基于数据挖掘及网络药理学方法探讨血管性痴呆用药规律及机制研究

A study on medication rules and action mechanism of treating vascular dementia based on data mining and network pharmacology

目的:基于数据挖掘探讨中药治疗血管性痴呆的用药规律,找出核心药对,进一步通过网络药理学及分子对接技术探讨核心药对治疗血管性痴呆的具体作用机制。方法:通过中国知网数据库、万方数据库、维普数据库、中国生物医学文献数据库、PubMed及Embase数据库,选取2011-2021年期间中药复方治疗血管性痴呆的相关文献。通过Excel 2018建立中药复方数据库,应用IBM SPSS Modeler 18.0软件中的Apriori算法得到使用频次最高的药对。利用中药系统药理学数据库与分析平台、STRING、DAVID数据库和Cytoscape软件等分析药对疾病间相互作用关系及相关通路,最后利用分子对接技术对核心化学成分与核心靶点进行对接验证。结果:筛选得到72篇有效文献,涉及药物130味。核心药对为“石菖蒲-川芎”,共获得此药对15个活性成分,包含相关靶点471个;血管性痴呆靶点去重整理后共获得638个,同药对靶点映射后得到91个共同靶点;运用Cytoscape 3.7.1软件分析发现丝氨酸/苏氨酸蛋白激酶1(AKT Serine/Threonine Kinase 1,AKT1)、半胱氨酸蛋白酶3(Caspase 3,CASP3)、SRC原癌基因(SRC Proto-Oncogene,SRC)等靶点在“石菖蒲-川芎”治疗血管性痴呆中具有重要意义;京都基因与基因组百科全书(KEGG)通路富集分析结果显示“石菖蒲-川芎”治疗血管性痴呆主要与Rap1信号通路、丝裂原活化蛋白激酶(Mitogen-activated Protein Kinase,MAPK)信号通路、RAS信号通路相关,其作用机制主要涉及细胞凋亡、痴呆病神经元的死亡、细胞增殖、细胞内葡萄糖代谢等生物功能。分子对接结果显示药对“石菖蒲-川芎”有效活性成分与血管性痴呆的靶点具有较高的亲和力。结论:基于数据挖掘得出治疗血管性痴呆的最常用药对为“石菖蒲-川芎”,结合网络药理学分析药对“石菖蒲-川芎”可能基于黄酮类等核心成分,通过调控表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)等靶点,作用于Rap1信号通路、MAPK信号通路、RAS信号通路,诱导血管性痴呆细胞凋亡,调节神经元信号,达到治疗血管性痴呆的目的,为中医治疗血管性痴呆的临床应用及基础研究提供了一定的方法和思路。

Objective:In this paper,based on data mining,the medication rules of TCM medicine on vascular dementia were discussed,the core medicine pairs were found,and the specific mechanism of the core medicine pairs on vascular dementia was further discussed through network pharmacology and molecular docking technology.Methods:In CNKI database,Wanfang database,VIP database,CBM database,Pubmed and Embase database,the relevant literature on treating vascular dementia with TCM medicine from 2011 to 2021 was selected.The medicine compound database was established through Excel 2018,and the Apriori algorithm in IBM SPSS Modeler 18.0 software was used to obtain the medicine pairs with the highest frequency.TCMSP,STRING,DAVID database and Cytoscape software were used to analyze the interaction between medicines and diseases,and the related pathways.Finally,the molecular docking technology was used to verify the docking between core chemical components and core targets.Results:A total of 72 effective studies were screened out,involving 130 medicines.The core medicine pair was“Shichangpu(Acorus gramineus)-Chuanxiong(Ligusticum chuanxiong)”.A total of 15 active ingredients of this medicine pair were obtained,including 471 related targets.A total of 638 vascular dementia targets were obtained after de-arrangement,and 91 common targets were obtained after mapping with medicine pairs.Through Cytoscape 3.7.1 software,it was found that AKT1,CASP3,SRC and other targets were of great significance in the treatment of vascular dementia with Shichangpu-Chuanxiong medicine pair.The KEGG pathway enrichment analysis showed that the treatment of vascular dementia with Shichangpu-Chuanxiong medicine pair was mainly related to Rap1 signaling pathway,MAPK signaling pathway and RAS signaling pathway.Its action mechanism mainly involved apoptosis,neuron death in dementia,cell proliferation,intracellular glucose metabolism and other biological functions.The molecular docking results showed that the active components of Shichangpu-Chuanxiong medicine pair had a high affinity with the targets of vascular dementia.Conclusion:Based on data mining,it is concluded that the most common medicine pair for vascular dementia is Shichangpu-Chuanxiong.Combined with network pharmacology analysis,Shichangpu-Chuanxiong medicine pair may be achieve the purpose of treating vascular dementia based on the core ingredients such as flavonoids,through regulating EGFR and other targets,acting on Rap1 signaling pathway,MAPK signal pathway,and RAS signaling pathway,inducing apoptosis in vascular dementia,and regulating neuronal signaling.It provides some methods and ideas for the clinical application and basic research of treating vascular dementia in TCM.