基于数据挖掘和网络药理学探析中医药治疗寒湿痹阻型类风湿关节炎的用药规律及机制分析

Exploration of the medication rules and mechanism of Chinese medicine in the treatment of rheumatoid arthritis with obstruction of cold-dampness syndrome based on data mining and network pharmacology

目的:探讨中医药治疗寒湿痹阻型类风湿关节炎(RA)的用药规律,运用网络药理学方法探究核心药物组合的作用机制,为寒湿痹阻型RA中医临床用药提供依据。方法:检索中国知网、万方知识服务平台、维普中文期刊数据库2000年1月—2023年3月收录的中医药治疗寒湿痹阻型RA的文献,建立数据库。运用Excel 2019、中医传承辅助平台v 2.50、SPSS Statistics 27.0、IBM SPSS Modeler 18.0等软件统计中药的使用频次及四气、五味、归经频次,挖掘常用药物、药对、核心处方,并利用TCMSP、STRING等数据库,Cytoscape软件等构建核心药对活性成分-靶点-疾病网络及PPI蛋白互作网络,对靶点进行通路富集分析。结果:纳入文献99篇,处方101个,涉及药味134味。桂枝使用频次最高,其次为白芍、当归。四气频次统计以温性药使用频次最高(670次,59%),其次为平性、寒性。五味频次统计以辛味药使用频次最高(669次,36%),其次为苦味、甘味。补益药使用频次最高(334次,27.31%),其次为祛风湿药(299次,24.28%)、解表药(221次,17.95%)。核心药物组合为“羌活-独活”,从“羌活-独活”中筛选出24个活性成分,作用靶点55个,RA作用靶点1493个,药物与RA交集靶点22个。根据度值(degree)排序,β-谷甾醇(beta-sitosterol)、乙酰二氢欧山芹酯(Oacetylcolumbianetin)、紫花前胡苷(nodakenin)等可能是改善RA的核心活性成分,胱天蛋白酶3(CASP3)、细胞周期素D1(CCND1)、环加氧酶2(PTGS2)、胱天蛋白酶(CASP8)、雌激素受体1(ESR1)等为核心靶点。KEGG通路富集分析主要涉及癌症通路(pathways in cancer)、p53信号通路(p53 signaling pathway)、细胞凋亡-多物种(apoptosis-multiple species)、多种疾病的神经退行性病变途径(pathways of neurodegeneration-multiple diseases)等。结论:中医药治疗寒湿痹阻型RA多以祛风除湿、散寒止痛为主,兼顾补虚,核心药对“羌活-独活”治疗RA的作用机制可能通过CASP3、CCND1、PTGS2等靶点通过调控癌症通路、p53号信号通路、细胞凋亡-多物种、多种疾病的神经退行性病变途径等通路发挥抗炎及诱导细胞凋亡等作用。

Objective:To explore the medication rules of Chinese medicine in the treatment of rheumatoid arthritis(RA)with obstruction of cold-dampness syndrome,and study the mechanism of core drug combination by network pharmacology,so as to provide evidence for the TCM clinical medication for RA with obstruction of cold-dampness syndrome.Methods:The literature of RA with obstruction of cold-dampness syndrome treated with Chinese medicine was retrieved from China National Knowledge Infrastructure,Wanfang Knowledge Service Platform and VIP database from January 2000 to March 2023,and a database was established.Excel 2019,traditional Chinese medicine inheritance support platform v 2.50,SPSS Statistics 27.0,IBM SPSS Modeler 18.0 and other software were used to calculate the frequency of the use of Chinese herbs and the frequency of the four properties,the five flavors and the channel tropism.The commonly used drugs,drug pairs and core prescriptions were searched.The active ingredient-target-disease network and PPI protein interaction network were constructed by TCMSP database,STRING database,Cytoscape software,etc.The pathway enrichment analysis of the targets was performed.Results:A total of 99 articles with 101 prescriptions were included,involving 134 Chinese herbs.Guizhi was the most frequently used,followed by Baishao and Danggui.According to the statistics of four properties frequency,the use frequency of warm drugs was the highest(670 times,59%),followed by moderate and cold drugs.According to the statistics of the five flavors frequency,the use frequency of pungent drugs was the highest(669 times,36%),followed by bitter and sweet drugs.The frequency of use of tonic drugs was the highest(334 times,27.31%),followed by winddampness-removing drugs(299 times,24.28%)and relieving exterior syndrome drugs(221 times,17.95%).The core drug combination was“Qianghuo-Duhuo”.Twenty-four active ingredients were screened from“Qianghuo-Duhuo”,with 55 targets of action,1493 targets of RA,and 22 intersection targets of drug and RA.According to degree,beta-sitosterol,Oacetylcolumbianetin and nodakenin might be the core active ingredients for improving RA.CASP3,CCND1,PTGS2,CASP8,ESR1 were the core targets.KEGG pathway enrichment analysis mainly involved pathways in cancer,p53 signaling pathway,apoptosis multiple species,pathways of neurodegeneration-multiple diseases,and so on.Conclusion:In the treatment of RA with obstruction of cold-dampness syndrome,Chinese medicine mainly focuses on eliminating wind and removing dampness,dissipating cold and relieving pain,and tonifying the deficiency.The mechanism of the core drug pair of“Qianghuo-Duhuo”in the treatment of RA may be through CASP3,CCND1,PTGS2 and other targets to regulate the pathways in cancer,p53 signaling pathway,apoptosis multiple species,pathways of neurodegeneration-multiple diseases to play an antiinflammatory and apoptosis-inducing roles.