基于数据挖掘和网络药理学探讨类风湿关节炎骨破坏的用药规律及机制

Exploring the medication rule and mechanism of bone destruction in rheumatoid arthritis based on data mining and network pharmacology

目的探究中医药治疗类风湿关节炎骨破坏的规律,预测核心中药组合的药理机制。方法2022年12月至2023年2月,通过搜索中国知网(CNKI)、万方(Wanfang)、维普(VIP)、PubMed数据库中关于中医药改善类风湿关节炎骨破坏的文献,建立处方数据库,统计出处方中药的性、味、归经和功效类别;通过关联规则分析确定核心药物组合;通过中药系统药理学数据库与分析平台(TCMSP)、Uniprot、GeneCards、DrugBank等数据库获取核心药物和疾病的靶点信息,并统计出交集靶点;通过对交集靶点进行蛋白质-蛋白质相互作用(PPI)分析、基因本体(GO)功能分析和京都基因和基因组数据库(KEGG)通路富集分析预测核心中药的作用机制;最后,通过分子对接法反向检验关键靶点和中药成分的关系。结果纳入78首方剂,涉及137味中药,以补虚药和祛风湿药为主,多性温,味苦、甘,归肝、肾经。关联规则结果表示“甘草-防风-白芍”为具有强关联性的核心药物组合,其主要成分为槲皮素、山柰酚、汉黄芩素、柚皮素、刺芒柄花素等。PPI分析得到信号转导及转录活化因子3(STAT3)、细胞肿瘤抗原p53(TP53)、转录因子p65(RELA)、蛋白激酶B(AKT)1、丝裂原活化蛋白激酶3(MAPK3)等为关键靶点。KEGG结果表示白细胞介素-17(IL-17)、肿瘤坏死因子(TNF)等信号通路可能与类风湿关节炎骨破坏相关。分子对接结果表示关键靶点与药物主要成分的对接活性较好,其中山柰酚与TP53具有最低的结合能,对接活性最好。结论中医药改善类风湿关节炎骨破坏以补益肝肾,祛风除湿为主。“甘草-防风-白芍”为核心药物组合,其作用机制以改善炎症、调整免疫、改善骨代谢过程为主。

Objective To explore the rule of traditional Chinese medicine(TCM)treating rheumatoid arthritis combined with bone destruction and predict the pharmacological mechanism of core herb combination.Methods From December 2022 to February 2023,a prescription database was established to count the frequency of four properties,five flavors,meridian tropism,and efficacy categories of prescription herbs by searching the literature related to the improvement of bone destruction in rheumatoid arthritis treated by TCM in CNKI,Wanfang,VIP and PubMed databases.The core herb combination was determined by association rule analysis.The target information of core herbs and diseases was obtained through traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP),Uniprot,GeneCards,DrugBank and other databases,and then the intersection targets were counted.Protein-protein interaction(PPI)analysis,gene ontology(GO)function enrichment analysis and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis were performed on the intersection targets to predict the mechanism of action of the core herbs.Finally,the relationship between key targets and core herbs components was reversely tested by molecular docking.Results The 78 prescriptions involved 137 herbs.These herbs were mainly tonics and rheumatism medicines,which were mostly warm,bitter and sweet,and mainly belong to the liver and kidney meridians.The association rules showed that"Glycyrrhizae Radix et Rhizoma-Saposhnikoviae Radix-Pae⁃oniae Radix Alba" was the core herb combination with strong correlation, and its main components were quercetin, kaempferol, wogo-nin, naringenin and formononetin. The PPI analysis showed that Signal transducer and activator of transcription 3 (STAT3), Cellular tu-mor antigen p53 (TP53), Transcription factor p65 (RELA), protein kinase B (AKT) 1, Mitogen-activated protein kinase 3 (MAPK3) and so on as key targets. The KEGG pathway enrichment analysis showed that major pathways involved in rheumatoid arthritis and bone de-struction include the interleukin-17 (IL-17), tumor necrosis factor (TNF) signaling pathway, etc. Molecular docking showed that the docking ability of key targets and components was promising. Kaempferol had the best docking activity with TP53 because of its lowest binding energy.Conclusions TCM improves the bone destruction of rheumatoid arthritis mainly by tonifying liver and kidney, dispel-ling wind and removing dampness. "Glycyrrhizae Radix et Rhizoma-Saposhnikoviae Radix-Paeoniae Radix Alba" is the core herb com-bination, and its mechanism of action is to improve inflammation, adjust immunity and improve bone metabolism.