基于网络药理学和分子对接的栀子对缺血性脑卒中与出血性脑卒中共性干预机制探讨

Discussion on common intervention mechanism of Gardeniae Fructus on ischemic stroke and hemorrhagic stroke based on network pharmacology and molecular docking

目的运用网络药理学和分子对接技术挖掘栀子对缺血性脑卒中和出血性脑卒中的共同干预机制,明确解毒中药治疗缺血性脑卒中和出血性脑卒中的共性靶点与关键通路。方法通过检索中药系统药理学数据库与分析平台(TCMSP)、中医百科全书(ETCM)、中药分子机制的生物信息学分析工具(BATMAN-TCM)以及中医药综合数据库(TCMID)收集栀子的活性成分,运用TCMSP、STTICH、Swiss数据库进行靶点预测,从在线人类孟德尔遗传数据库(OMIM)、GeneCard数据库、DisGeNET数据库、TTD疾病数据库搜集缺血性脑卒中和出血性脑卒中的疾病靶点,将2者取交集得到的靶标导入STRING平台进行蛋白质相互作用(PPI)网络分析,运用Cytoscape软件进行网络拓扑分析,同时运用DAVID软件对交集靶标进行基因本体论(GO)富集分析和京都基因组百科全书(KEGG)通路分析,最后利用分子对接技术验证栀子有效成分与核心靶点的结合作用。结果从栀子中共筛选出68个活性成分,包括山柰酚、芹菜素、槲皮素、熊果酸、京尼平苷、栀子苷等,栀子活性化合物与缺血性脑卒中和出血性脑卒中相关的治疗靶点有205个,主要包括IL6、AKT1、INS、IL1B、VEGFA、TP53、MAPK3、CASP3、JUN、EGFR、MMP9等。分子对接显示栀子的有效成分芹菜素、槲皮素、山柰酚、熊果酸等与IL6、AKT1、IL1B、TP53、MAPK3、CASP3、MMP9具有良好的结合能力。栀子主要通过调节肿瘤坏死因子(TNF)、低氧诱导因子-1(HIF-1)、(叉头框蛋白)FoxO、磷脂酰肌醇-3激酶/蛋白激酶(PI3K-Akt)等信号通路发挥缺血性脑卒中和出血性脑卒中共性干预的作用。结论栀子对缺血性脑卒中和出血性脑卒中的共性干预主要通过抑制免疫炎症反应、调控细胞凋亡等过程发挥治疗作用。

Objective To explore the common intervention mechanism of Gardeniae Fructus on ischemic stroke and hemorrhagic stroke by using network pharmacology and molecular docking technology,and to explore the common targets and key pathways of detoxifying Chinese medicine in treating ischemic stroke and hemorrhagic stroke.Methods The active components of Gardeniae Fructus were collected by searching the databases TCMSP,ETCM,BATMAN-TCM,and TCMID.The Online Mendelian inheritance in man(OMIM)database,Gene Card database,DisGeNET database and TTD database were used to collect the disease targets of ischemic stroke and hemorrhagic stroke.The targets obtained from the intersection of the Gardeniae Fructus and the diseases were imported into STRING platform for protein-protein interaction(PPI)network analysis.Cytoscape software was used for network topology analysis,and David software was used for Gene Ontology(GO)enrichment analysis and Kyoto encyclopedia of genomes(KEGG)pathway analysis of intersection targets.Finally,molecular docking technology was used to verify the binding effect of effective components of Gardeniae Fructus with core targets.Results A total of 68 active components were screened from Gardeniae Fructus including kaempferol,apigenin,quercetin,ursolic acid,genipin and so on.There were 205 therapeutic targets of the active compounds of Gardeniae Fructus related to ischemic stroke and hemorrhagic stroke including IL6,AKT1、INS,IL1 B,VEGFA,TP53,MAPK3,CASP3,JUN,EGFR and so on.Molecular docking showed that the effective components of Gardeniae Fructus,such as apigenin,quercetin,kaempferol and ursolic acid,had good binding ability with IL6,AKT1,IL1 B,TP53,MAPK3,CASP3 and MMP9.Gardeniae Fructus mainly played the role of common intervention on ischemic stroke and hemorrhagic stroke by regulating TNF signal pathway,HIF-1 signal pathway,FoxO signal pathway,PI3 K-Akt signal pathway and so on.Conclusion The common mechanisms of Gardeniae Fructus on ischemic stroke and hemorrhagic stroke mainly involve in inhibiting immune inflammatory response and regulating cell apoptosis.