基于网络药理学探讨六味地黄丸治疗儿童注意缺陷多动障碍的作用机制

Mechanism of Liuwei Dihuang Wan(六味地黄丸)in the treatment of children with attention deficit hyperactivity disorder based on network pharmacology

目的 基于网络药理学探讨六味地黄丸治疗儿童注意缺陷多动障碍(ADHD)的作用机制。方法检索中药系统药理学分析平台(TCMSP),收集六味地黄丸的活性成分及靶点。使用GeneCards及OMIM数据库筛选ADHD的相关基因并与六味地黄丸活性成分靶点基因取交集,构建蛋白相互作用网络(PPI),使用Cytoscape 3.7.1软件构建六味地黄丸治疗ADHD的“活性成分-靶点”网络图,并利用CytoNCA插件对该网络进行拓扑属性分析,筛选出核心靶点。应用Metascape对筛选出的核心靶点进行基因生物过程(GO)富集分析与信号通路(KEGG)富集分析,利用R语言对分析结果进行可视化处理。结果 六味地黄丸治疗ADHD共有28个有效活性成分和110个对应靶点。槲皮素、山柰酚、β-谷甾醇是3个最主要的有效活性成分。丝裂原蛋白活化激酶1(MAPK1)、表皮生长因子受体(EGFR)、白细胞介素-6(IL-6)、低聚果糖(FOS)、肿瘤坏死因子(TNF)、肿瘤蛋白p53(TP53)、癌基因MYC、雌激素受体1(ESR1)、丝氨酸/苏氨酸蛋白激酶1(AKT1)是9个核心靶点。GO富集分析主要涉及活性氧代谢、脂多糖代谢、对细菌来源分子的反应、对营养水平的反应等生理过程。KEGG富集分析结果表明磷脂酰肌醇-3-激酶-蛋白激酶B(PI3K-Akt)信号通路、丝裂原活化蛋白激酶(MAPK)信号通路、内分泌抵抗、TNF信号等通路是六味地黄丸治疗ADHD的核心信号通路。结论 六味地黄丸通过槲皮素、山柰酚、β-谷甾醇等活性成分作用于MAPK1、FOS、TNF、AKT1等核心靶点,在神经发育和突触信号传递过程中发挥MAPK信号通路等核心通路作用,体现了六味地黄丸通过多成分、多靶点、多通路治疗ADHD的特点,为治疗ADHD提供了理论依据和临床用药思路。

Objective To discuss the mechanism of Liuwei Dihuang Wan(六味地黄丸,LWDHW)in the treatment of children with attention deficit hyperactivity disorder(ADHD)based on network pharmacology.Methods The active components and targets of LWDHW were collected by retrieving traditional Chinese medicine systems pharmacology database and analysis Platform(TCMSP).The genes related to ADHD were screened out by GeneCards and Online Mendelian Inheritance in Man(OMIM)database and were intersect with the target genes of the active components of LWDHW to construct the protein-protein interaction network(PPI)and Cytoscape software was used to create the“active component-target”network diagram of LWDHW in the treatment of children with ADHD,and CytoNCA plug-in was used to analyze the topology properties and screen out the core targets.Metascape was used to conduct gene biological processes of gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)signal pathway enrichment analysis on the core targets screened out,and the analysis results were visualized by R language.Results There were 28 active components and 110 corresponding targets in the treatment of ADHD with LWDHW.Quercetin,kaempferol andβ-sitosterol were the 3 main active components.Mitogen activated kinase 1(MAPK1),epidermal growth factor receptor(EGFR),interleukin-6(IL-6),fructooligosaccharides(FOS),tumor necrosis factor(TNF),tumor protein p53(TP53),oncogene MYC,estrogen receptor 1(ESR1)and serine/threonine protein kinase 1(AKT1)were 9 core targets.GO enrichment analysis mainly involved physiological processes such as reactive oxygen species metabolism,lipopolysaccharide metabolism,response to molecules from bacteria,and response to nutritional levels.KEGG enrichment analysis showed that phosphatidylinositol-3-kinase-protein kinase B(PI3K-Akt)signal pathway,mitogen activated protein kinase(MAPK)signal pathway,endocrine resistance,TNF signal pathway were the core signal pathways of LWDHW in the treatment of ADHD.Conclusion LWDHW acts on core targets such as MAPK1,FOS,TNF and AKT1 through active components like quercetin,kaempferolβ-sitosterol and plays the role of core pathways such as MAPK signal pathway in the process of nerve development and synaptic signal transmission,which reflects the characteristics of LWDHW in the treatment of ADHD through multiple components,multiple targets and multiple pathways,and provides a theoretical basis and clinical medication ideas for the treatment of ADHD.