基于网络药理学从巨噬细胞极化途径研究维药刺山柑治疗RA的作用机制

Study on the Mechanism of Uygur Medicine Capparis spinosa in Treating RA from Macrophage Olarization Pathway Based on Network Pharmacology

摘要: 目的：应用网络药理学方法筛选刺山柑治疗类风湿关节炎(rheumatoid arthritis, RA)的靶点，从巨噬细胞极化途径探讨刺山柑防治类风湿关节炎的药理机制。方法：通过查阅相关文献检索刺山柑的主要化学成分；通过Pubchem有机小分子生物活性数据库检索化学成分的SMILES结构式，经Swiss ADME数据库筛选后将符合标准的化学成分上传至Swiss Target Prediction数据库预测药物活性靶点；通过人类基因数据库(Gencards)、在线人类孟德尔遗传数据库(online mendelian inheritance in man, OMIM)数据库获取巨噬细胞极化相关靶点；绘制韦恩图并获取刺山柑活性成分与巨噬细胞极化的共同靶点；基于String平台构建药物疾病共同靶点的蛋白互作网络；基于David平台进行基因本体(gene ontology, GO)生物功能分析和京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes, KEGG)通路富集分析；采用Cytoscape-v3.9.0软件构建“成分–靶点–通路”网络，应用网络分析仪(network analyzer)功能获得各成分、靶点的网络拓扑参数，筛选刺山柑发挥调控巨噬细胞极化的重要活性成分及核心靶点。结果：通过文献检索获得25个刺山柑活性成分及186个相关靶点；通过Gene Cards、OMIM数据库获得4081个巨噬细胞极化潜在靶点；将药物成分作用靶点与巨噬细胞极化相关靶点映射后，得到刺山柑调控巨噬细胞极化治疗RA的靶点165个；GO生物功能富集分析得到681个条目，其中生物过程445条，细胞组分74条，分子功能162条；KEGG通路富集分析获得136个信号通路，主要涉及HIF-1信号通路、氮素代谢通路、ROS通路、PI3K-Akt信号通路等生物学途径；网络拓扑分析得出刺山柑调控巨噬细胞极化的重要活性成分异鼠李素、木犀草素、山柰酚、芹菜素等化合物，重要靶点基因主要有AKT1、TNF、EGFR等。结论：刺山柑可能通过异鼠李素、山奈酚、木犀草素、芹菜素等潜在药效成分调控AKT1、TNF、EGFR等多个靶点基因的表达，通过HIF-1信号通路、氮素代谢通路、ROS通路、PI3K-Akt信号通路等多个信号通路协同作用，发挥调控巨噬细胞极化介导RA治疗的作用。

Abstract: Objective: To investigate the mechanism of treatment of rheumatoid arthritis (RA) with macro-phage polarization pathway of capers based on network pharmacology. Methods: The main chemi-cal constituents of capers were retrieved by referring to relevant literature. SMILES structural ex-pressions of chemical components were retrieved through Pubchem organic small molecule bioac-tivity database, and chemical components meeting the criteria were screened by Swiss ADME data-base and uploaded to Swiss Target Prediction Database for drug active targets prediction. Targets related to macrophage polarization were obtained from the Human Gene Database (Gencards) and the online mendelian inheritance in man (OMIM) database. The common target of active compo-nents of capers and macrophage polarization was obtained by Wynn diagram. The protein interac-tion network of common target of drug disease was constructed based on String platform. The bio-logical functions were analyzed based on the gene ontology (GO) platform and the enrichment anal-ysis of the kyoto encyclopedia of genes and genomes (KEGG) pathway was conducted based on the David platform. Cytoscape-v3.9.0 software was used to construct the “component-target-pathway” network, network topology parameters of each component and target were obtained by network analyzer, and important active components and core targets of Capers were selected to play a role in regulating macrophage polarization. Results: 25 active ingredients and 186 related targets of ca-pers were obtained by literature search. A total of 4081 potential targets for macrophage polariza-tion were obtained by Gene Cards and OMIM database. After mapping the targets of drug compo-nents to the targets related to macrophage polarization, 165 targets of capers regulating macro-phage polarization for RA treatment were obtained. GO biological function enrichment analysis ob-tained 681 items, including 445 biological processes, 74 cell components, and 162 molecular func-tions. KEGG pathway enrichment analysis obtained 136 signaling pathways, mainly involving HIF-1 signaling pathway, nitrogen metabolism pathway, ROS pathway, PI3K-Akt signaling pathway and other biological pathways. Network topology analysis showed that isorhamnetin, luteolin, kaempferol, apigenin and other important active components of capers regulate the polarization of macrophages, and the important target genes were mainly AKT1, TNF, EGFR and so on. Conclusions: Capers may regulate the expression of AKT1, TNF, EGFR and other target genes through potential pharmacodynamic components such as isorhamnetin, kaempferol, luteolin and apigenin, and through the synergistic effect of HIF-1 signaling pathway, nitrogen metabolism pathway, ROS path-way, PI3K-Akt signaling pathway and other signaling pathways. Play a role in regulating macro-phage polarization mediating RA therapy. Keywords