Article(id=1206995861721137496, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1206995859061952854, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.12.1190, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1630512000000, receivedDateStr=2021-09-02, revisedDate=null, revisedDateStr=null, acceptedDate=1634659200000, acceptedDateStr=2021-10-20, onlineDate=1765699838333, onlineDateStr=2025-12-14, pubDate=1672156800000, pubDateStr=2022-12-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765699838333, onlineIssueDateStr=2025-12-14, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765699838333, creator=13701087609, updateTime=1765699838333, updator=13701087609, issue=Issue{id=1206995859061952854, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='12', pageStart='1169', pageEnd='1270', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1765699837699, creator=13701087609, updateTime=1765700204449, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1206997397385859947, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1206995859061952854, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1206997397385859948, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1206995859061952854, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1190, endPage=1200, ext={EN=ArticleExt(id=1206995862006350170, articleId=1206995861721137496, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Molecular mechanism of Astragalus membranaceus and Angelica sinensis combination for diabetes mellitus with cardiovascular complications based on GEO database, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To explore the molecular mechanism of a classic traditional Chinese medicine compatibility combination of Astragalus membranaceus (A.m) and Angelica sinensis (A.s) in treatment of diabetes mellitus with cardiovascular complications. Methods The BATMAN database was used to analyze A.m and A.s respectively. The chips data related to diabetes mellitus with cardiovascular complications were retrieved from GEO database. The differential genes were analyzed by GEO2R to construct the protein-protein interaction (PPI) network, and the key target genes of A.m-A.s were obtained by topology, and DAVID database was used for gene ontology (GO) and KEGG pathway enrichment analysis of key genes. A total of 20 SD rats were randomly divided into healthy control group, diabetes mellitus complicated with cardiovascular complications group, metformin group, and A.m-A.s group (5 each). All the rats except those in HC group were fed with high fat and high sugar feeds, and used to establish the model of diabetes mellitus with cardiovascular complications. The expressions of PI3K and Akt3 in cardiomyocytes of the rats in each group were observed. Results (1) A total of 1332 target genes related to A.m-A.s combination were analysis obtained from BATMAN database, and 3 chip data files related to diabetes with cardiovascular diseases (GSE26887, GSE43950 and GSE46262)were retrieved from GEO database including 2759 differential genes screened by GEO2R analysis and 247 key genes of A.m-A.s combination in treatment of diabetes mellitus with cardiovascular complications. (2) The protein-protein interaction (PPI) network diagram of key targets was constructed by STRING database, and the "A.m-A.s- active ingredients-targets" network was constructed by Cytoscape 3.7.2. The functional enrichment analysis with DAVID database showed that the biological process of A.m-A.s in treatment of diabetes mellitus and cardiovascular complications was mainly concentrated in positive and negative regulation of RNA polymerase II promoter transcription, redox process, signal transduction, apoptosis process, inflammatory reaction, and positive regulation of cell proliferation, etc. The signaling pathways mainly include metabolic pathway, cancer pathway, TNF signaling pathway, cAMP signaling pathway, cGMP-PKG signaling pathway, PI3K-Akt signaling pathway, non-alcoholic fatty liver disease pathway, and insulin resistance pathway and so on. (3) The animal model experiment with SD rats in vivo of A.m-A.s combination in treatment of diabetes mellitus with cardiovascular complications suggested that, compared with healthy control group, the expressions of PI3K and Akt3 decreased in cardiomyocytes of the untreated model group, and the difference was statistically significant (P<0.05, P<0.01); the expressions of PI3K in the treatment groups were higher than that in the model group, but lower than that in the healthy control group, and the difference was statistically significant (P<0.01). Conclusion The characteristics of A.m-A.s combination in treatment of diabetes mellitus with cardiovascular complications are "multi-components, multi-targets and multi-pathways", and multiple key genes and signal pathways can play important roles. Further research is expected to broaden the ideas of diagnosis and treatments of diabetes with traditional Chinese medicine.

