基于数据挖掘和网络药理学探讨益气活血核心药对治疗阿尔兹海默症的作用机制

Discussion on the mechanism of Qi-nourishing and blood-activating core herbal pairs in treating Alzheimer′s disease based on data mining and network pharmacology

目的:基于数据挖掘技术和网络药理学方法,筛选益气活血药对治疗阿尔兹海默症(AD)的核心药对,并探讨其潜在分子作用机制。方法:以中国知网、万方数据知识服务平台、维普生物医学数据库及Web of Science等中英文数据库作为数据来源,结合R Studio、Apriori关联规则函数进行数据挖掘,得到益气活血核心药对。使用TCMSP、UniProt、SwissTargetPrediction等数据库,检测出核心药物的有效成分及作用靶点,通过GeneCards、OMIM、CTD数据库提取AD疾病靶点,匹配整合得到核心药对治疗疾病的潜在作用靶点。利用CytoScape 3.9.1软件建立核心药对治疗疾病的“成分-靶点-疾病”网络图,并利用STRING平台构建核心靶点蛋白质相互作用(PPI)网络,利用Metascape工具实现KEGG通路富集及GO功能分析的可视化,将主要通路信息导入通过CytoScape 3.9.1软件建立的靶点-通络网络图中,通过Autodock Vina软件进行分子对接验证。结果:筛选得到益气活血核心药对为黄芪-川芎,共得到药物活性成分黄芪20个,川芎7个,215个潜在作用靶点;AD疾病靶点6584个,映射后得到益气活血核心药对黄芪-川芎治疗AD的潜在靶点183个。黄芪-川芎药对治疗AD的核心活性成分有槲皮素、山柰酚、芒柄花素等;治疗AD的关键靶点为Akt1、IL-6、TNF、TP53等。GO功能分析靶基因主要富集于脂多糖反应、膜阀、核受体等。KEGG通路富集分析结果表明,主要与AGE-RAGE信号通路、IL-17信号通路等受体信号通路有关。分子对接结果表明,关键成分槲皮素、山柰酚和芒柄花素与核心靶点Akt1、TNF具有良好的结合性。结论:益气活血核心药对黄芪-川芎可能通过多种核心活性成分,以多作用靶点、多通路调控来治疗AD,涉及抗炎、调节谷氨酸兴奋性、激活神经营养因子等多方面,为后续治疗AD及药物开发提供了理论基础。

Objective:Based on data mining technology and network pharmacology methods,this study aimed to screen the core herbal pairs of Qi-nourishing and blood-activating herbs in the treatment of Alzheimer′s disease(AD)and to explore their potential molecular mechanisms.Methods:Databases including CNKI,Wanfang Data,VIP Biomedical Database,and Web of Science served as data sources.Using R Studio and Apriori association rule functions,we performed data mining to identify the core herbal pairs of Qi-nourishing and blood-activating herbs.The Traditional Chinese Medicine Systems Pharmacology Database(TCMSP),UniProt,and SwissTargetPrediction databases were utilized to detect the active ingredients and target proteins of the core herbs.Disease targets for AD were extracted from GeneCards,OMIM,and CTD databases,and matching and integration were performed to obtain the potential targets of the core herbal pairs in treating AD.Cytoscape 3.9.1 software was used to construct the“ingredient-target-disease”network diagram for the core herbal pairs in treating AD.The STRING platform was employed to build a protein-protein interaction(PPI)network for the core targets.Metascape was used for visualization of KEGG pathway enrichment and GO functional analysis.The main pathway information was imported into the target-pathway network diagram constructed by Cytoscape 3.9.1.Molecular docking verification was performed by Autodock Vina software.Results:The core herbal pair of Qi-nourishing and blood-activating herbs for treating AD was identified as Huangqi-Chuanxiong.A total of 20 active ingredients were obtained from Huangqi and 7 from Chuanxiong,with 215 potential target proteins.There were 6584 AD disease targets,and after mapping,183 potential targets of the core herbal pair Huangqi-Chuanxiong in treating AD were obtained.The core active ingredients of Huangqi-Chuanxiong in treating AD included quercetin,kaempferol,and formononetin.The key targets for treating AD were Akt1,IL-6,TNF,TP53,etc.GO functional analysis revealed that the target genes were mainly enriched in lipopolysaccharide response,membrane raft,and nuclear receptors.KEGG pathway enrichment analysis indicated that the pathways were primarily associated with AGERAGE signaling,IL-17 signaling,and other receptor signaling pathways.Molecular docking results showed that the key components quercetin,kaempferol,and formononetin had good binding affinity with the core targets Akt1 and TNF.Conclu⁃sion:The core herbal pair Huangqi-Chuanxiong of Qi-nourishing and blood-activating herbs may treat AD through multiple core active ingredients,targeting multiple pathways,including anti-inflammatory effects,regulation of glutamate excitability,and activation of neurotrophic factors,providing a theoretical foundation for subsequent AD treatment and drug development.