北京中医药大学学报2025，Vol.48Issue(6)：791-801,11.DOI:10.3969/j.issn.1006-2157.2025.06.009
左归降糖解郁方对糖尿病并发抑郁症大鼠海马H3K18乳酸化修饰表达的影响及其调控基因预测研究
Effect of Zuogui Jiangtang Jieyu Formula on hippocampal H3K18la modification in a rat model of diabetes mellitus complicated with depression and prediction of related regulatory genes
摘要
Abstract
Objective To investigate the effects of Zuogui Jiangtang Jieyu Formula(ZGJTJYF)on histone H3 lysine 18 lactylation(H3K18la)in the hippocampus of rats with diabetes mellitus complicated with depression(DD)and predict the regulatory genes of H3K18la.Methods Male Sprague-Dawley rats were divided into control,model,and positive drug(metformin[0.18g/kg]and fluoxetine[1.8mg/kg])groups,and the three groups were treated with high,medium,and low ZGJTJYF doses(20.52,10.26,and 5.13 g/kg,respectively),with 10 rats per group.After treatment,the forced swimming and water maze tests were performed to assess depressive-like behaviors and cognitive function.An enzyme-linked immunosorbent assay was used to measure blood insulin,glycosylated hemoglobin,lactate levels,and lactate content in the hippocampus.Western blotting was used to detect H3K18la expression in the hippocampus.Cleavage Under Targets and lagmentation(CUT&Tag)experiments targeted hippocampal H3K18la epigenetic modification regions to analyze the transcription factors bound by H3K18la.Kyoto Encyclopedia of Genes and Genomes and Protein-Protein Interaction networks were constructed to identify key pathways and target genes regulated by H3K18la.Results Compared with the normal group,the model group rats showed prolonged immobility time in the forced swim test,increased escape latency in the water maze experiment,decreased target quadrant distance ratio(P<0.01),increased serum lactate content,and decreased lactate content in hippocampal homogenate(P<0.01),as well as decreased H3K18la protein expression in the hippocampus(P<0.01).Compared with the model group,ZGJTJYF reduced the immobility time in the forced swim test and the escape latency in the water maze test(P<0.01),while the distance ratio in the target quadrant increased(P<0.01)in model rats.Lowered fasting blood glucose,insulin,and glycosylated hemoglobin levels(P<0.05,P<0.01)were also observed.ZGJTJYF also increased the lactate content and H3K18la protein expression in hippocampal homogenate(P<0.05,P<0.01).The DNA sequences bound by H3K18la were predominantly enriched at the transcription start sites.ZGJTJYF modulated H3K18la-associated pathways,including cell adhesion junctions,tumor growth factor-beta(TGF-β)signaling,stem cell pluripotency regulation,mitogen-activated protein kinase(MAPK)signaling pathway,and insulin resistance,leading to the identification of 12 target genes.Conclusion ZGJTJYF enhances hippocampal lactate levels and H3K18la modification in DD rats,which may regulate neural cell interactions,neurogenic stem cell function,TGF-β signaling,MAPK signaling,and insulin resistance pathways.关键词
左归降糖解郁方/糖尿病并发抑郁症/乳酸化修饰/组蛋白3赖氨酸残基18/大鼠Key words
Zuogui Jiangtang Jieyu Formula/diabetes mellitus complicated depression/lactylation modification/histone H3 lysine 18(H3K18)/rats分类
中医学引用本文复制引用
杨蕙,李薇,雷诗卉,王瑾茜,柳卓,孟盼,刘林,姜帆,王宇红..左归降糖解郁方对糖尿病并发抑郁症大鼠海马H3K18乳酸化修饰表达的影响及其调控基因预测研究[J].北京中医药大学学报,2025,48(6):791-801,11.基金项目
国家自然科学基金面上项目(No.82474476,No.82104839) （No.82474476,No.82104839）
湖南省自然科学基金项目(No.2024JJ4033,No.2023JJ30476,No.2025JJ80936) （No.2024JJ4033,No.2023JJ30476,No.2025JJ80936）
湖南中医药大学校院联合基金项目(No.2024XYLH026)National Natural Science Foundation of China(Nos.82474476 and 82104839) （No.2024XYLH026）
