马甲子总三萜对大鼠炎性肠病的干预作用及相关靶点/通路预测  

Effect of Paliurus ramosissimus Total Triterpenes on Inflammatory Bowel Disease in Rats and Prediction of Related Targets/Pathways

作　　者：郑文浩 白筱璐[2] 胡竟一[2] 陈旺 谢林碧 雷玲[2] 余悦[2] 吴瑕[2] 李东晓[2] 徐超群[1] Zheng Wenhao;Bai Xiaolu;Hu Jingyi;Chen Wang;Xie Linbi;Lei Ling;Yu Yue;Wu Xia;Li Dongxiao;Xu Chaoqun(School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 610041;Sichuan Provincial Key Laboratory of Quality and Innovation Research of Chinese Materia Medica,Sichuan Academy of Chinese Medicine Sciences,Chengdu 610041)

机构地区：[1]成都中医药大学药学院,成都611100 [2]四川省中医药科学院,中药材品质及创新中药研究四川省重点实验室,成都610041

出　　处：《中药药理与临床》2021年第5期38-44,共7页Pharmacology and Clinics of Chinese Materia Medica

基　　金：国家重大新药创制项目(编号:2018ZX09731013);四川省中药药理学重点学科建设项目(编号:2020ZDXK01)。

摘　　要：目的:考察马甲子总三萜对大鼠实验性炎性肠病(IBD)的干预作用,并预测其主要成分白桦脂酸干预IBD的相关靶点和通路。方法:以白桦脂酸为配体分子,利用在线数据库对相关靶点进行基因功能注解(GO)、基因组数据库(KEGG)富集分析和分子对接,预测白桦脂酸干预IBD的潜在靶点和通路并对预测结果进行初步验证。以2,4,6-三硝基苯磺酸(TNBS)灌肠建立大鼠IBD模型,设置模型对照组、阳性对照组(美沙拉嗪315 mg/kg)、白桦脂酸30 mg/kg组、马甲子总三萜50 mg/kg组,灌胃给药10 d,通过疾病活动指数(DAI)、结肠粘膜损伤指数(CMDI)和结肠组织病理评分等指标评价马甲子总三萜对大鼠结肠炎症的干预作用。结果:通过网络药理学方法共筛选出13个与IBD相关的白桦脂酸潜在作用靶点,其中前列腺素氧化环化酶2(PTGS2/COX2)、紧密连接蛋白1(TJP1)等8个关键蛋白靶点与白桦脂酸存在亲和力,涉及4条疾病相关信号通路。与正常对照组比较,模型对照组大鼠DAI、CMDI及病理评分显著升高(P<0.01),结肠长度显著缩短(P<0.01),血清中COX2、PGE_(2)含量显著升高(P<0.01);与模型对照组比较,白桦脂酸30 mg/kg组、马甲子总三萜50 mg/kg组CMDI评分显著降低(P<0.01),组织病理评分明显降低(P<0.05);马甲子总三萜50 mg/kg组血清中COX2、PGE_(2)含量显著降低(P<0.01)。结论:马甲子总三萜及其主要成分白桦脂酸均可抑制TNBS诱导的IBD模型大鼠的结肠炎性损伤;其机制可能与其抑制COX2活性,影响花生四烯酸合成等信号通路,进而抑制PGE_(2)等炎症介质的生成有关。Objective:This study aims to investigate the effect of Paliurus ramosissimus total triterpenes(PRTT)on inflammatory bowel disease(IBD)and predict the targets and pathways of betulinic acid,the main effective component.Methods:With the ligand betulinic acid,Gene Ontology(GO)term enrichment,kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment,and molecular docking of related targets were performed.Thereby,the potential targets and pathways of betulinic acid intervening IBD were predicted and the results were verified.The 2,4,6-trinitrobenzenesulfonic acid(TNBS)was employed(pr)to induce IBD in rats.Rats were then randomized into model group,positive group(methalazine 315 mg/kg),betulinic acid(30 mg/kg)group,and PRTT(50 mg/kg)group.Rats in each group were treated(ig)for 10 days and then the effect of PRTT on colonitis in rats was evaluated with disease activity index(DAI),colonic mucosal damage index(CMDI),and colonic histopathological score.Results:A total of 13 potential targets of betulinic acid associated with IBD were screened by network pharmacology.Among them,8 key protein targets,such as prostaglandin synthase 2/cyclooxygenase 2(PTGS2/COX2)and tight junction protein 1(TJP1),showed affinity to betulinic acid,which involved 4 disease-related signaling pathways.Rats in the model group had higher DAI,CMDI,and histopathological score(P<0.01),larger serum concentration of COX2 and prostaglandin E2(PGE_(2))(P<0.01),and shorter colons(P<0.01)than those in the normal control group.PRTT(50 mg/kg)group and betulinic acid(30 mg/kg)group had lower CMDI(P<0.01)and histopathological score(P<0.05)than the model group.The serum content of COX2 and PGE_(2)was significantly reduced in the PRTT(50 mg/kg)group compared with that in the model group(P<0.01).Conclusion:PRTT and the main component betulinic acid can significantly alleviate the IBD in rats induced by TNBS,which may be related to the inhibition of COX2,the influence on arachidonic acid synthetic pathway,and further the suppression of inflammatory mediator sy

关 键 词：马甲子 白桦脂酸 炎性肠病 网络药理学 分子对接 

分 类 号：R285.5[医药卫生—中药学]