摘要
目的基于网络药理学方法探讨黄芪-百合-沙棘(ALH)联用治疗阿尔茨海默病(Alzheimer’s disease,AD)的可能作用机制。方法利用TCMSP数据库筛选ALH的活性成分及作用靶点,通过GeneCards、OMIM数据库收集AD相关靶点,将药物活性成分靶点与AD疾病相关靶点取交集,获得药物-疾病共同靶点;采用Cytoscape 3.7.2软件构建药物-活性成分-靶点-疾病网络,并采用STRING平台构建蛋白互作(PPI)网络,筛选关键活性成分和靶点;采用Autodock软件对关键活性成分与核心靶点进行分子对接;采用Clue GO插件进行KEGG通路富集分析。采用D-半乳糖联合氯化铝诱导AD小鼠模型,通过Morris水迷宫实验、海马组织病理学观察(HE染色法)及ELISA法检测海马组织中TNF-α、IL-6、IL-17含量,对ALH治疗AD的作用机制进行初步验证。结果经筛选共获得ALH活性成分39个,如槲皮素、山柰酚、7-O-甲基异丙醇胺、芒柄花黄素、异鼠李素等,主要作用于ATK1、MAPK1、JUN、TP53、TNF等靶点,涉及PI3K-Akt、MAPK、AGE-RAGE、IL-17、TNF等信号通路,共同发挥治疗AD的作用。药理学实验结果显示,ALH可显著提高小鼠学习记忆能力(P<0.05,P<0.01),减轻海马组织损伤,降低海马组织中TNF-α、IL-6、IL-17含量(P<0.05,P<0.01)。结论 ALH治疗AD是多成分、多靶点、多通路相互作用的结果,其机制与抑制炎性因子表达,减轻炎症损伤有关。
Objective To investigate pharmacological mechanism of Astragalus radix-Lilii bulbus-Hippophae fructus(ALH)in treating Alzheimer’s disease(AD)by network pharmacology and molecular docking.Methods The active components and targets of ALH were obtained by TCMSP database,and AD related targets were collected by GeneCards and OMIM database.The intersection of drug active component targets and AD related targets were used to obtain drug-disease common targets.Cytoscape 3.7.2 software was used to construct drug-active ingredient-targetdisease network,and STRING platform was used to construct PPI network to screen key active components and targets.Autodock software was used for molecular docking of key active components and targets.KEGG pathway enrichment analysis was performed using Clue GO.The AD mice model were induced by D-galactose combined with AlCl_(3),then the Morris water maze test,pathological observation of hippocampal tissue(HE staining method)and ELISA were used to preliminarily verify the mechanism of ALH in treating AD.Results There are 39 active components in ALH were involved,such as quercetin,kaempferol,7-O-methylisomucronulatol,formononetin,isorhamnetin.The active components mainly target ATK1,MAPK1,JUN,TP53,TNF,and so on,which involving PI3K-Akt,MAPK,AGE-RAGE,IL-17,TNF,and other signaling pathways,to play a role in treatment of AD.The results of validation experiment showed that ALH could significantly improve the learning and memory abilities of AD mice(P<0.05,P<0.01),decrease the damage of hippocampal tissue,and reduce the contents of TNF-α,IL-6 and IL-17 in hippocampal tissue in mice(P<0.05,P<0.01).Conclusion The results of this study preliminarily revealed the effective mechanism of ALH for AD,which is inhibiting the expression of inflammatory factors,and alleviating inflammatory damage by the combination of multi-components,multi-targets,and multi-pathways.
作者
赵宏
于登君
汤威威
孔令洲
高琪
张宇
王丽红
ZHAO Hong;YU Dengjun;TANG Weiwei;KONG Lingzhou;GAO Qi;ZHANG Yu;WANG Lihong(College of Pharmacy,Jiamusi University,Jiamusi 154007 Heilongjiang,China)
出处
《中药新药与临床药理》
CAS
CSCD
北大核心
2021年第12期1817-1824,共8页
Traditional Chinese Drug Research and Clinical Pharmacology
基金
黑龙江省自然科学基金青年项目(QC2018119)
中央支持地方高校改革发展基金项目(2019zyzcdf-01)
黑龙江省博士后专项经费资助项目(LBH-Q20185)
黑龙江省北药与功能食品特色学科建设项目(2018-TSXK-02)
佳木斯大学优秀学科团队项目(JDXKTD-2019005)。
关键词
黄芪
百合
沙棘
阿尔茨海默病
网络药理学
炎性因子
Astragalus radix
Lilii bulbus
Hippophae fructus
Alzheimer’s disease
network pharmacology
inflammatory factor
