摘要
目的基于系统药理学方法挖掘槲皮素治疗帕金森病的作用机制并进行动物实验验证。方法首先在中药系统药理学数据库及分析平台、Swiss Target Prediction和Pharm Mapper数据库查询“槲皮素”的作用靶点,在GeneCards、DisGeNET、DrugBank、OMIM和Therapeutic Target Database数据库搜集“帕金森病”的相关靶点,通过InteractiVenn软件获得槲皮素-帕金森病的共同靶点,运用String数据库构建共同靶点的蛋白质-蛋白质相互作用网络,筛选获取槲皮素治疗帕金森病的关键靶点。然后经基因本体、京都基因与基因组百科全书进行功能和通路富集分析,构建“槲皮素-关键靶点-主要通路-帕金森病”的网络图。最后运用DockThor软件将关键靶点与槲皮素进行分子对接,并通过文献对比和动物实验进行验证。结果共筛选得到242个槲皮素-帕金森病共同靶点,核心靶点有SRC、HSP90AA1、TP53、MAPK1、AKT1等。涉及癌症通路、ErbB信号通路、FoxO信号通路、HIF-1信号通路、PI3K-Akt信号通路、催乳素信号通路、TNF信号通路等,生物学过程主要涉及对衰老、炎症反应、细胞增殖、基因表达等的调控。分子对接亲和力平均为-7.1 kcal·mol^(-1),提示槲皮素与关键靶蛋白结合稳定性较好。在MPTP诱导的PD亚急性小鼠模型,槲皮素可显著增加旷场实验中小鼠的活动总路程和中央区域停留时间(P<0.01),缩短小鼠的胶布移除时间(P<0.01),增加小鼠纹状体DA含量及TH蛋白表达(P<0.05),减少小鼠纹状体TNF-α和IL-1β蛋白表达(P<0.01)。结论槲皮素治疗帕金森病的药理作用机制具有多靶点、多通路的特点,本研究为阐明其治疗帕金森病的作用机制提供了参考依据。
Objective To explore the pharmacological mechanism of quercetin in the treatment of Parkinson’s disease by systemic pharmacological methods and to verify it in PD model mice.Methods The targets of"quercetin"were queried in Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,Swiss Target Prediction and Pharm Mapper databases.The related targets of“Parkinson’s disease”were collected by GeneCards,DisGeNET,DrugBank,OMIM and Therapeutic Target Database.Then,the common targets of quercetin and Parkinson’s disease were obtained from Venn diagram.The protein-protein interaction network of the common targets was constructed by String database,and the key targets of quercetin in the treatment of Parkinson’s disease were analyzed and screened out.Next,Gene Ontology and Kyoto Encyclopedia of genes and genomes pathway enrichment analysis on the common targets were carried out through David database.The network diagram of“quercetin-key targets-main pathways-Parkinson’s disease”was constructed by Cytoscape software.Finally,the results were verified by docking the key targets with quercetin through DockThor software in combination with literature comparison and animal experiments.Results Totally 242 common targets of quercetin and Parkinson’s disease were obtained,among which the key targets included SRC,HSP90AA1,TP53,MAPK1,AKT1 and so on.The cancer pathway,ErbB signaling pathway,FOXO signaling pathway,HIF-1 signaling pathway,PI3K-Akt signaling pathway,prolactin signaling pathway,TNF signaling pathway,etc.were involved.Biological processes mainly included the regulation of aging,inflammatory response,cell proliferation and gene expression,etc.The average molecular docking affinity was-7.1 kcal·mol^(-1),suggesting that quercetin had stable combination with the key target proteins.In the MPTP-induced subacute mice model of PD,QC could significantly increase the total movement distance and the center stay time of mice in the open field experiment(P<0.01),shorten the adhesive tape removal time(P<0.01),increase the content of DA and the expression of TH protein in the mice striatum(P<0.05),and reduce the protein expression of TNF-αand IL-1βin the mice striatum(P<0.01).Conclusion The results indicated that the pharmacological mechanism of quercetin in the treatment of Parkinson’s disease presents the characteristics of multi-target and multi-pathway,which provides reference for clarifying the mechanism of quercetin in the treatment of Parkinson’s disease.
作者
陈勃麟
曾琨鹏
王宇辰
李飞
申晓雪
马怡晖
李继安
储金秀
Chen Bolin;Zeng Kunpeng;Wang Yuchen;Li Fei;Shen Xiaoxue;Ma Yihui;Li Jian;Chu Jinxiu(School of Basic Medical Sciences,North China University of Science and Technology,Tangshan 063210,China;School of Traditional Chinese Medicine,North China University of Science and Technology,Tangshan 063210,China;Hebei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Diabetes and its Complications,Tangshan 063210,China;Hebei Key Laboratory for Chronic Diseases,Tangshan 063210,China)
出处
《世界科学技术-中医药现代化》
CSCD
北大核心
2023年第2期752-762,共11页
Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology
基金
教育部高等教育司国家级大学生创新创业训练计划项目(202110081004):槲皮素治疗帕金森病机制的网络药理学研究,负责人:陈勃麟
华北理工大学校级大学生创新创业训练计划项目(X2021007):槲皮素治疗帕金森病机制的网络药理学研究,负责人:陈勃麟
国家科学技术部国际合作司对发展中国家科技援助项目(KY201904005):中-匈合作中药培植基地建设与中药产品开发,负责人:李继安
关键词
网络药理学
槲皮素
帕金森病
信号通路
分子对接
Network pharmacology
Quercetin
Parkinson’s disease
Signaling pathway
Molecular docking
