基于网络药理学和分子对接探讨人参汤改善心肌缺血再灌注损伤的潜在作用机制
关键词:
心肌缺血再灌注, 人参汤, 网络药理学, 分子对接, 作用机制摘要
目的：运用网络药理学和分子对接技术探讨人参汤改善心肌缺血再灌注损伤（MIRI）的潜在作用靶点及机制。方法：首先应用中药系统药理学数据库与分析平台（TCMSP）筛选出人参汤的有效活性成分和作用靶点；采用UniProt数据库注释靶点基因；利用人类基因数据库（GeneCards）、在线人类孟德尔遗传数据库（OMIM）获得MIRI的靶点；运用Venn在线软件获取人参汤与MIRI的共同靶点基因，并以Venn图展示；采用Cytoscape 3.9.1软件构建“药物-药物有效成分-靶点”可视化网络图；应用注释、可视化和综合发现数据库（DAVID）对交集靶点进行基因本体（GO）及京都基因和基因组百科全书（KEGG）富集分析；通过STRING数据库将交集靶点进行蛋白-蛋白相互作用（PPI）分析，利用Cytoscape 3.9.1软件Cytohubba插件对PPI网络进行分析，获取关键靶点。通过AutoDock Tools 1.5.7软件与PyMOL 2.5.0对筛选后的3个关键靶点蛋白受体和药物活性成分配体进行分子对接验证。结果：筛选得到人参汤的45个有效活性成分和709个靶点基因，MIRI相关靶点基因1503个，210个药物与疾病交集靶点；获得关键核心靶点有信号转导与转录激活因子3 (STAT3)、核因子KB亚基1（NFKB1）、α-丝氨酸/苏氨酸蛋白激酶（AKT1），其主要参与炎症因子、抗凋亡及增殖相关蛋白的生物合成，由JAK-STAT、NF-kB、PI3K-AKT信号通路介导调控炎症、细胞存活、氧化应激反应及心肌保护相关基因表达，参与炎症反应、细胞凋亡、增殖、组织修复及心肌缺血再灌注损伤等生物学过程。KEGG通路富集分析显示主要作用机制可能与EGFR酪氨酸激酶抑制剂耐药信号通路、血管内皮生长因子VEGF信号通路、糖尿病并发症中的晚期糖基化终末产物（AGE）-晚期糖基化终末产物受体（RAGE）信号通路、缺氧诱导因子-1（HIF-1）信号通路、肿瘤坏死因子（TNF）信号通路等有关。结论：人参汤对MIRI的干预作用具有多成分、多靶点、多通路、多环节的调控特点，其调控靶点可能主要涉及STAT3、NFKB1、AKT1等；其调控的通路可能涉及氧化应激和炎症反应相关信号通路、细胞凋亡、血管生成及缺氧适应信号通路等，这为后续深入探讨人参汤改善MIRI的潜在分子作用机制奠定了基础。
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