基于数据挖掘与网络药理学探究中医药治疗黄疸的用药规律与潜在作用机制

Exploration on medication regularity and potential mechanism of traditional Chinese medicine for jaundice treatment based on data mining and network pharmacology

目的:基于中医古方挖掘探究中医药治疗黄疸的用药规律,并通过网络药理学研究其潜在作用机制。方法:通过中医资源网检索治疗黄疸的方剂,统计所涉及药物的性味归经、分类及频次,采用关联规则分析及聚类分析获得治疗黄疸的核心药物组合。通过中药系统药理学数据库与分析平台(TCMSP)、中医药百科全书数据库(ETCM)及文献,检索和筛选核心药物组合所涉及药物的化学成分,运用SwissTargetPrediction数据库进行靶点预测。通过OMIM(Online Mendelian Inheritance in Man)、GeneCards、TTD(Therapeutic Target Database)等数据库收集黄疸相关靶点。将成分靶点与疾病靶点相映射,获得交集靶点,采用STRING平台进行蛋白相互作用分析,构建“中药-成分-靶点-疾病”网络,获得治疗黄疸的关键靶点和潜在活性成分。基于Metascape平台对关键靶点进行京都基因和基因组百科全书(KEGG)和基因本体(GO)富集分析,构建“靶点-通路”网络,获得核心靶点。结果:共纳入处方273首,涉及中药329味。纳入中药的药性以寒、温为主,药味以苦、辛、甘为主,主要归胃、肝、肺、脾经,功效以利水渗湿、清热、补虚、解表为主。高使用频次中药共计80味,通过关联规则分析共获得核心药物组合18条,核心药物组合共涉及10味中药,聚类分析获得3首核心基础方。网络药理学结果显示,核心药物组合治疗黄疸的作用机制与物质基础聚焦得到16个潜在活性成分、8个核心靶点,富集得到25条相关通路。结论:中医古方中治疗黄疸的核心药物主要有茵陈、栀子、大黄等10味中药,功效以利水、清热、燥湿、补虚为主,其作用机制可能是通过木蝴蝶素、西红花酸、槲皮素、β-谷甾醇等活性成分,作用于肿瘤坏死因子(TNF)、肿瘤抑制蛋白p53(TP53)、信号转导因子和转录激活因子3(STAT3)、白介素-8(IL-8)等核心靶点,进而影响磷脂酰肌醇-3-激酶/蛋白激酶B(PI3K/Akt)信号通路、缺氧诱导因子-1(HIF-1)信号通路、Toll样受体(TLR)信号通路、核因子-κB(NF-κB)信号通路、细胞凋亡信号通路等,发挥治疗黄疸的作用。

Objective:To explore the medication regularity of traditional Chinese medicine in the treatment of jaundice based on the excavation of ancient traditional Chinese medicine formulas,and study its potential mechanism through network pharmacology.Methods:The formulas for the treatment of jaundice were searched through the traditional Chinese medicine resources website.The nature and flavor,meridian affinity,classification and frequency of the related drugs were counted.The core drug combinations for the treatment of jaundice were obtained by association rule analysis and cluster analysis.The chemical components of the drugs involved in the core drug combination were searched and screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),The Encyclopedia of Traditional Chinese Medicine(ETCM)database and literature,and the targets were predicted by SwissTargetPrediction database.Jaundice-related targets were collected through Online Mendelian Inheritance in Man(OMIM),GeneCards,DrugBank,Therapeutic Target Database(TTD)and other databases.Component targets were mapped to disease targets to obtain intersection targets.The STRING platform was used for protein interaction analysis,and the“traditional Chinese medicine-component-target-disease”network was constructed to obtain key targets and potential active ingredients for the treatment of jaundice.Based on the Metascape platform,the Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)enrichment analysis of the key targets was carried out,and the“target-pathway”network was constructed to obtain the core targets.Results:A total of 273 prescriptions and 329 traditional Chinese medicines were included.The properties of the included traditional Chinese medicines were mainly cold and warm,with bitter,spicy and sweet flavors,and mainly belonged to the stomach,liver,lung and spleen meridians.The main functions of included medicines were disinhibiting water and percolating dampness,clearing heat,tonifying deficiency and releasing exterior.A total of 80 traditional Chinese medicines were used with high frequency.A total of 18 core drug combinations were obtained through association rule analysis,involving a total of 10 traditional Chinese medicines.Three core fundamental formulas were obtained by cluster analysis.The results of network pharmacology showed that the mechanism and material basis of core drug combinations in the treatment of jaundice were focused on 16 potential active components,8 core targets,and enriched to 25 related pathways.Conclusion:There are 10 core medicines for jaundice treatment in ancient prescriptions of traditional Chinese medicine,mainly including Artemisiae Scopariae Herba,Gardeniae Fructus,Rhei Radix Et Rhizoma and so on.These medicines mainly exhibit the effects of promoting urination,clearing heat,drying dampness,and tonifying deficiency.The mechanisms of these medicines are probably based on the active ingredients such as tumor necrosis factor(TNF),tumor suppressor protein p53(TP53),signal transducer and activator of transcription 3(STAT3),interleukin-8(IL-8),and acting on phosphatidylinositol-3-kinase/protein kinase B(PI3K/Akt)signal pathway,hypoxia inducible factor-1(HIF-1)signal pathway,toll-like receptor(TLR)signal pathway,nuclear factor(NF-κB)signal pathway,apoptosis signal pathway and so on,so as to play a role in the treatment of jaundice.