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
10.3969/j.issn.1006-2157.2025.06.009
- VernacularTitle: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
- Author:
Hui YANG
1
;
Wei LI
1
;
Shihui LEI
1
;
Jinxi WANG
1
;
Zhuo LIU
2
;
Pan MENG
2
;
Lin LIU
1
;
Fan JIANG
1
;
Yuhong WANG
3
Author Information
1. The First Hospital of Hunan University of Chinese Medicine
2. The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine
3. The Science and Technology Innovation Center, Hunan University of Chinese Medicine
- Publication Type:Journal Article
- Keywords:
Zuogui Jiangtang Jieyu Formula;
diabetes mellitus complicated depression;
lactylation modification;
histone H3 lysine 18 (H3K18);
rats
- From:
Journal of Beijing University of Traditional Chinese Medicine
2025;48(6):791-801
- CountryChina
- Language:Chinese
-
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 [0.18 g/kg] and fluoxetine [1.8 mg/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.
