基于网络药理学及分子对接探讨白藜芦醇防治子宫内膜癌的作用及分子机制  

Effect of resveratrol on endometrial cancer and its molecular mechanism based on network pharmacology and molecular docking

作　　者：周佳韫 印泽远 王晴 刘利 李妍雨 鲁慧[4] 周雪妍 张蓓 ZHOU Jiayun;YIN Zeyuan;WANG Qing;LIU Li;LI Yanyu;LU Hui;ZHOU Xueyan;ZHANG Bei(Graduate School,Xuzhou Medical University,Xuzhou,Jiangsu 221004,China;Department of Obstetrics and Gynecology,Xuzhou Clinical College of Xuzhou Medical University,Xuzhou Central Hospital,Xuzhou,Jiangsu 221000;Graduate School,Bengbu Medical College,Bengbu,Anhui 233000;Physical Examination Center,Xuzhou Central Hospital)

机构地区：[1]徐州医科大学研究生院,江苏徐州221004 [2]徐州医科大学徐州临床学院,徐州市中心医院妇产科,江苏徐州221000 [3]蚌埠医学院研究生院,安徽蚌埠233000 [4]徐州市中心医院体检中心

出　　处：《徐州医科大学学报》2023年第4期280-286,共7页Journal of Xuzhou Medical University

基　　金：江苏省中医药科技发展计划项目(ZT202114)。

摘　　要：目的基于网络药理学、分子对接及动物实验验证,探讨白藜芦醇防治子宫内膜癌的作用及分子机制。方法通过HERB、ECTM数据库获得白藜芦醇作用靶点,从Genecards数据库获得子宫内膜癌相关靶点,获取白藜芦醇治疗子宫内膜癌交集靶点,导入STRING数据库,使用Cytoscape软件构建药物-疾病-靶点网络。通过OmicShare云平台对交集靶点进行GO富集分析和KEGG通路富集分析。将白藜芦醇与核心靶点进行分子对接分析。采用1-甲基-3-硝基-1-亚硝基胍(MNNG)诱导EC小鼠模型,将小鼠随机分为Control组、Res组、MNNG组、MNNG+Res组、MNNG+Res+丝裂原活化蛋白激酶/细胞外信号调节激酶抑制剂(MAPK/ERKi)组。Western blot检测小鼠子宫内膜组织中细胞外信号调节激酶(ERK)及磷酸化ERK(p-ERK)蛋白表达水平;LC-MS/MS检测小鼠血清及子宫内膜组织中15种雌激素活性物质组的含量。结果共获得白藜芦醇治疗子宫内膜癌潜在靶点174个。KEGG富集信号通路包括PI3K-Akt信号通路、MAPK信号通路等。筛选前10核心靶点并与白藜芦醇进行分子对接显示,白藜芦醇与MAPK3结合活性较为稳定。Western blot结果显示,与Control组相比,Res组、MNNG+Res组、MNNG+Res+MAPK/ERKi组中子宫内膜组织中ERK磷酸化水平增加。LC-MS/MS检测结果显示,在MNNG组小鼠血清和子宫内膜组织中,具有保护作用的雌激素代谢物2-甲氧基雌酮(2-MeOE1)、2-甲氧基雌二醇(2-MeOE2)和4-甲氧基雌酮(4-MeOE1)含量明显下降,毒性代谢产物4-羟基雌二醇(4-OHE2)的含量明显增加(P<0.05)。与MNNG组相比,MNNG+Res组中小鼠血清中4-MeOE1含量明显升高,子宫内膜组织中2-MeOE1和2-MeOE2含量明显增加,而4-OHE2的含量在小鼠血清和子宫内膜组织中明显下降(P<0.05)。MNNG+Res+MAPK/ERKi组中,白藜芦醇逆转雌激素稳态失衡作用效果均被显著减弱。结论白藜芦醇防治子宫内膜癌具有多靶点、多途径的特点。白藜芦醇通过激�Objective To investigate the effect of resveratrol on endometrial cancer based on network pharmacology,molecular docking and experimental verification.Methods The target of resveratrol was retrieved from HERB and ECTM databases,and the target of endometrial cancer was obtained from Genecards database.The intersection genes of resveratrol for the treatment of endometrial cancer were imported to the STRING database to establish a drug-disease-target network by Cytoscape software.Then,GO and KEGG pathway enrichment analyses were performed for intersection targets using OmicShare cloud platform.Resveratrol and hub targets were analyzed by molecular docking.Furthermore,a 1-methyl-3-nitro-1-nitrosoguanidine(MNNG)-induced EC model of mice was constructed and the mice were randomly divided into five groups:a Control group,a Res group,a MNNG group,a MNNG+Res group,and a MNNG+Res+MAPK/ERKi group.The protein levels of ERK and p-ERK in mouse uterus were detected by Western blot.The contents of 15 estrogen active substances in serum and endometrial tissue of mice were detected by LC-MS/MS.Results A total of 174 intersection targets were obtained for the treatment of endometrial cancer by resveratrol.KEGG enrichment signaling pathways included PI3K-Akt signaling pathway and MAPK signaling pathway.The top ten hug targets were screened and resveratrol showed stable binding activity with MAPK3,according to molecular docking.Moreover,compared with the Control group,the Res group,MNNG+Res group and MNNG+Res+MAPK/ERKi group showed increased phosphorylated ERK levels in endometrial tissues.According to LC-MS/MS analysis,the MNNG group showed significantly decreases in the contents of 2-MeOE1,2-MeOE2 and 4-MeOE1 in serum and uterine tissue and increases in the content of 4-OHE2(P<0.05).Compared with the MNNG group,the MNNG+Res group presented remarkable increases in the levels of 4-MeOE1 in serum as well as 2-MeOE1 and 2-MeOE2 in endometrial tissue,but decrease in the content of 4-OHE2 in serum and endometrial tissues(P<0.05).In the M

关 键 词：子宫内膜癌 白藜芦醇 网络药理学 MAPK信号通路 雌激素 

分 类 号：R737.3[医药卫生—肿瘤]