Chronic unpredictable mild stress (CUMS) can not only lead to depression-like behavior but also change the composition of the gut microbiome. Regulating the gut microbiome can have an antidepressant ...effect, but the mechanism by which it improves depressive symptoms is not clear. Short-chain fatty acids (SCFAs) are small molecular compounds produced by the fermentation of non-digestible carbohydrates. SFCAs are ubiquitous in intestinal endocrine and immune cells, making them important mediators of gut microbiome-regulated body functions. The balance between the pro- and anti-inflammatory microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. Non-absorbable antibiotic rifaximin can regulate the structure of the gut microbiome. We hypothesized that rifaximin protects against stress-induced inflammation and depression-like behaviors by regulating the abundance of fecal microbial metabolites and the microglial functions.
We administered 150 mg/kg rifaximin intragastrically to rats exposed to CUMS for 4 weeks and investigated the composition of the fecal microbiome, the content of short-chain fatty acids in the serum and brain, the functional profiles of microglia and hippocampal neurogenesis.
Our results show that rifaximin ameliorated depressive-like behavior induced by CUMS, as reflected by sucrose preference, the open field test and the Morris water maze. Rifaximin increased the relative abundance of Ruminococcaceae and Lachnospiraceae, which were significantly positively correlated with the high level of butyrate in the brain. Rifaximin increased the content of anti-inflammatory factors released by microglia, and prevented the neurogenic abnormalities caused by CUMS.
These results suggest that rifaximin can regulate the inflammatory function of microglia and play a protective role in pubertal neurodevelopment during CUMS by regulating the gut microbiome and short-chain fatty acids.
Early life stress alters brain‐derived neurotrophic factor (BDNF) promoter IV methylation and BDNF expression, which is closely related to the pathophysiological process of depression. However, the ...role of abnormal methylation of BDNF induced by stress during adolescence due to depression has not yet been clarified. In this study, adolescent mice were exposed to chronic unpredictable mild stress (CUMS). Depression‐like behaviors, BDNF promoter IV methylation, expression of DNA methyltransferases (DNMTs), demethylation machinery enzymes, BDNF protein levels, and neuronal development in the prefrontal cortex (PFC) and hippocampus (HIP) were assessed in adolescent and adult mice. The DNMT inhibitor, 5‐Aza‐2‐deoxycytidine (5‐AzaD), was used as an intervention. Stress in adolescence induces behavioral dysfunction, elevated methylation levels of BDNF promoter IV, changes in the expression of DNMT, and demethylation machinery enzymes in adolescent and adult mice. Additionally, the stress in adolescence induced lower levels of BDNF and abnormal hippocampal doublecortin (DCX) expression in adolescent and adult mice. However, DNMT inhibitor treatment in adolescent‐stressed mice relieved the abnormal behaviors, normalized the methylation level of BDNF promoter IV, BDNF protein expression, expression of DNMTs, and demethylation machinery enzymes, and improved the neuronal development of adult mice. These results suggest that stress in adolescence induces short‐ and long‐term hypermethylation of BDNF promoter IV, which is regulated by DNMTs, and leads to the development of depression.
We proposed methylation of brain‐derived neurotrophic factor (BDNF) promoter IV involved the depression and depression‐like behaviors: stress in the adolescent period induced alterations of the expression of DNA methyltransferase (DNMT), ten‐eleven translocation enzymes (Tet), and growth arrest and DNA damage 45 (Gadd45), which cause the abnormal of BDNF promoter IV methylation. The abnormal of BDNF promoter IV methylation alters the transcription repression of BDNF, doublecortin‐positive (DCX+) hippocampal immature neurons, and the development of dendrites. Additionally, these effects induce depression‐like behaviors in adulthood. We think these findings provide a novel target for preventing depression in advance.
Rationale and objective
Post-traumatic stress disorder (PTSD) is a prevalent and debilitating psychiatric disorder. However, its specific etiological mechanism remains unclear. Previous studies have ...shown that traumatic stress changes metabotropic glutamate receptor 5 (mGluR5) expression in the hippocampus (HIP) and prefrontal cortex (PFC). More importantly, mGluR5 expression is often accompanied by alterations in brain-derived neurotrophic factor (BDNF). Furthermore, BDNF/tropomyosin-associated kinase B (TrkB) signaling plays multiple roles, including roles in neuroplasticity and antidepressant activity, by regulating glutamate transporter-1 (GLT-1) expression. This study aims to explore the effects of inhibiting mGluR5 on PTSD-like behaviors and BDNF, TrkB, and GLT-1 expression in the HIP and PFC of inevitable foot shock (IFS)-treated rats.
Methods
Seven-day IFS was used to establish a PTSD rat model, and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (10 mg/kg, intraperitoneal injection) was used to inhibit the activity of mGluR5 during IFS in rats. After modeling, behavioral changes and mGluR5, BDNF, TrkB, and GLT-1 expression in the PFC and HIP were examined.
Results
First, the IFS procedure induced PTSD-like behavior. Second, IFS increased the expression of mGluR5 and decreased BDNF, TrkB, and GLT-1 expression in the PFC and HIP. Third, the mGluR5 antagonist blocked the above behavioral and molecular alterations.
Conclusions
mGluR5 was involved in IFS-induced PTSD-like behavior by changing BDNF, TrkB, and GLT-1 expression.
