基于网络药理学探讨羌活、独活、苍术治疗类风湿性关节炎的作用机制

Exploring the Mechanism of Action of Qi-angwu, Duhu and Cangzhi in the Treatment of Rheumatoid Arthritis Based on Network Pharmacology

摘要: 目的：基于网络药理学研究羌活、独活、苍术对治疗类风湿性关节炎作用机制。方法：从TCMSP、OMIM、Drugbank、GeneCards、PharmGkb、TTD数据库中确定羌活、独活、苍术潜在活性成分、作用靶点和疾病的差异基因映射筛选出共同靶点，利用Cytoscape 3.8.1软件建立“中药–活性成分–靶点网络–疾病”调控网络图，将筛选得到的靶点在相互作用基因/蛋白质搜索工具平台STRINGV 10.5构建起靶蛋白相互作用(PPI)网络，通过R包进行基因组百科全书(KEGG)信号通路和基因本体(GO)富集分析，以研究其抗炎机制。结果：通过中药系统药理学分析平台(TCMSP)从羌活、独活、苍术药中共筛选得到41个化合成分，211个药物靶标；经OMIM、Drugbank、GeneCards、PharmGkb、TTD数据库分析确定羌活、独活、苍术治疗类风湿性关节炎(RA)共同靶点83个，利用string数据构建羌活、独活、苍术和类风湿性关节炎的靶点。GO分析表明生物过程(BP)涉及对药物的反应、对氧化应激的反应、细胞对化学压力等，细胞成分(CC)涉及膜筏、膜微域、膜区等区域，分子功能(MF)涉及核受体活性、配体激活的转录因子活性、DNA结合的转录因子结合等生物学过程。KEGG结果表明，羌活、独活、苍术对于治疗类风湿性关节炎的途径信号通路包括药物的反应(信号通路包括IL-17途径、TNF)、氧化应激反应、细胞对化学压力的反应、活性氧代谢过程等通路。结论：羌活、独活、苍术对于改善类风湿性关节炎的作用机制是通过影响前列腺素PTGS2、原癌基因(Ctnnb1)、肾上腺素能受体β2 (ADRB2)、原癌基因c-FOS (FOS)、A型γ-氨基丁酸受体α亚基蛋白GABRA1、热休克蛋白、雌激素受体基因(ESR1)、苏氨酸蛋白激酶(AKT1)、细胞外信号调节激酶(MAPK1)的表达进而调控氧化应激反应、免疫球蛋白、前列腺素反应等途径实现的。

Abstract: OBJECTIVE: This paper aims to investigate the mechanism of action of Qiangwu, Doklam and Cangzhi in the treatment of rheumatoid arthritis based on network pharmacology. METHODS: We identified potential active ingredients, targets and diseases from TCMSP, OMIM, Drugbank, Gene-Cards, PharmGkb and TTD databases and screened out common targets using Cytoscape 3.8.1 soft-ware to establish a “Chinese herbal medicine-active ingredient-target network-disease” regulatory network. The screened targets were then used to construct their target protein interaction (PPI) networks in STRINGV 10.5, an interactive gene/protein search tool platform, and the genomic ency-clopedia (KEGG) signaling pathways and gene ontology (GO) enrichment analysis were performed by R package to investigate their anti-inflammatory mechanisms. RESULTS: A total of 41 chemotac-tic components and 211 drug targets were obtained from Qiangwu, Duxue and Cangjiao drugs by the Traditional Chinese Medicine Systematic Pharmacology Analysis Platform (TCMSP); 83 common targets of Qiangwu, Duxue and Cangjiao for the treatment of rheumatoid arthritis (RA) were identi-fied by OMIM, Drugbank, GeneCards, PharmGkb and TTD database analysis. The string data were used to construct targets for Qiang Zhi, Doklamia, Cang Zhi and rheumatoid arthritis. GO analysis showed that biological processes (BP) involved response to drugs, response to oxidative stress, cel-lular response to chemical stress, etc., cellular components (CC) involved regions such as membrane rafts, membrane microdomains, membrane regions, etc., and molecular functions (MF) involved nuclear receptor activity, ligand-activated transcription factor activity, DNA-bound. The KEGG results showed that the pathway signaling pathways of Qiangwu, Doklam and Cangzhi for the treatment of rheumatoid arthritis include the response to drugs (signaling pathways including IL-17 signaling pathway, TNF signaling), oxidative stress response, cellular response to chemical stress, reactive oxygen metabolic process and other pathways. CONCLUSION: The mechanism of action of Qiangwu, Duxue, and Cangjiao for improving rheumatoid arthritis is through affecting prostaglandins (PTGS2), proto-oncogene (Ctnnb1), adrenergic receptor beta 2 (ADRB2), proto-oncogene c-FOS (FOS), type A gamma-aminobutyric acid receptor alpha subunit protein (GABRA1), heat shock protein (HSP90AB1), and The expression of estrogen receptor gene (ESR1), threonine protein kinase (AKT1), extracellular signal-regulated kinase (MAPK1) and thus regulate signaling pathways such as oxidative stress response, immunoglobulin, and prostaglandin response were achieved.