整合化学物质组学和网络药理学的雷公藤片治疗类风湿性关节炎作用机制研究

Mechanism of Tripterygium wilfordii tablets for the treatment of rheumatoid arthritis based on integrated chemomics and network pharmacology

目的基于化学物质组学和网络药理学方法研究雷公藤片治疗类风湿性关节炎的作用机制。方法基于超高效液相色谱-串联四极杆飞行时间高分辨质谱(UPLC-Q-TOF/HRMS)分析技术,在正、负离子模式下鉴定雷公藤片的化学成分,在此基础上,通过Swiss Target Prediction和PharmMapper在线数据库对雷公藤片化学成分的作用靶点进行预测,并运用中国系统药理学数据库与分析平台(TCMSP)、治疗靶点数据库(TTD)、毒性与基因比较数据库(CTD)等在线数据库获取类风湿性关节炎疾病的作用靶点,将其与成分靶点取交集得到雷公藤片治疗类风湿性关节炎的直接共有靶点,使用GeneMANIA数据库获取间接靶点,并通过Cytoscape 3.7.1软件构建潜在作用靶点的蛋白相互作用(PPI)网络并筛选关键靶点,运用基因本体论(GO)数据库和京都基因与基因组百科全书(KEGG)数据库对所有潜在作用靶点进行基因功能富集分析和通路富集分析以确定其关键作用通路,探讨雷公藤片治疗类风湿性关节炎的作用机制。结果从雷公藤片中共鉴别出31个化学成分,经预测共得到66个潜在作用靶点,反向筛选发现其中的27个活性成分可能是雷公藤片治疗类风湿性关节炎的重要成分,同时筛选出5个核心靶点,可能积极参与到关键通路中对类风湿性关节炎进行干预和相应的调节。结论本研究运用网络药理学发现雷公藤片中的活性成分通过多靶点、多途径发挥重要作用,相关的靶点和途径均涉及到炎症反应和免疫调节。

Objective To explore the mechanism of Leigongteng Pian(Tripterygium wilfordii tablets)for the treatment of rheumatoid arthritis(RA)based on chemomics and network pharmacology.Method UPLC-Q-TOF/HRMS was used to analyze the chemical constituents of Tripterygium wilfordii tablets under the positive and negative ion modes.Thereafter,the ingredient targets of Tripterygium wilfordii tablets were predicted by Swiss Target Prediction and PharmMapper databases,and the targets of RA diseases were obtained by Traditional Chinese Medicine Systems Pharmacology(TCMSP),Therapeutic Target Database(TTD)and Comparative Toxicogenomics Database(CTD).By taking the intersection of ingredient targets and disease targets,the direct common targets of Tripterygium wilfordii tablets for the treatment of rheumatoid arthritis were obtained.Then the GeneMANIA database was used to obtain indirect targets,and the software of Cytoscape 3.7.1 was used to construct the protein-protein interaction(PPI)networks of potential targets,by which the key targets were screened.Enrichment of gene function and pathways of all potential targets were conducted by Gene Ontology(GO)database and Kyoto Encyclopedia of Genes and Genomes(KEGG)database to explore the mechanism of Tripterygium wilfordii tablets for the treatment of rheumatoid arthritis.Results Thirtyone chemical constituents of Tripterygium wilfordii tablets were screened out and sixtysix potential targets were predicted.Twentyseven active components in the Tripterygium wilfordii tablets might be important components for the treatment of rheumatoid arthritis as indicated by the reverse screening.At the same time,five core targets were screened out,which might be involved in the key pathways that actively participate in the intervention and adjustion of rheumatoid arthritis.Conclusion In this study,we found that the active components in Tripterygium wilfordii tablets could exert important biological effects via multiple targets and pathways,and these targets and pathways are all involved with the inflammation and immune regulation of RA.