基于网络药理学的黄连解毒汤抗缺血性脑卒中机制研究

Study on the Mechanism of Huanglian Jiedu Decoction( 黄连解毒汤) in Ischemic Stroke: Based on Network Pharmacology

目的基于网络药理学研究黄连解毒汤治疗缺血性脑卒中的潜在生物学机制。方法利用TCMSP数据库,通过筛选符合口服利用率、药物相似性和血脑屏障透过率阈值得到黄连解毒汤的有效成分组。通过药物靶点预测和脑卒中治疗靶点挖掘,分析两个靶点数据集找到交集靶点,对应相应成分作为有效成分并使用Cytoscape 3. 6软件构建活性成分-靶点网络和有效成分-靶点网络。通过分析有效成分-靶点网络Degree参数,找到重要有效成分和靶点。通过蛋白质相互作用分析/KEGG富集分析,找出黄连解毒汤抗缺血性脑卒中的潜在信号通路。结果筛选出了黄连解毒汤的60个活性成分,包括黄芩新素、榄核莲黄酮、二氢木蝴蝶素等。5个抗脑缺血的有效成分,包括汉黄芩素、β谷甾醇、吴茱萸碱、黄芩素、韧黄芩素Ⅰ。10个重要的抗脑缺血靶点,包括雄激素受体、雌激素受体1、前列腺素内过氧化物合成酶2、凝血因子Ⅱ、一氧化氮合成酶3、凝血因子Ⅶ、核受体亚家族3 C组成员1、5-羟色胺受体3A、B淋巴细胞瘤2、激酶插入域受体。基于蛋白质相互作用网络,黄连解毒汤的重要靶点显著富集于晚期糖基化终产物-晚期糖基化终产物受体、凋亡、白细胞介素17、缺氧诱导因子1、NOD样受体、雌激素和Toll样受体7个信号通路中。结论黄连解毒汤抗缺血性脑卒中具有多靶点、多途径、多通路的特点,其主要生物学机制可能与以晚期糖基化终产物受体为中心的信号通路有关。

Objective To study the potential biological mechanism of Huanglian Jiedu Decoction(黄连解毒汤)in the treatment of ischemic stroke by network pharmacology method.Methods Traditional Chinese Medicine Systems Pharmacology(TCMSP)database was used to obtain effective constituents of Huanglian Jiedu Decoction by screening eligible oral utilization,drug similarity and blood-brain barrier permeability threshold.By drug target prediction and stroke treatment target mining,the 2 target data sets were analyzed to find intersection targets,and the corresponding constituents were used as active constituents.An active constituent target network and an effective constituent target network were constructed by using Cytoscape 3.6 software.Degree parameters of the effective constituent target network were analyzed to find important effective constituents and targets.Through protein interaction analysis/Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis,potential signaling pathways of Huanglian Jiedu Decoction in ischemic stroke were found out.Results A total of 60 active constituents of Huanglian Jiedu Decoction were screened out,including neobaicalein,panicolin,dihydrooroxylin,etc.There were 5 active constituents against cerebral ischemia,including wogonin,β-sitosterol,evodiamine,baicalein and skullcapflavoneⅠ.And 10 important targets for anti-cerebral ischemia,including androgen receptor,estrogen receptor 1,prostaglandinendoperoxide synthase 2,blood coagulation factorⅡ,nitric oxide synthase 3,blood coagulation factorⅦ,nuclear receptor 3 C subfamily member 1,5-serotonin receptor 3 A,B lymphocytoma 2 and kinase insert domain-containing receptor(KDR).Based on protein interaction network,the important targets of Huanglian Jiedu Decoction were significantly enriched in 7 signaling pathways such as receptor for advanced glycation and products,apoptosis,interleukin17,hypoxia induction factor 1,NOD-like receptors,estrogen and Toll-like receptors.Conclusion Huanglian Jiedu Decoction in ischemic stroke has characteristics like multiple targets,multiple approaches and multiple pathways.Its main biological mechanism may be related to the RAGE-centered signaling pathway.