基于网络药理学从线粒体自噬途径探讨八味沉香散抗缺血性心脏病的作用机制  

Mechanism of Bawei Chenxiang powder in treatment of ischemic heart disease through mitophagy based on network pharmacology

作　　者：岳栋芳 李彩霞 官敏 李永芳 YUE Dong-fang;LI Cai-xia;GUAN Min;LI Yong-fang(the Department of Medical,Qinghai University,Xining 810001,China)

机构地区：[1]青海大学医学部,青海西宁810001

出　　处：《中国药理学通报》2023年第10期1957-1965,共9页Chinese Pharmacological Bulletin

基　　金：青海省科技计划项目(No 2022-ZJ-746);国家自然科学基金项目(No 81760761)。

摘　　要：目的基于网络药理学结合分子对接技术及细胞实验验证,探讨八味沉香散经线粒体自噬途径抗缺血性心脏病(ischemic heart disease,IHD)的潜在机制。方法利用Swiss target prediction平台预测八味沉香散入血成分靶点;从GeneCards、NCBI、OMIM数据库中筛选缺血性心脏病、线粒体自噬相关靶点;取三者交集得到八味沉香散经线粒体自噬途径抗缺血性心脏病的潜在靶点。构建“成分-疾病-潜在靶点”网络及蛋白质相互作用网络,分别进行网络分析筛选出关键活性成分和核心靶点,并进行分子对接。利用DAVID数据库进行GO富集及KEGG富集分析。构建H9C2细胞缺氧模型,考察八味沉香散含药血清对H9C2细胞存活率、自噬水平及关键通路相关蛋白表达的影响。结果筛选得到八味沉香散经线粒体自噬途径抗IHD的关键活性成分9种,核心靶点8个;分子对接结果显示关键活性物质和核心靶点均有较好的结合活性。KEGG结果显示八味沉香散经线粒体自噬途径抗IHD的作用可能与EGFR、PI3K-Akt、MAPK、FoxO等信号通路有关。细胞实验结果表明八味沉香散可增加缺氧条件下H9C2细胞的细胞活性,明显降低细胞中LC3、p62的蛋白相对表达量,升高p-PI3K/PI3K、p-AKT/AKT的蛋白相对表达量。结论八味沉香散可能通过槲皮素、山奈酚、柚皮素、去氢二异丁香酚等活性成分作用于AKT1、STAT3、MAPK3,EGFR等多个靶点调控线粒体自噬发挥抗缺血性心脏病的作用,其具体机制可能与PI3K-AKT信号通路相关。Aim To explore the potential mechanism of Bawei Chenxiang powder against ischemic heart disease(IHD)through mitophagy based on network pharmacology,molecular docking and verification in vitro.Methods The targets of serum constituents of Bawei Chenxiang powder were mined by Swiss target prediction,and then the targets related to IHD and mitophagy were selected from Genecards,NCBI and OMIM databases to obtain the intersection targets of the three as the potential targets of Bawei Chenxiang powder for the treatment of IHD through mitophagy.Then the“ingredients-disease-potential target”network and“protein-protein interaction”(PPI)network were constructed to perform network analysis in order to screen the key active ingredients and core targets,using Autodock vina software for molecular docking operation.The targets GO function enrichment analysis and KEGG pathway enrichment analysis were analyzed by DAVID databases.The effects of Bawei Chenxiang powder containing serum on cell viability,levels expressions mitophagy and key signaling pathway related protein in H9C2 cells were investigated by hypoxia-induced injury of H9c2 myocardial cells model in vitro.Results The 9 key active compounds and 8 core targets of Bawei Chenxiang powder were screened;molecular docking showed a good binding ability of key active ingredients and core targets.KEGG pathway enrichment analysis showed that the effect of Bawei Chenxiang powder on IHD through mitophagy was related to EGFR,PI3K-Akt,MAPK,FoxO signaling pathway,etc.Cell experiments showed that Bawei Chenxiang powder containing serum treatment could significantly improve the survival rate by hypoxia-induced injury in H9c2,the expression of LC3II and p62 were significantly down-regulated,and the expressions of p-PI3K/PI3K and p-AKT/AKT were significantly up-regulated.Conclusions Bawei Chenxiang powder plays an anti-IHD role by regulating mitophagy,which may be involved in AKT1,STAT3,MAPK3 and EGFR and other targets,through quercetin,Kaempferol,Naringenin and Dehydrodiisoeugenol

关 键 词：八味沉香散 缺血性心脏病 线粒体自噬 网络药理学 PI3K-AKT 机制 

分 类 号：R289.5[医药卫生—方剂学] R319[医药卫生—中药学] R329.24[医药卫生—中医学] R392R542.2