基于网络药理学分析五味消毒饮治疗关节假体周围感染的作用机制

Action mechanism of Wuwei Xiaodu Yin in the treatment of periprosthetic joint infection based on network pharmacology

背景:五味消毒饮在临床中已被用于治疗关节假体周围感染,但因五味消毒饮所含有效成分复杂,其分子作用机制尚不明确。目的:探究五味消毒饮治疗关节假体周围感染的作用机制。方法:通过中药系统药理学成分分析数据库(BATMAN-TCM)预测获得五味消毒饮的有效化合物及靶点基因,利用Gene Cards和OMIM数据库获得关节假体周围感染疾病的相关靶点基因,取两者交集后得到五味消毒饮-关节假体周围感染疾病交集基因。随后采用STRING在线数据库构建蛋白相互作用网络(PPI),根据度值筛选核心基因。将交集基因输入Cytoscape3.7.2软件以构建WWXDY-靶点-关节假体周围感染可视化网络图,并借助DAVID在线工具进行交集靶点的基因本体论(GO)功能和京都基因与基因组百科全书(KEGG)通路富集分析,探讨其抗关节假体周围感染的作用机制。结果与结论:①从BATMAN-TCM平台共预测出五味消毒饮的有效化合物37个,作用靶点共914个;从Gene Cards和OMIM数据库筛选出关节假体周围感染疾病的相关靶点基因286个;取交集获得药物与疾病交集靶点39个,经筛选得到核心基因16个;②GO分析结果显示,交集靶基因的生物过程主要是趋化因子生物合成过程的正向调控、蛋白激酶B信号、炎症反应、脂多糖媒介的信号通路、细胞因子分泌的负调控参与免疫应答等;分子功能为细胞因子活性、生长因子活性、ICAM-3受体活性、Ⅲ型转化生长因子受体结合、前列腺素-内过氧化物合酶活性;细胞组分为细胞外空间、细胞表面、细胞膜外侧面、胞外区、整合蛋白αL-β2复合体;③KEGG通路富集结果主要涉及类风湿性关节炎、疟疾、细胞因子-细胞因子受体相互作用、南美锥虫病、利什曼病、炎症性肠病、阿米巴病、肿瘤坏死因子信号通路、肺结核、自然杀伤细胞介导的细胞毒性等信号通路;④提示五味消毒饮治疗关节假体周围感染疾病的作用机制呈多个有效化合物、多个作用途径以及多个靶点基因的特点,为后续实验提供了新思路、新方向。

BACKGROUND:Wuwei Xiaodu Yin has been used to treat periprosthetic joint infection in clinic,but its molecular mechanism is not clear due to the complexity of its active ingredients.OBJECTIVE:To investigate the action mechanism of Wuwei Xiaodu Yin in the treatment of periprosthetic joint infection.METHODS:The active compounds and targets of Wuwei Xiaodu Yin were obtained by using Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine(BATMAN-TCM)database.The disease targets corresponding to periprosthetic joint infection were obtained by using GeneCards and OMIM database.The intersection of the two was taken to obtain the Wuwei Xiaodu Yin-periprosthetic joint infection disease intersection target.The STRING online database was used to construct the protein-protein interaction network.Core genes were screened according to degree value.The intersection genes were fed into Cytoscape 3.7.2 software to construct the Wuwei Xiaodu Yin-target-periprosthetic joint infection visual network map.Furthermore,by means of DAVID online tool,the gene ontology(GO)function and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment of the intersection target were analyzed to explore the actin mechanism of Wuwei Xiaodu Yin control over periprosthetic joint infection.RESULTS AND CONCLUSION:A total of 37 active compounds were predicted from the BATMAN-TCM platform,with 914 target sites.A total of 286 periprosthetic joint infection target genes were screened from GeneCards and OMIM databases.Totally 39 drug and disease intersection targets were obtained by intersection,and 16 core genes were obtained by screening.(2)GO analysis results showed that the biological function of intersection target mainly included positive regulation of chemokine biosynthetic process,protein kinase B signaling,inflammatory response,lipopolysaccharide-mediated signaling pathway,negative regulation of cytokine secretion involved in immune response and so on.Molecular functions included cytokine activity,growth factor activity,ICAM-3 receptor activity,type III transforming growth factor beta receptor binding,and prostaglandin-endoperoxide synthase activity.Cell composition mainly included extracellular space,cell surface,external side of plasma membrane,extracellular region,and integrin alphaL-beta2 complex.(3)KEGG pathway enrichment showed that above targets were mainly related to rheumatoid arthritis,malaria,cytokine-cytokine receptor interaction,American trypanosomiasis,leishmaniasis,inflammatory bowel disease,amoebiasis,tumor necrosis factor signaling pathway,tuberculosis,and natural killer cell mediated cytotoxicity.(4)The action mechanism of Wuwei Xiaodu Yin in treating periprosthetic joint infection disease is characterized by multiple effective compounds,multiple action pathways and multiple target genes,providing new ideas and new directions for subsequent experiments.