基于网络药理学探讨龟鹿二仙胶治疗骨关节炎的作用及机制

Role and mechanism of Guilu Erxianjiao in treatment of osteoarthritis based on network pharmacology

背景:临床研究表明龟鹿二仙胶治疗骨关节炎效果显著,但其药理机制尚不明确。目的:文章运用网络药理学研究方法,分析龟鹿二仙胶治疗骨关节炎的潜在靶点、作用网络及潜在机制。方法:文章借助TCMSP,BATMAN-TCM和TCMID数据库获取龟鹿二仙胶的化学成分及对应靶点,OMIM,Gene Cards和Drug Bank数据库检索骨关节炎的已知疾病靶点;运用Perl语言将药物活性成分靶点与疾病靶点相映射得到龟鹿二仙胶治疗骨关节炎的作用靶点,运用Cytoscape3.7.2软件构建“药物-化合物-靶点”作用网络,运用STRING软件构建蛋白相互作用(PPI)网络,对所得PPI网络进行拓扑分析,筛选发挥治疗作用的关键成分与关键靶点;运用R语言对关键靶点进行GO富集分析和KEGG通路富集分析获知其潜在作用机制,构建龟鹿二仙胶“通路-靶点”,获知主要作用通路与靶点之间的关系。结果与结论:①文章预测得到龟鹿二仙胶治疗骨关节炎的有效成分69个,靶点201个,关键成分有槲皮素、山奈酚及β-谷甾醇等6个,关键靶点有白细胞介素6、丝裂原活化蛋白激酶1和含半胱氨酸的天冬氨酸蛋白水解酶3等20个;②GO和KEGG分析结果显示,龟鹿二仙胶通过以上关键靶点,影响丝裂原活化蛋白激酶信号通路、白细胞介素17信号通路和肿瘤坏死因子信号通路等13个主要通路,集中于调控炎症、软骨代谢、细胞凋亡与增殖等功能来发挥防治骨关节炎的作用;③结果证实,以上关键靶点和通路构建了龟鹿二仙胶防治骨关节炎的作用网络,其多成分-多靶点-多途径的治疗特点为龟鹿二仙胶进一步的基础研究以及临床应用提供了新的思路与线索。

BACKGROUND:Clinical studies have shown that Guilu Erxianjiao has a remarkable effect on osteoarthritis,but its pharmacological mechanism is not yet clear.OBJECTIVE:To analyze the potential targets,action networks and potential mechanisms of Guilu Erxianjiao for the treatment of osteoarthritis using network pharmacology.METHODS:The chemical constituents and corresponding targets of Guilu Erxianjiao were obtained with the help of TCMSP,BATMAN-TCM and TCMID databases,and the known disease targets of osteoarthritis were searched in OMIM,GeneCards and Drug Bank databases.Perl language was used to map the targets of the active ingredients of the drug to the targets of the disease to obtain the targets of Guilu Erxianjiao for treating osteoarthritis.Cytoscape 3.7.2 software was used to build a“drug-compound-target”interaction network.STRING software was used to construct a protein-protein interaction network,followed by a topological analysis on the obtained protein-protein interaction network to screen the key components and key targets that play a therapeutic role.R language was used to perform gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Gnomes(KEGG)pathway enrichment analysis to understand its potential mechanism of action,construct the“pathway-target”of the Guilu Erxianjiao.The relationship between the main pathway and targets was then obtained.RESULTS AND CONCLUSION:It is predicted that 69 active ingredients and 201 targets of Guilu Erxianjiao for treating osteoarthritis will be obtained.There are 6 key components such as quercetin,kaempferol andβ-sitosterol,and 20 key targets such as interleukin-6,mitogen-activated protein kinase 1,and cysteinecontaining aspartate proteolytic enzyme 3.The results of GO and KEGG analysis showed that,through the above key targets,the Guilu Erxianjiao affected 13 major pathways,including mitogen-activated protein kinase signaling pathway,interleukin-17 signaling pathway,and tumor necrosis factor signaling pathway,and played a role in preventing and treating osteoarthritis by the focus on regulating inflammation,cartilage metabolism,apoptosis and proliferation.In conclusion,the above key targets and pathways have constructed an action network for the prevention and treatment of osteoarthritis by Guilu Erxianjiao,and its multi-component-multi-target-multi-channel treatment features provide new ideas and clues for the further basic research and clinical application of Guilu Erxianjiao.