基于网络药理学探讨京制牛黄解毒片治疗口腔溃疡的作用机制及实验验证  

Mechanism and Experimental Verification of Jingzhi Niuhuangjiedu Tablets in Treatment of Oral Ulcer Based on Network Pharmacology

作　　者：范春兰 张思玉 左泽平 杜菁[3] 张志聪 张晓笛 曹欣垚 尹琼 李晋生[3] 彭平 王志斌 Fan Chunlan;Zhang Siyu;Zuo Zeping;Du Jing;Zhang Zhicong;Zhang Xiaodi;Cao Xinyao;Yin Qiong;Li Jinsheng;Peng ping;Wang Zhibin(Beijing Zhongyan Tongrentang Pharmaceutical R&D Co.,Ltd./National Engineering Research Center for R&D of TCM Multi-ingredient Drugs,Beijing 100079,China;Beijing Tongrentang Science and Technology Development Co.Ltd.,Beijing 100079,China;Beijing Tongrentang Co.,Ltd.Scientific Research Institute,Beijing 100079,China)

机构地区：[1]北京中研同仁堂医药研发有限公司/中药复方新药开发国家工程研究中心,北京100079 [2]北京同仁堂科技发展股份有限公司制药厂,北京100079 [3]北京同仁堂股份有限公司科学研究所,北京100079

出　　处：《世界科学技术-中医药现代化》2023年第1期94-106,共13页Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology

基　　金：国家科学技术部重点研发计划项目(2017YFC1702604):黄连大品种开发,负责人:彭平。

摘　　要：目的 运用网络药理学和动物实验验证,探讨京制牛黄解毒片治疗口腔溃疡(Oral ulcer,OU)的作用机制。方法 通过中药成分数据库(TCMSP、TCMID)筛选出京制牛黄解毒片组成药物的主要化学成分及其潜在靶点;通过Genecards、OMIM、Drugbank和PharmGKB数据库获得OU疾病相关基因;利用cytoscape3.8.2软件构建药物-化学成分-靶点-疾病网络图;采用STRING数据库构建靶点相互作用(Protein-protein interaction,PPI)网络。采用R软件(4.0.4)将京制牛黄解毒片中化学成分预测靶点和OU疾病的共同靶点进行基因本体(Gene ontology,GO)及基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)富集分析;最后通过复制大鼠口腔溃疡模型,对京制牛黄解毒片治疗口腔溃疡的药效及核心信号通路进行验证。结果 经数据库分析,共获得京制牛黄解毒片29个关键活性成分,核心靶点包括Mitogen-activated protein kinase 1/3(MAPK1/3)、Protein kinase B(AKT1/PKB)、Signal transducer and activator of transcription(STAT3)、Heat shock protein90(HSP90)、Vascularendothelialgrowthfactor(VEGF)、Interleukin-6(IL-6)、Epidermalgrowthfactor receptor(EGFR)等,GO功能富集和KEGG通路富集主要影响PI3K-AKT(Phosphoinositide 3-kinase/protein kinase B)、Tumor necrosis factor(TNF)、Interleukin-17(IL-17)及Hypoxia-inducible factor 1(HIF-1)等信号通路。大鼠实验证实京制牛黄解毒片可显著减小溃疡面积,明显改善口腔溃疡程度和溃疡的病理变化,显著降低血清促炎因子TNFα、IL-1β、IL-6和Interferon γ(IFN-γ)水平,升高抗炎因子IL-4水平;同时显著降低溃疡组织VEGF蛋白水平。结论 京制牛黄解毒片具有多成分、多靶点、多通路的作用特点,对大鼠实验性口腔溃疡具有治疗作用,其作用机制与调节炎症信号通路有关,为后续京制牛黄解毒片临床应用和机制研究提供了参考。Objective To explore the mechanism of Jingzhi Niuhuangjiedu tablets in treating oral ulcer(OU) based on network pharmacology and animal experimental verification.Methods Main chemical components and potential targets of Jingzhi Niuhuangjiedu(JN) tablets were obtained from Traditional Chinese Medicine Systems Pharmacology Database(TCMSP) and Traditional Chinese Medicine Integrated Database(TCMID).Disease genes of OU were obtained from GeneCards,OMIM,Drugbank and PharmGKB.Cytoscape 3.8.2 was used to construct the drug-chemical componenttarget-disease network.The protein-protein interaction(PPI) network was constructed by STRING database platform.The Gene Ontology(GO) biological process enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway enrichment analysis was performed by R databases(4.0.4).Then some of the key targets were verified by animal experiments.Results Through database analysis,a total of 29 active components were obtained.Network pharmacology revealed key targets including MAPK1/3,AKT1/PKB,STAT3,HSP90,VEGF,IL-6 and EGFR etc,and key signaling pathways including PI3K-AKT signaling pathway,TNF signaling pathway,IL-17 signaling pathway and HIF-1 signaling pathway.Animal experiments showed that compared with the model group,the ulcer area in the JN tablets treatment group was significantly decreased.Treatment with JN tablets could also improve the pathological changes in ulcer tissue,decrease the serum level of TNFα,IL-1β,IL-6 and IFN-γ,and increased the level of IL-4.Meanwhile,JN tablets decreased the expression of VEGF in the ulcer tissue.Conclusion The active components of JN tablets can regulate multiple targets in the important pathway of OU.In vivo experiments showed that JN tablets have a therapeutic effect against a rat model of OU.The protective effects of JN tablets are related to the regulation of the inflammation signaling pathway;this effect of JN tablets may help to provide references for clinical application and further mechanism study.

关 键 词：京制牛黄解毒片 口腔溃疡 网络药理学 作用机制 炎症信号通路 

分 类 号：R-058[医药卫生]