基于网络药理学探讨桂枝-白芍药对治疗类风湿性关节炎作用机制

Discussion on Mechanism of Cinnamomi Ramulus-Paeoniae Radix Alba Couplet Medicinals in Treating Rheumatoid Arthritis Based on Network Pharmacology

目的:基于GEO基因芯片、生物信息学及分子对接技术探讨桂枝-白芍药对治疗类风湿性关节炎(RA)的作用机制。方法:通过GEO数据库下载RA的基因芯片数据集,利用R软件筛选出差异表达靶点;通过TCMSP、PharmMapper等数据库获取桂枝-白芍药对的化学成分、药物靶点,运用Cytoscape 3.9.1、R软件对药物-疾病交集靶点进行蛋白互作(PPI)网络拓扑分析;应用clusterProfiler等程序包对于交集靶点进行基因本体(GO)、京都基因和基因组(KEGG)富集分析;使用AutoDock Vina等软件进行分子对接初步验证。结果:共获得17个药物化学成分,RA靶点3 781个、药物靶点410个;筛选出药物-疾病交集靶点98个。PPI拓扑分析得出的核心靶点有基质金属蛋白酶-9 (MMP-9)、基质金属蛋白酶-2 (MMP-2)、过氧化氢酶(CAT)、丝氨酸蛋白酶抑制剂家族A成员1 (SERPINA1)、组织蛋白酶B (CTSB)等;桂枝-白芍药对治疗RA主要化学化合物有二氢槲皮素、β-谷甾醇、(+)-儿茶素、芍药苷等。潜在作用靶点参与了胶原分解代谢过程、细胞外基质分解、炎症反应调节等生物过程,涉及通路有溶酶体、过氧化物酶体增殖物激活受体(PPAR)信号通路、细胞色素P450代谢等。分子对接显示,桂枝-白芍药对主要化学化合物与核心靶点间结合能有较高的结合活性。结论:桂枝-白芍治疗RA多靶点、多成分、多途径的作用机制,为桂枝-白芍药对的后续研究提供了理论依据。

Objective:To discuss the mechanism of Cinnamomi Ramulus-Paeoniae Radix Alba couplet medicinals in treating rheumatoid arthritis(RA) based on GEO gene chip,bioinformatics and molecular docking.Methods:The gene chip data set of RA was downloaded from the GEO database,and the differential expression targets were screened by R software;databases,such as TCMSP and PharmMapper,were used to obtain the chemical components and targets of Cinnamomi Ramulus-Paeoniae Radix Alba couplet medicinals,and Cytoscape 3.9.1 and R software were used to carry out the topology analysis of the protein-protein interaction(PPI) network of medicine-disease intersection targets;packages,including clusterProfiler package,were used to perform gene ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis on the intersection targets;softwares,such as AutoDock Vina,were used to perform molecular docking for preliminary validation.Results:A total of 17 chemical components of medicine,3 781 RA targets and 410 medicine targets were obtained;a total of 98 medicinedisease intersection targets were screened out.The core targets of topology analysis of PPI included matrix metalloproteinase-9(MMP-9),matrix metalloproteinase-2(MMP-2),catalase(CAT),Serpin Family A Member 1(SERPINA1),cathepsin B(CTSB) and so on;the main chemical compounds of Cinnamomi Ramulus-Paeoniae Radix Alba couplet medicinals in treating RA are taxiflin,β-sitosterol,(+)-catechin,paeoniflorin and so on.Potential targets involved in collagen decomposition and metabolism,extracellular matrix decomposition,inflammatory response regulation and other biological processes,involving pathways such as lysosomes,peroxisome proliferator-activated receptor(PPAR) signaling pathway and cytochrome P450 metabolism.Molecular docking showed that Cinnamomi Ramulus-Paeoniae Radix Alba couplet medicinals had high binding activity between the main chemical compounds and the core targets.Conclusion:The multi-target,multi-component and multi-pathway mechanism of Cinnamomi RamulusPaeoniae Radix Alba in treating RA provides a theoretical basis for the follow-up study of Cinnamomi Ramulus-Paeoniae Radix Alba couplet medicinals.