基于网络药理学探讨四氢姜黄素改善KKAy小鼠认知障碍的可能机制  

Mechanism Study of Tetrahydrocurcumin in the Treatment of Cognitive Impairment in KKAy Mice Based on Network Pharmacology

作　　者：余丽垚 张仲林[1] 李莉[2] 曾瑾[2] 戴瑛[2] 赵军宁[2] Yu Liyao;Zhang Zhonglin;Li Li;Zeng Jin;Dai Ying;Zhao Junning(Chengdu Medical College,Chengdu 610500;Translational Chinese Medicine Key Laboratory of Sichuan Province,Sichuan Academy of Chinese Medicine Sciences,Sichuan Institute for Translational Chinese Medicine,Sichuan Geoherbs Formation Principles and Quality Evaluation Research Center,Sichuan Geoherbs System Engineering Technology Research Center,State Key Laboratory of Quality Evaluation of Traditional Chinese Medicine,Chengdu 610041)

机构地区：[1]成都医学院,成都610500 [2]中医药转化医学四川省重点实验室,四川省中医药科学院,四川省中医药转化医学中心,四川省道地药材形成原理与品质评价工程研究中心,四川省道地药材系统开发工程技术研究中心,国家中医药管理局中药质量生物评价重点研究室,成都610041

出　　处：《中药药理与临床》2021年第3期85-95,共11页Pharmacology and Clinics of Chinese Materia Medica

基　　金：国家科技重大专项“重大新药创制”(编号:2018ZX09731-008);四川省科学技术厅重点研发项目(编号:2020YFS0368);抗糖尿病及代谢综合征1类创新中药四氢姜黄素(THC)的临床前研究(编号:2020JDZH0022)。

摘　　要：目的:利用KKAy转基因小鼠模型探究四氢姜黄素(tetrahydrocurcumin)对糖尿病相关认知障碍(Diabetes-associated cognitive impairment,DACI)的改善作用,并通过网络药理学挖掘四氢姜黄素改善KKAy糖尿病小鼠认知障碍的作用靶点及通路,探讨其可能的作用机制。方法:选用C57小鼠作为正常对照组,KKAy小鼠分为:模型对照组、四氢姜黄素50、100、200、400 mg/kg组、罗格列酮3 mg/kg组,给药结束后利用Morris水迷宫实验检测学习记忆改善情况;通过数据库筛选获取四氢姜黄素分子靶标、DACI疾病靶点,利用Draw Venny Diagram在线平台导获取交集靶点,将获得的交集靶点提交至PPI在线分析数据库STRING构建蛋白互作网络,运用Cytoscape3.7.1软件进行拓扑参数分析并构建四氢姜黄素-靶蛋白-DACI通路网络,借助Metascape进行GO功能注释和KEGG通路富集分析,最后对可能的核心靶点进行分子对接验证,揭示四氢姜黄素改善DACI的作用机制。结果:水迷宫实验结果显示:四氢姜黄素50、200、400 mg/kg和罗格列酮3 mg/kg组逃避潜伏期显著缩短(P<0.05或P<0.01);网络药理学结果共获得四氢姜黄素靶点共184个,DACI靶点1023个,四氢姜黄素与DACI交集靶点78个;PPI拓扑学分析结果显示,度值排名前20的靶点分别为EGFR、HRAS、IGF1、ESR1、CASP3、HSP90AA1、MAPK14、IGF1R、SOD2、PPARG、XIAP、PGR、GSK3B、PARP1、F2、CDK2、LCK、CHEK1、PTPN1,涉及的通路包括:癌症信号通路、PI3k-AKT信号通路、MAPK信号通路等,分子对接结果显示四氢姜黄素能与GSK3β、XIAP、EGFR稳定结合。结论:四氢姜黄素能明显改善KKAy糖尿病小鼠的学习记忆障碍;四氢姜黄素可能通过作用于靶蛋白GSK3β、EGFR、IGF1等进而参与调控PI3K-AKT和MAPK信号通路发挥抗DACI作用。Objective:To explore the improvement effect of tetrahydrocurcumin on Diabetes-associated cognitive impairment(DACI)in KKAy transgenic mice model,then to investigate the targets and pathways involved in tetrahydrocurcumin in the treatment of cognitive impairment through network pharmacology,in order to study its possible mechanism.Methods:C57 mice were selected as the control mice.The KKAy mice were divided into the model group,50 mg/kg,100 mg/kg,200 mg/kg and 400 mg/kg tetrahydrocurcumin groups,and 3 mg/kg rosiglitazone group.Morris water maze test was used to detect the learning and memory function of mice after the treatment.The database was used to analyze the targets of tetrahydrocurcumin and DACI.Draw Venny Diagram online platform was used to obtain intersection targets,and then a protein interaction network was constructed through PPI online analysis STRING database.Cytoscape 3.7.1 software was used to analyze the topology parameters and built a tetrahydrocurcumin-target protein-DACI pathway network.Metascape was used for GO function annotation and KEGG pathway enrichment analysis.Finally,molecular docking method was used to verify possible core targets,to reveal the mechanism of tetrahydrocurcumin.Results:The results in the water maze test showed that,compared with the control group,the escape latencies were significantly shortened in 50 mg/kg,200 mg/kg and 400 mg/kg tetrahydrocurcumin groups and rosiglitazone group(P<0.01 or P<0.05).The network pharmacology results showed that a total of 184 targets of tetrahydrocurcumin,1023 targets of DACI,and 78 intersection targets were involved.The topology analysis of PPI network results showed that the degree value of targets ranked in the top 20 were EGFR,HRAS,IGF1,ESR1,CASP3,HSP90 AA1,MAPK14,IGF1 R,SOD2,PPARG,XIAP,PGR,GSK3 B,PARP1,F2,CDK2,LCK,CHEK1 and PTPN1,the involved pathways included cancer signaling pathway,PI3 k-Akt signaling pathway,MAPK signaling pathway.The molecular docking results showed that tetrahydrocurcumin was stably bound to GSK3β,XIAP,and EGFR

关 键 词：糖尿病相关认知障碍 四氢姜黄素 网络药理学 分子对接 

分 类 号：R285.5[医药卫生—中药学]