| 摘要: |
| 目的 通过网络药理学结合分子对接的研究方法预测甘草附子汤治疗类风湿关节炎（RA）的作用靶点，探究其治疗RA的作用机制。方法 通过中药系统药理学数据库与分析平台（TCMSP）检索甘草附子汤中包含的4种中药的有效成分及其靶基因。从基因表达汇编（GEO）数据库中下载RA数据，筛选RA患者与健康人群关节滑膜组织的差异基因并与甘草附子汤有效成分靶基因取交集，获得甘草附子汤治疗RA的潜在靶基因。通过Cytoscape 3.7.1软件构建中药-活性成分-疾病靶点网络，并分析网络节点度值以筛选关键活性成分。通过蛋白质-蛋白质相互作用（PPI）网络分析得到甘草附子汤治疗RA的关键蛋白靶点，利用Metascape数据库对甘草附子汤治疗RA的潜在靶基因进行基因本体（GO）分析及京都基因和基因组百科全书（KEGG）通路富集分析预测其作用机制。应用AutoDockTools-1.5.6及PyMOL软件进行分子对接，验证甘草附子汤的活性成分与其治疗RA关键靶点的结合能力。结果 获得甘草附子汤治疗RA的潜在靶基因44个。构建的中药-活性成分-疾病靶点网络包含药材节点4个、活性成分节点95个、潜在靶基因节点44个。网络拓扑结构分析显示槲皮素度值最高，可能为甘草附子汤治疗RA的关键活性成分。甘草附子汤治疗RA的机制涉及对无机物的反应等生物过程、膜筏等细胞组分、CXCR趋化因子受体结合等分子功能。KEGG分析显示甘草附子汤活性成分主要通过IL-17信号通路、TNF信号通路、破骨细胞分化等途径作用于RA。PPI网络分析结果显示基质金属蛋白酶9（MMP9）、C-X-C基序趋化配体8（CXCL8）、过氧化物酶体增殖物激活受体γ（PPARγ）、表皮生长因子受体（EGFR）为甘草附子汤治疗RA的关键靶点。分子对接证实槲皮素与关键靶点分子MMP9、CXCL8、PPARγ、EGFR具有较高的亲和力。结论 甘草附子汤中的活性成分可能通过MMP9、CXCL8、PPARγ、EGFR等靶点调节多条信号通路，发挥对RA的治疗作用。 |
| 关键词: 类风湿关节炎 甘草附子汤 网络药理学 作用机制 |
| DOI：10.16781/j.CN31-2187/R.20220060 |
| 投稿时间：2022-01-15修订日期：2022-04-29 |
| 基金项目: |
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| Effect of Gancao Fuzi decoction on rheumatoid arthritis: a mechanism study based on network pharmacology and molecular docking |
| YE Qian-yi1,MU Xing1,LU Hong-juan1,CAI Bin1,ZHANG Lu-ding2*,WU Xin1* |
(1. Department of Rheumatology and Immunology, The Second Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200003, China;
2. Department of Health Management, The Second Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200003, China
*Corresponding authors) |
| Abstract: |
| Objective To predict the target and explore the mechanism of Gancao Fuzi decoction for the treatment of rheumatoid arthritis (RA) by using network pharmacology and molecular docking. Methods The active ingredients and target genes of 4 kinds of traditional Chinese medicines contained in Gancao Fuzi decoction were searched through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Data on RA were downloaded from Gene Expression Omnibus (GEO) database, and differentially expressed genes in synovium between patients with RA and healthy people were screened and intersected with target genes of active ingredients of Gancao Fuzi decoction to obtain potential targets of Gancao Fuzi decoction for the treatment of RA. The Chinese medicine-active ingredient-disease target network was constructed and the network node degree value was analyzed to screen important key activity scores by Cytoscape 3.7.1 software. Key protein targets of Gancao Fuzi decoction in treatment of RA were obtained by protein-protein interaction (PPI) network analysis. Gene Ontology (GO) analysis and Kyoto Gene and Genome Encyclopedia (KEGG) pathway enrichment analysis of the core targets were performed by Metascape database to predict its mechanism of action. Finally, AutoDockTools-1.5.6 and PyMOL software were used for molecular docking to verify its binding ability. Results Forty-four potential target genes for Gancao Fuzi decoction in treating RA were obtained. The traditional Chinese medicine-active ingredient-disease target network contained 4 nodes of traditional Chinese medicines, 95 nodes of active ingredients and 44 nodes of potential target genes. Network topology analysis showed that the degree of quercetin was the highest and might be the possible key active ingredients of Gancao Fuzi decoction in the treatment of RA. The mechanism of Gancao Fuzi decoction in treating RA involves biological process including response to inorganic sunstance, cellular component including membrane raft, and molecular function including CXCR chemokine receptor binding. KEGG analysis showed that the active ingredients of Gancao Fuzi decoction mainly acted on RA through interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, osteoclast differentiation, and other signaling pathways. PPI network analysis showed that matrix metalloproteinase 9 (MMP9), C-X-C motif chemotactic ligand 8 (CXCL8), peroxisome proliferator activated receptor γ (PPARγ) and epidermal growth factor receptor (EGFR) were the key target molecules of Gancao Fuzi decoction in the treatment of RA. And it was confirmed by molecular docking that quereetin had high affinity with key target molecules MMP9, CXCL8, PPARγ and EGFR. Conclusion The active ingredients in Gancao Fuzi decoction can regulate multiple signaling pathways through MMP9, CXCL8, PPARγ and EGFR to treat RA. |
| Key words: rheumatoid arthritis Gancao Fuzi decoction network pharmacology mechanism of action |
