目的 基于网络药理学和体外细胞实验探究柚皮苷治疗动脉粥样硬化的作用机制.方法 利用PubChem和Pharmmapper在线分析平台获取柚皮苷的作用靶点,在Genecards、PharmGkb、TTD、Disgenet和Drugbank数据库中获取动脉粥样硬化疾病相关靶点.构建蛋白质-蛋白质相互作用网络筛选核心靶点,通过基因本体(gene ontology,GO)功能分析和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)富集分析筛选出主要作用靶点和相关通路,利用分子对接技术确定柚皮苷与核心靶点相互作用的分子基础.通过人脐静脉内皮细胞(human umbilical vein endothelial cells,HUVEC)进行体外实验验证相关预测结果.结果 共筛选出柚皮苷潜在作用靶点220个,动脉粥样硬化疾病相关靶点5 253个,共同作用靶点94个.GO功能注释共得到281个条目,其中生物学过程215个,细胞组分25个,分子功能41个;KEGG富集共得到36条与动脉粥样硬化治疗有关的通路.分子对接结果证明柚皮苷与5个核心靶点之间具有良好的结合能力.细胞实验结果表明,柚皮苷能够降低HUVEC的迁移和粘附能力.结论 柚皮苷可能是通过血管内皮生长因子-2、基质金属蛋白酶-2和神经源性位点Notch同源蛋白1等关键靶点调节脂质与动脉粥样硬化、癌症蛋白多糖和MAPK等信号通路参与调节内皮细胞功能、血管生成、细胞增殖和凋亡等生物学过程发挥抗动脉粥样硬化作用.
Anti-atherosclerotic mechanisms of naringin based on network pharmacology and cellular experiments
Objective To explore the mechanism of action of naringin in the treatment of atherosclerosis based on network pharmacology and vitro cellular assays.Methods The PubChem platform and Pharmmapper online analysis platform were used to obtain targets of naringin,and Genecards,PharmGkb,TTD,Disgenet and Drugbank databases were searched for targets related to atherosclerosis diseases.The protein-protein interaction network was constructed to screen for the core targets while the main pathways and target proteins were screened via GO and KEGG enrichment analyses.Molecular docking was performed to determine the molecular basis of the interactions between naringin and the core targets.In vitro experiments were conducted with human umbilical vein endothelial cells(HUVEC)to verify the predicted results.Results A total of 220 potential targets of naringin were screened,5 253 targets were related to atherosclerosis,and 94 co-acting targets were identified.GO functional annotation resulted in a total of 281 entries,including 215 biological processes,25 cellular components,and 41 molecular functions.KEGG enrichment revealed a total of 36 pathways related to therapies for atherosclerosis.The molecular docking results demonstrated that naringin bound well to the five core targets.The results of cellular experiments showed that naringin could significantly reduce the migration and adhesion ability of HUVEC.Conclusion Naringin may inhabit atherosclerosis by regulating lipids,proteoglycan in cancer and MAPK signaling pathways through such key targets as the kinase insert domain receptor,recombinant plasminogen activator inhibitor 1 and tissue inhibitor of matrix metalloproteinase-1 which exert anti-atherosclerosis effects by regulating endothelial cell function,angiogenesis,cell proliferation and apoptosis.
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