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目的 探究经典中药配伍组合黄芪-当归药对(芪归药对)对糖尿病合并心血管并发症的治疗作用及分子机制。方法 运用BATMAN数据库对芪归药对进行分析，检索GEO数据库中关于糖尿病合并心血管并发症的相关基因芯片数据，借助GEO2R分析差异基因，构建靶点互作关系网络，拓扑得到芪归药对治疗糖尿病心血管并发症的关键基因；运用DAVID 数据库对关键基因进行基因本体功能和KEGG通路富集分析。将20只SD大鼠随机分为健康对照组、糖尿病合并心血管并发症模型组、阳性对照二甲双胍治疗组和芪归药对治疗组，每组5只；除健康对照组外，其余各组均给予高脂高糖饲料并建立糖尿病合并心血管并发症模型；观察各组大鼠心肌细胞中PI3K、Akt3蛋白的表达情况。结果 (1)在BATMAN数据库中分析得到芪归药对的相关靶点基因1332个，在GEO数据库中检索得到3个糖尿病合并心血管病变的芯片数据文件(GSE26887、GSE43950、GSE46262)，利用GEO2R分析筛选出2759个差异基因；经映射得到芪归药对治疗糖尿病合并心血管并发症的关键基因247个。(2)通过STRING数据库构建关键靶点的差异蛋白相互作用(PPI)网络图，运用 Cytoscape 3.7.2 构建“芪归药对—活性成分—靶点”网络。采用DAVID数据库进行功能富集分析提示，芪归药对治疗糖尿病合并心血管并发症的生物学进程主要集中在RNA聚合酶Ⅱ启动子转录的正负调控、氧化还原过程、信号转导、凋亡过程、炎症反应、细胞增殖的正调控等，信号通路涉及新陈代谢通路、癌症通路、肿瘤坏死因子(TNF)信号通路、5'-单磷酸(cAMP)信号通路、环磷酸鸟苷酸-蛋白激酶(cGMP-PKG)信号通路、磷脂酰肌醇3-激酶与丝氨酸/苏氨酸激酶(PI3K-Akt)信号通路、非酒精性脂肪肝通路、胰岛素抵抗通路等。(3)采用SD大鼠的动物模型实验结果显示，与健康对照组比较，未接受治疗的糖尿病合并心血管并发症模型组心肌细胞中PI3K、Akt3蛋白表达量均明显降低(P<0.01)；芪归药对治疗组和二甲双胍治疗组心肌细胞中PI3K表达量均高于模型组(P<0.01)，但低于健康对照组(P<0.01)；芪归药对治疗组Akt3蛋白表达量低于健康对照组(P<0.05)，二甲双胍治疗组Akt3蛋白表达量高于模型组(P<0.05)。结论 芪归药对治疗糖尿病合并心血管并发症的特点是“多成分、多靶点、多途径”，多个关键基因和信号通路发挥了重要作用，进一步研究有望拓宽糖尿病中医药诊疗的思路。

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A. 芪归药对－成分－靶点基因网络图；B－C. 维恩图

, figureFileSmall=cg+gUZgo2vuRUsWMTczGyw==, figureFileBig=cyrxEQe9kvaUVizhFOvD8g==, tableContent=null), ArticleFig(id=1207064329132786147, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=EN, label=Fig. 2, caption=Flow chart of the molecular mechanism of treatment of diabetes with cardiovascular complications with A.m-A.s combination, figureFileSmall=zJ0SIym6Rq1h2dDlGzVWSA==, figureFileBig=km3bseb3dYA+M7PeC1dYMQ==, tableContent=null), ArticleFig(id=1207064329308946922, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=CN, label=图2, caption=芪归药对治疗糖尿病合并心血管并发症的分子机制研究流程

