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Effects of caffeic acid on epigenetics in the brain of rats with chronic unpredictable mild stress.

ABSTRACT: The present study hypothesized that caffeic acid (3,4?dihydroxycinnamic acid; CaA) may exert antidepressant?like effects in rats with chronic unpredictable mild stress via epigenetic mechanisms, such as DNA methylation and hydroxymethylation. The chronic unpredictable mild stress (CUMS) model was used to analyze the effects of CaA on behavioral phenotypes, and to evaluate the distribution of 5?methylcytosine (5mC) and 5?hydroxymethylcytosine (5hmC) in the hippocampus and prefrontal cortex using immunohistochemistry and immunofluorescence. mRNA levels of the genes encoding brain?derived neurotropic factor (BDNF) and catechol?O?methyltransferase (COMT), and key enzymes regulating DNA methylation [DNA methyltransferase (DNMT)1 and DNMT3A] and hydroxymethylation [Ten?eleven translocation (TET)1?3] were examined using quantitative (q)PCR. Furthermore, enrichment of 5mC and 5hmC at the promotor regions of the Bdnf and Comt genes was quantified using chromatin immunoprecipitation?qPCR. Behavioral data showed that CaA exerted a slight antidepressant?like effect. Bdnf and Comt genes showed differential expression patterns due to CUMS. CaA intervention induced different Dnmt1/Dnmt3a and Tet1/Tet2 mRNA levels in the hippocampus and prefrontal cortex, respectively. CaA regulated the ratio of 5mC/5hmC at the promotor region of the Bdnf and Comt genes and therefore influenced gene expression, which may be a valuable therapeutic option for major depressive disorder (MDD). In conclusion, there were epigenetic changes in the hippocampus and prefrontal cortex in CUMS rats, and CaA may function as a modulator of DNA methylation to regulate gene transcription, thus providing a mechanistic basis for the use of this phytochemical agent in the treatment of MDD.

SUBMITTER: Hu J

PROVIDER: S-EPMC7647007 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Effects of caffeic acid on epigenetics in the brain of rats with chronic unpredictable mild stress.

Hu Jinye J Cao Shuyuan S Zhang Zhan Z Wang Li L Wang Di D Wu Qian Q Li Lei L

Molecular medicine reports 20201016 6

The present study hypothesized that caffeic acid (3,4‑dihydroxycinnamic acid; CaA) may exert antidepressant‑like effects in rats with chronic unpredictable mild stress via epigenetic mechanisms, such as DNA methylation and hydroxymethylation. The chronic unpredictable mild stress (CUMS) model was used to analyze the effects of CaA on behavioral phenotypes, and to evaluate the distribution of 5‑methylcytosine (5mC) and 5‑hydroxymethylcytosine (5hmC) in the hippocampus and prefrontal cortex using ...[more]

PMID: 33173990

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Project description:BACKGROUND:It is known that bioenergetics of aerobic and resistance exercise are not the same but both can effectively improve depression. However, it is not clear whether and how different types of exercise can influence depression through the same metabolic regulatory system. Metabolomics provides a way to study the correlation between metabolites and changes in exercise and/or diseases through the quantitative analysis of all metabolites in the organism. The objective of this study was to investigate the effects of aerobic and resistance training on urinary metabolites by metabolomics analysis in a rodent model of depression. METHODS:Male Sprague-Dawley rats were given chronic unpredictable mild stress (CUMS) for eight weeks. The validity of the modeling was assessed by behavioral indices. After four weeks of CUMS, the rats that developed depression were randomly divided into a depression control group, an aerobic training group and a resistance training group. There was also a normal control group. From week 5, the rats in the exercise groups were trained for 30 min per day, five days per week, for four weeks. The urine samples were collected pre and post the training program, and analyzed by proton nuclear magnetic resonance (1H-NMR) spectroscopy. RESULTS:Both types of training improved depression-like behavior in CUMS rats. Compared with normal control, 21 potential biomarkers were identified in the urine of CUMS rats, mainly involved in energy, amino acids and intestinal microbial metabolic pathways. Common responses to the training were found in the two exercise groups that the levels of glutamine, acetone and creatine were significantly recalled (all P<0.05) Aerobic training also resulted in changes in pyruvate and trigonelline, while resistance training modified ?-Oxoglutarate, citric acid, and trimethylamine oxide (all P<0.05). CONCLUSIONS:Aerobic and resistance training resulted in common effects on the metabolic pathways of alanine-aspartate-glutamate, TCA cycle, and butyric acid. Aerobic training also had effects on glycolysis or gluconeogenesis and pyruvate metabolism, while resistance training had additional effect on intestinal microbial metabolism.

Project description:Purpose:In our present study, a rat depression model induced by 6 weeks of chronic unpredictable mild stress (CUMS) was established, and we investigated how Xiaoyaosan affects the intestinal permeability of depressed rats and alterations in tight-junction proteins (TJs) involved in this process. Methods:The rat depression model was established using CUMS for 6 consecutive weeks. A total of 40 healthy male Sprague-Dawley rats were randomly sorted into four groups: the control group, CUMS group, Xiaoyaosan group, and fluoxetine group. All groups, excluding the control group, were subjected to the 6-week CUMS program to generate the depression model. Body weight, food intake, and behaviors were observed during the modeling period. Histopathological alterations of colon tissue were evaluated by hematoxylin-eosin staining (H&E), and mucus-containing goblet cells were detected by periodic acid-Schiff (PAS) staining. The ultrastructural morphology of colonic mucosa was observed by transmission electron microscopy. Furthermore, immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to determine the expression of TJs. The concentrations of 5-hydroxytryptamine (5-HT) in the hypothalamus and colon were also assessed using enzyme-linked immunosorbent assay (ELISA). Results:Treatment of depressed rats with Xiaoyaosan alleviated depression-like behaviors as demonstrated by increases in the total distance traveled, the number of entries into the central area in the open field test, the duration spent in the central area, and sucrose preference. Xiaoyaosan treatment also increased body weight gain and food intake in depressed rats. Moreover, Xiaoyaosan treatment effectively improved the colonic pathological and ultrastructural changes, upregulated the expression of ZO-1, occludin, and claudin-1 in the colon, and increased 5-HT levels in the hypothalamus and colonic mucosa. Conclusions:Xiaoyaosan treatment attenuates depression-like behaviors caused by CUMS and ameliorates CUMS-induced abnormal intestinal permeability, which may be associated with the expression of TJs. These results suggest that Xiaoyaosan exerts an antidepressant effect that may be related to an improvement of intestinal barrier function via the brain-gut axis.

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Effects of caffeic acid on epigenetics in the brain of rats with chronic unpredictable mild stress.

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Effects of caffeic acid on epigenetics in the brain of rats with chronic unpredictable mild stress.

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