基于网络药理学和分子对接技术探究黄芪-淫羊藿治疗甲状腺功能减退症的机理

Exploration of the Mechanism of Huangqi(Astragali Radix)-Yinyanghuo(Epimedii Wushanensis Folium)in Treating Hypothyroidism Based on Network Pharmacology and Molecular Docking Technology

目的基于网络药理学和分子对接技术探究黄芪-淫羊藿治疗甲状腺功能减退症的可能机制。方法使用中药系统药理数据库(TCMSP)获取药物有效成分,并且预测靶点。获取2D结构图,并录入Phrammarpper数据库获得成分靶点。使用PharmGKb数据库、GeneCard数据库、DrugBank数据库、Therapeutic Target Database数据库预测疾病靶点。使用R 4.3.3获取药物疾病交集靶点。使用String数据库构建靶点蛋白互作网络(protein-protein interaction netuorks,PPI)。使用R 4.3.3和Cytoscape软件中Citispace获取核心靶点。通过R 4.3.3中BiocManager包和OrgDb包等和R Studio软件进行基因百科全书(kyoto encyclopedia of genes and genomes,KEGG)和基因本体(gene ontology,GO)富集分析。使用Cytoscape软件,建立“药物-成分-靶点-通路”网络关系图。结果获得药物核心成分10个,为槲皮素(quercetin)、山柰酚(kaempferol)、木犀草素(luteolin)、白桦脂酸(betulinic acid)等10个核心成分;PPI蛋白互作网络分析得到RAC-α丝氨酸/苏氨酸蛋白激酶(RAC-alphaserine/threonine-proteinkinase,AKT1)、白细胞介素-6(interleukin-6,IL-6)、肿瘤坏死因子(tumornecrosisfactor,TNF)、白细胞介素-1β(interleukin-1β,IL-1β)、细胞肿瘤抗原p53(cellular tumor antigen p 53,TP53)等16个淫羊藿-黄芪与甲减的关键靶点。GO富集主要是于质膜外侧、囊泡腔等组分上进行的细胞凋亡与增殖、对氧化应激的反应等过程。KEGG富集主要包括脂质和动脉粥样硬化通路、糖尿病并发症中的糖基化终末产物(advanced glycation end products,AGE)-糖基化终末产物受体(receptor for advanced glycation end products,RAGE)信号通路、磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase,PI3K)-蛋白激酶B(protein kinase B,AKT)信号通路等前30个信号通路。通过药物-成分-靶点-通路网络得到了槲皮素、AKT1、脂质与动脉粥样硬化通路3个关键节点。结论黄芪-淫羊藿可能通过多种成分共同作用于多个靶点形成多条信号通路来发挥对甲减的治疗作用,其中槲皮素-PI3K/AKT信号通路可能是其关键途径之一。

Objective This study aimed to investigate the potential mechanism by which Huangqi(Astragali Radix)and Yinyanghuo(Epimedii Wushanensis Folium)treat hypothyroidism using network pharmacology and molecular docking technology.Methods Active ingredients of Huangqi(Astragali Radix)and Yinyanghuo(Epimedii Wushanensis Folium)were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database(TCMSP),and their corresponding targets were predicted using the PharmMapper database.Disease targets related to hypothyroidism were identified through databases including PharmGKB,GeneCards,DrugBank,and the Therapeutic Target Database.Intersection targets between the drugs and the disease were identified using R language.Protein-protein interaction networks(PPI)were constructed using the STRING database,and core targets were identified using R language and Cytoscape software.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were conducted using R and OrgDb package in R Studio.A"drug-component-targetpathway"network relationship diagram was visualized using Cytoscape software.Results 10 core components of the drug were obtained,including quercetin,kaempferol,luteolin,betulinic acid,etc.Protein interaction network analysis obtained AKT1,IL-6,TNF,IL-1β,TP53 and other 16 key targets of Astragalus-Epimedium and hypothyroidism.GO enrichment is mainly due to processes such as cell apoptosis,proliferation,and response to oxidative stress that occur on the outside of the plasma membrane,the vesicle cavity,and other components.KEGG enrichment mainly includes the top 30 signaling pathways such as lipid and atherosclerosis pathways,AGE/RAGE signaling pathway in diabetic complications,and PI3K/AKT signaling pathway.Three key nodes of quercetin,AKT1,lipid and atherosclerosis pathways were obtained through the drug-component-target-pathway network.Conclusion Huangqi(Astragali Radix)-Yinyanghuo(Epimedii Wushanensis Folium)may alleviate hypothyroidism through synergistic effects of multiple components acting on diverse targets and pathways.Specifically,the quercetin-PI3K/AKT signaling pathway emerges as a potential key pathway mediating their therapeutic effects.