索马鲁肽治疗阿尔茨海默病的潜在靶点:沉默信息调节因子1  

Silent information regulator 1:A potential target of semaglutide in the treatment of Alzheimer’s disease

作　　者：柴世凡 李欣儒 叶育采 孙俊丽 蔡红艳 王昭君[1] Chai Shifan;Li Xinru;Ye Yucai;Sun Junli;Cai Hongyan;Wang Zhaojun(Department of Physiology,School of Basic Medicine,Shanxi Medical University,Key Laboratory of Cell Physiology,Ministry of Education,Shanxi Key Laboratory of Cell Physiology,Taiyuan 030000,Shanxi Province,China;School of Anesthesiology,School of Basic Medicine,Shanxi Medical University,Taiyuan 030000,Shanxi Province,China;Department of Microbiology and Immunology,School of Basic Medicine,Shanxi Medical University,Taiyuan 030000,Shanxi Province,China)

机构地区：[1]山西医科大学基础医学院生理学系,细胞生理学教育部重点实验室,细胞生理学山西省重点实验室,山西省太原市030000 [2]山西医科大学麻醉学院,山西省太原市030000 [3]山西医科大学基础医学院微生物与免疫教研室,山西省太原市030000

出　　处：《中国组织工程研究》2024年第20期3235-3239,共5页Chinese Journal of Tissue Engineering Research

基　　金：国家自然科学基金面上项目(82171428),项目负责人:蔡红艳;山西省基础研究自然科学研究面上项目(20210302123306),项目负责人:王昭君。

摘　　要：背景:研究发现胰高血糖素样肽1及其类似物具有显著的神经保护作用,并且已有部分药物应用到阿尔茨海默病临床三期研究阶段,然而其发挥神经保护作用的具体机制尚不明确,有待进一步探讨阐明。目的:拟通过生物信息学和网络药理学分析方法筛选出阿尔茨海默病发病机制的相关基因,以及索马鲁肽(一种胰高血糖素样肽1受体激动剂)治疗阿尔茨海默病的相关靶点,对两者进行综合分析挑选出潜在靶点基因,并在细胞水平加以验证。方法:利用DisGeNET数据库筛选出阿尔茨海默病患者与健康人群的差异基因,利用PubChem在线数据库得到索马鲁肽的化学结构式和2D结构图,利用DAVID在线数据库进行GO/KEGG富集分析,利用STRING数据库进行蛋白互作网络的构建,利用HPA数据库判断目的蛋白在人体各组织中的分布特点,最后使用蛋白印迹技术和免疫荧光技术检测索马鲁肽干预HT22细胞之后的蛋白表达情况。结果与结论:①利用DisGeNET数据库内数据得到3374个阿尔茨海默病患者与健康人群的差异基因,同时获得索马鲁肽潜在药物的101个靶基因,取两者交集得到23个相关基因;结合蛋白互作网络从中筛选出10个关键基因,分别是沉默信息调节因子1(SIRT1)、CASP9、CCND1、CASP1、KEAP1、DLG4、CASP4、GRB2、GRIA1、EDNRA;②GO基因功能分析显示关键基因主要富集在:半胱氨酸型内肽酶的正向调节活动,蛋白溶解的正向调节,半胱氨酸型内肽酶的正向调节,涉及凋亡活动过程的细胞质部分,AMPA谷氨酸受体复合物,炎症复合物,CARD结构域结合,半胱氨酸型内肽酶活性,半胱氨酸型内肽酶活性参与凋亡过程;KEGG信号通路分析结果主要为:结直肠癌,非小细胞癌,子宫内膜癌,上述均与免疫浸润、炎症、自噬凋亡相关;此外,根据关键基因的关联度排名及在HPA在线数据库不同组织中的分布情况,挑选出最显著的差异基因为SIRBACKGROUND:Studies have found that glucagon-like peptide-1 and its analogues have a significant neuroprotective effect,and some drugs have been applied to the clinical stage III study of Alzheimer’s disease.However,the mechanism of its neuroprotective effect is still unclear,which needs to be further explored and clarified.OBJECTIVE:To screen out the genes related to the pathogenesis of Alzheimer’s disease and the related targets of semaglutide for the treatment of Alzheimer’s disease based on bioinformatics and network pharmacology analyses,to identify the potential target genes by comprehensive analysis of the two and to verify them at the cellular level.METHODS:Using DisGeNET database,differentially expressed genes between Alzheimer’s disease patients and healthy population were screened out.The chemical structure formula and two-dimensional structure diagram of semaglutide were obtained using PubChem online database.GO/KEGG enrichment analysis was performed using DAVID online database.A protein-protein interaction network was constructed by using the STRING database.The HPA database was used to determine the distribution characteristics of the target proteins in various human tissues.Finally,western blot was used to detect relevant protein expression in HT22 cells after semaglutide intervention.RESULTS AND CONCLUSION:With the dataset in DisGeNET database,3374 differentially expressed genes between Alzheimer’s disease patients and healthy people were obtained,and meanwhile,101 target genes of semaglutide potential drugs were obtained.There were 23 intersection genes between them.Ten key genes were identified based on the protein-protein interaction network,which were silent information regulator 1(SIRT1),CASP9,CCND1,CASP1,KEAP1,DLG4,CASP4,GRB2,GRIA1,and EDNRA.The results of GO gene functional annotation analysis of key genes showed that the positive regulatory activity of cysteine endopeptidase,the positive regulation of proteolysis,and the positive regulation of cysteine endopeptidase involved the c

关 键 词：DisGeNet数据库 阿尔茨海默病 索马鲁肽 2型糖尿病 生物信息学 网络药理学 沉默信息调节因子1 

分 类 号：R459.9[医药卫生—治疗学] R338[医药卫生—临床医学] R741