 143 common targets of active ingredients of Mahuang Xixin Fuzi decoction and rheumatoid arthritis were obtained.PPI network analysis showed that there were 77 key targets including transcription factor p65(RELA),prostaglandin G/H synthetase 2(PTGS2),AKT serine/threonine kinase 1(AKT1),mitogen activated protein kinase 1(MAPK1)and transcription factor AP-1(JUN).KEGG pathway enrichment analysis yielded 39 important signal pathways including TNF signaling pathway,IL-17 signaling pathway,NF-κB signaling pathway,PI3 K-Akt signaling pathway,and HIF-1 signaling pathway.Conclusion Mahuang Xixin Fuzi decoction may play a therapeutic role on rheumatoid arthritis mainly through regulating multiple targets and multiple pathways by multiple components,from the aspects of regulating inflammation,immunity and cell proliferation,apoptosis,and migration function.