基于网络药理学及分子对接技术探讨药食两用中药栀子致肾损伤的毒理机制  

Probe into the Toxicological Mechanism of Kidney Damage Induced by Zhizi with Dual Use of Medicine and Food Based on Network Pharmacology and Molecular Docking Technology

作　　者：丁彦敏 袁颢宸 王宁[1] DING Yanmin;YUAN Haochen;WANG Ning(Shandong University of Traditional Chinese Medicine,Jinan,Shandong,China,250355)

机构地区：[1]山东中医药大学,山东济南250355

出　　处：《河南中医》2023年第7期1023-1029,共7页Henan Traditional Chinese Medicine

基　　金：国家自然科学基金青年科学基金项目(82004087);山东省中医药科技发展计划项目(2019-0039);2022年省级大学生创新创业训练计划项目(S202210441015)。

摘　　要：目的:通过网络药理学和分子对接探索栀子导致肾损伤的毒理机制。方法:采用中药系统药理学数据库与分析平台、中医药综合数据库筛选栀子活性成分和潜在靶点,同时用Swiss Target Prediction平台预测活性成分的潜在靶点。利用NCBI临床突变数据库、人类基因注释数据库、在线人类孟德尔遗传数据库、治疗靶点数据库检索肾损伤的靶点。通过Venny软件对药物相关靶点与疾病靶点取交集,认为是栀子导致肾损伤的潜在靶点。在Cytoscape 3.8.0中构建“中药-化学成分-潜在靶点-疾病”网络并进行拓扑分析。在STRING平台构建潜在靶点的蛋白质相互作用网络(protein-protein interaction networks,PPI)。通过Metascape平台对潜在靶点进行基因本体(gene ontology,GO)功能富集分析及京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)信号通路富集分析。运用Cytoscape 3.8.0构建“关键通路-潜在靶点-化学成分”网络,并进一步筛选栀子导致肾损伤的关键靶基因及有效成分。利用AutoDock Vina软件对筛选出的活性成分和关键靶点进行分子对接。结果:栀子活性成分119个,相关靶点920个;肾损伤相关靶点1234个;栀子导致肾损伤的潜在靶点244个;“中药-活性成分-潜在靶点-疾病”网络分析发现栀子苷、槲皮素、urushioⅲ、5,7,3′,4′,5′-五甲氧基黄酮和绿原素可能是栀子导致肾损伤的主要活性成分;PPI网络分析发现AKT1、APP、HRAS、EGFR、CTNNB1等可能是栀子导致肾损伤的关键靶点;GO富集分析得到497个条目;KEGG信号通路富集分析得到276条信号通路;分子对接显示活性成分与靶点蛋白结合良好。结论:栀子导致肾损伤的关键靶点为AKR1B1、EGFR、KDR、MMP2,可能通过AGEs-RAGE、cAMP和NF-κB信号通路产生作用。Objective:To probe into the toxicological mechanism of kidney damage caused by Zhizi(Fructus Gardeniae)based on network pharmacology and molecular docking.Methods:The active ingredients and potential targets of Zhizi(Fructus Gardeniae)were screened by Pharmacology Database and Analysis Platform of TCM System,Traditional Chinese medicine comprehensive database.At the same time,the Swiss Target Prediction Platform was used to predict potential targets for active ingredients.The NCBI Clinical Mutation Database,Human Gene Annotation Database,Online Human Mendelian Genetic Database,and Treatment Target Database were used to retrieve targets for kidney injury.By using Venny software to intersect drug-related targets with disease targets,it was considered a potential target for kidney damage caused by Zhizi(Fructus Gardeniae).In Cytoscape 3.8.0,the"Chinese medicinal-chemical ingredient-potential target-Disease"network was constructed and topologically analyzed.The protein-protein interaction networks(PPI)with potential targets in the STRING platform were constructed.Through Metascape platform,the potential targets were analyzed for gene ontology(GO)function enrichment and Kyoto encyclopedia of genes and genomes(KEGG)signal pathway enrichment.Cytoscape 3.8.0 was used to construct a"key pathway-potential target-chemical ingredient"network and further screen for key target genes and active ingredients causing kidney damage by Zhizi(Fructus Gardeniae).Auto Dock Vina software was used for the molecular docking of selected active ingredients and key targets.Results:There were 119 active ingredients,920 related targets Zhizi(Fructus Gardeniae),1234 targets related to kidney injury,and 244 potential targets for kidney damage caused by Zhizi(Fructus Gardeniae).The network analysis of"Chinese medicinal-active ingredient-potential target-disease"found that geniposide,quercetin,urushio ii,5,7,3',4',5'-pentamethoxyflavones,and chlorogenin may be the main active ingredients of Zhizi(Fructus Gardeniae)causing kidney damage.PPI network

关 键 词：栀子 肾损伤 网络药理学 分子对接 药食两用 毒理机制 

分 类 号：R285[医药卫生—中药学]