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作者中文名	作者英文名	单位中文名	单位英文名	E-Mail
安君	AN Jun	天津红日康仁堂药业有限公司，天津 301700	Tianjin HongRi Kangrentang Pharmaceutical Co., Ltd., Tianjin 301700, China
裴帅	PEI Shuai	天津中医药大学中药学院，天津 301617	School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
丁辉*	DING Hui	天津中医药大学中药学院，天津 301617	School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
王琳琳	WANG Lin-lin	天津中医药大学第二附属医院，天津 300250 道地药材国家重点实验室，北京 100700	Second Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300250, China State Key Laboratory of Dao-di Herbs, Beijing 100700, China

基金项目:中央本级重大增减支项目（2060302）

中文摘要:目的基于网络药理学及分子对接技术，构建泽泻汤治疗高脂血症的成分-通路-靶点网络，探讨其潜在作用机制。方法通过检索中药系统药理学数据库与分析平台（TCMSP）并结合文献，筛选泽泻汤的活性成分；借助TCMSP和PharmMapper数据库筛选泽泻汤活性成分的作用靶点，并建立活性成分靶点库；利用OMIM、TTD、DrugBank、PharmGKB和GeneCards数据库获取高脂血症的相关靶点，并建立疾病靶点库；运用STRING数据库和Cytoscape软件构建成分靶点与疾病靶点的蛋白质-蛋白质相互作用（PPI）网络，筛选得到核心靶点；采用DAVID数据库和OmicsBean平台分别对核心靶点进行京都基因与基因组百科全书（KEGG）通路分析和基因本体（GO）功能分析；最后通过Discovery Studio软件验证泽泻汤中活性成分与髓过氧化物酶（MPO）、基质金属蛋白酶9（MMP9）、凝血因子Ⅱ（F2）、过氧化物酶增殖物激活受体a（PPARA）和哺乳动物雷帕霉素靶蛋白（mTOR）5个靶点的结合活性。结果共挖掘到泽泻汤中16个活性成分及369个潜在成分靶点，与284个高脂血症相关靶点相互映射，并通过PPI网络分析筛选得到16个核心靶点，包括MPO、MMP9、F2、PPARA和mTOR等，推测这些靶点可能为泽泻汤治疗高脂血症的核心靶点。同时，分子对接结果显示，泽泻汤中所含的泽泻醇类、大黄素和白术三醇与高脂血症的核心靶点有较强的结合能力。KEGG富集分析发现与高脂血症相关的主要调控通路涉及缺氧诱导因子-1（HIF-1）、胰岛素抵抗、胰岛素信号等。结论泽泻汤的活性成分可能通过作用于MPO、MMP9、F2、PPARA和mTOR等多个高脂血症相关靶点，调节HIF-1、胰岛素抵抗、胰岛素信号通路，从而发挥治疗高脂血症的作用，为后续研究泽泻汤治疗高脂血症的分子机制提供了思路。

中文关键词:泽泻汤高脂血症网络药理学分子对接作用机制

Mechanism of Zexie Decoction in Treatment of Hyperlipidemia Based on Network Pharmacology and Molecular Docking

Abstract:Objective To establish the "component-pathway-target" network for exploring the mechanism of Zexie Decoction in the treatment of hyperlipidemia based on the network pharmacology and molecular docking.Methods The active ingredients of Zexie Decoction were screened from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and literature. The targets of the active ingredients of Zexie Decoction were obtained from TCMSP and PharmMapper. The targets of hyperlipidemia were retrieved from Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), DrugBank, PharmGKB, and GeneCards. STRING and Cytoscape were employed to establish the protein-protein interaction (PPI) network of the targets shared by the active ingredients and hyperlipidemia, from which the core targets were screened out. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) functional annotation were carried out for the core targets with DAVID and OmicsBean, respectively. Finally, the binding activities of the active ingredients in Zexie Decoction with myeloperoxidase (MPO), matrix metalloproteinase 9 (MMP9), coagulation factor Ⅱ (F2), peroxisome proliferator-activated receptor a (PPARA), and mammalian target of rapamycin (mTOR) were verified by Discovery Studio.Results Sixteen active ingredients corresponding to 369 targets were predicted for Zexie Decoction, and 284 targets associated with hyperlipidemia were predicted. Sixteen core targets were screened by PPI network analysis, which were involved in 11 pathways, including hypoxia-inducible factor-1, insulin resistance, and insulin signaling pathways. Moreover, the molecular docking showed that the alisol, emodin, and atractylol had strong binding activities with five core protein targets of hyperlipidemia.Conclusion The active ingredients in Zexie Decoction may act on multiple hyperlipidemia targets via multiple pathways to treat hyperlipidemia. The findings of this study provide research ideas for the follow-up verification of the predicted molecular mechanism.

keywords:Zexie Decoction hyperlipidemia network pharmacology molecular docking mechanism

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