PPI. 蛋白相互作用；GO. 基因本体

, figureFileSmall=zJ0SIym6Rq1h2dDlGzVWSA==, figureFileBig=km3bseb3dYA+M7PeC1dYMQ==, tableContent=null), ArticleFig(id=1207064329392833007, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=EN, label=Fig. 3, caption=Volcano diagrams of differentially expressed genes in 3 gene chip data sets on diabetes with cardiovascular complications, figureFileSmall=KeUr6OplYh8ju0p1NzZfBQ==, figureFileBig=3EXWFBbhgUd2cdDBpGvc6A==, tableContent=null), ArticleFig(id=1207064329522856440, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=CN, label=图3, caption=3个基因芯片数据集中糖尿病合并心血管并发症的差异基因火山图, figureFileSmall=KeUr6OplYh8ju0p1NzZfBQ==, figureFileBig=3EXWFBbhgUd2cdDBpGvc6A==, tableContent=null), ArticleFig(id=1207064329598353916, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=EN, label=Fig. 4, caption=Cluster diagrams of differentially expressed genes in 3 gene chip data sets on diabetes with cardiovascular complications, figureFileSmall=3t7McMQJBO5tk8AY1+MCxA==, figureFileBig=RysNJSvIbgWl67ciCc5iQQ==, tableContent=null), ArticleFig(id=1207064329673851395, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=CN, label=图4, caption=3个基因芯片数据集中糖尿病合并心血管并发症的差异基因聚类图, figureFileSmall=3t7McMQJBO5tk8AY1+MCxA==, figureFileBig=RysNJSvIbgWl67ciCc5iQQ==, tableContent=null), ArticleFig(id=1207064329757737481, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=EN, label=Fig. 5, caption=PPI network diagram (A) and topological map (B) of core genes in treatment of diabetes with cardiovascular complications with A.m-A.s combination, figureFileSmall=WmG4eTzCvLz/JmfvkKO25w==, figureFileBig=LLqmjpVhj7jIHNo6D3U9xg==, tableContent=null), ArticleFig(id=1207064329824846351, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=CN, label=图5, caption=芪归药对治疗糖尿病合并心血管并发症的关键基因PPI网络图(A)及拓扑图(B), figureFileSmall=WmG4eTzCvLz/JmfvkKO25w==, figureFileBig=LLqmjpVhj7jIHNo6D3U9xg==, tableContent=null), ArticleFig(id=1207064329896149526, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=EN, label=Fig. 6, caption=Protein expression of PI3K and Akt3 in cardiomyocytes of SD rats in each group, figureFileSmall=u1FjIOlSvKwvQDpvV4PGFQ==, figureFileBig=063qsJfcP/EAv7V0kdwIZg==, tableContent=null), ArticleFig(id=1207064329971647001, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=CN, label=图6, caption=免疫组化检测各组SD大鼠心肌细胞PI3K和Akt3蛋白表达

NC组. 健康对照组；DM组. 糖尿病合并心血管并发症模型组；AM-AS组. 芪归药对治疗组；PC组. 二甲双胍治疗组；PI3K. 磷脂酰肌醇3-激酶；Akt3. 一种丝氨酸/苏氨酸激酶；与NC组比较，(1)P<0.05，(2)P<0.01；与DM组比较，(3)P<0.05，(4)P<0.01

, figureFileSmall=u1FjIOlSvKwvQDpvV4PGFQ==, figureFileBig=063qsJfcP/EAv7V0kdwIZg==, tableContent=null), ArticleFig(id=1207064330055533092, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=EN, label=Tab. 1, caption=

The retrieval strategy on gene chips for diabetes mellitus with cardiovascular complications in GEO database

, figureFileSmall=null, figureFileBig=null, tableContent=

序号	检索策略
1#	(cardiovascular disease) OR (atherosclerotic heart disease)OR (heart failure) OR (cardiomyopathy)OR (coronary heart disease)
2#	(diabetes) OR (diabetes mellitus) OR (diabetic complications)
3#	(1#) AND (2#)

), ArticleFig(id=1207064330139419175, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1206995861721137496, language=CN, label=表1, caption=

GEO数据库中糖尿病合并心血管并发症相关基因芯片的检索策略

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序号	检索策略
1#	(cardiovascular disease) OR (atherosclerotic heart disease)OR (heart failure) OR (cardiomyopathy)OR (coronary heart disease)
2#	(diabetes) OR (diabetes mellitus) OR (diabetic complications)
3#	(1#) AND (2#)

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