•Traumatic stress in adolescence leads to immediate and long-term mental disorders.•Traumatic stress in adolescence causes morphological changes of neuron in amygdala.•Traumatic stress in adolescence ...leads to lower BDNF level and increased H3K9me2 level in the amygdala.
Early detrimental experiences increase the risk of psychiatric disorders, including posttraumatic stress disorder (PTSD). In a previous experiment, we demonstrated that traumatic stress in adolescence triggers changes in the expression of the epigenetic marker H3K9me2 in the hippocampus and prefrontal cortex of adolescent and adult rats, which suppresses transcription of the brain-derived neurotrophic factor (Bdnf) gene that promotes dendrite development and synaptic growth. However, corresponding changes in the amygdala in response to traumatic stress in early life have not yet been fully elucidated. In the current study, we used the inescapable foot shock (IFS) procedure to establish a PTSD model. Half an hour after the end of electric shocks, intraperitoneal injection of the G9a enzyme inhibitor Unc0642, a small molecule inhibitor of EHMT2 that can decrease H3K9me2 expression, was applied to reverse the corresponding epigenetic changes. Exploratory behaviors, anxiety-like behavior, social communication ability, spatial exploration and memory were determined using the open field test (OFT), elevated plus maze (EPM) test, three-chamber sociability test (SIT), Morris water maze (MWM) test, and Y maze test (YMZ), respectively. Additionally, the levels of H3K9me2 and BDNF were measured by quantitative reverse transcription-polymerase chain reaction (qPCR) and Western blotting. Furthermore, neuronal development was examined using Golgi staining. The results showed that the IFS procedure induced anxiety-like and depression-like behaviors, social skills dysfunction, and spatial exploration and memory disorders. It also decreased the mRNA expression of BDNF and BDNF and increased the expression of H3K9me2 in the amygdala. More importantly, compared to unstressed animals, traumatic stress during adolescence induced dendrite maldevelopment in adolescent and adult rats. In summary, the present study indicates that early-life stress alters the epigenetic marker expression of H3K9me2 and decreases levels of BDNF in the amygdala, resulting in dendrite maldevelopment and a higher risk of mental disorders.
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Chronic unpredictable mild stress (CUMS) can induce depressive behaviours and alter the composition of the gut microbiome. Although modulating gut microbiota can improve depression-like behaviour in ...rats, the mechanism of action is unclear. Additionally, gut microbiota can affect brain function through the neuroendocrine pathway. This pathway may function by regulating the secretion of neurotransmitters such as tryptophan (TRP). Metabolites of TRP, such as 5-hydroxytryptamine (5-HT) and kynurenine (KYN), are related to the pathophysiological process of depression. Indoleamine-2, 3-dioxygenase-1 (IDO1) and Tryptophan hydroxylase 2 (TPH2) are the key rate-limiting enzymes in TRP metabolism and play an important role in KYN and 5-HT metabolism.
Rats were subjected to four weeks of CUMS and given rifaximin150 mg/kg by oral gavage daily. After modelling, we investigated the rat's behaviours, composition of the faecal microbiome, neurotransmitter metabolism and key metabolic enzymes of the TRP pathway in the hippocampus (HIP).
Rifaximin administration improved depressive behaviour in rats, corrected intestinal microbiota disorders and HIP TRP metabolism and regulated the expression of IDO1 and TPH2 in the HIP.
Rifaximin improves depression-like behaviour in CUMS rats by influencing the gut microbiota and tryptophan metabolism.
•Rifaximin can improve the imbalance of gut microbiota caused by CUMS.•Rifaximin ameliorates hippocampal tryptophan pathway metabolic disorders caused by CUMS.•Gut microbiota is closely related to tryptophan metabolism in the hippocampus.
We aimed to investigate the correlation between lymphocyte subpopulations expressing inhibitor receptors, IL-6 levels, and the efficacy of immunotherapy in patients with hepatocellular carcinoma. ...Blood samples were prospectively collected before and after immunotherapy from patients with intermediate and advanced hepatocellular carcinoma who were treated with immunotherapy at the Fifth Medical Center of the PLA General Hospital from August 2022 to October 2023. According to the efficacy of the patients, patients were divided into effective and ineffective groups, with 40 in the effective group and 44 in the ineffective group. We compared changes in lymphocyte subsets and IL-6 levels between the two groups. Optimal cut-off value was determined using ROC curves. Then, patients were categorized into high and low groups based on cut-off value, and the disease control rates and progression free survival were compared. Before immunotherapy, there were no significant differences in the baseline levels of lymphocyte subsets (PD1 + TIM3 + T/T, TIGIT + T/T, TIM3 + T/T, CTLA4 + T/T, LAG3 + T/T, PD1 + T/T) and IL-6 between the two groups (P > 0.05). After immunotherapy, the levels of PD1 + TIM3 + T/T, TIGIT + T/T, and IL-6 in the effective group were lower than those in the ineffective group and these differences were statistically significant (P = 0.001, P = 0.008, P = 0.000). However, the levels of other lymphocyte subsets showed no significant difference. Using the ROC curve to assess efficacy prediction, PD1 + TIM3 + T/T, TIGIT + T/T and IL-6 demonstrated high predictive ability (AUC = 0.79, AUC = 0.81, AUC = 0.78). The predictive value of efficacy was further improved when all three factors were combined (AUC = 0.92, P = 0.000). Based on the ROC curve, we identified optimal cut-off value for three factors. Notably, patients with values below the optimal cut-off value had higher disease control rate and progression free survival. The levels of PD1 + TIM3 + T/T, TIGIT + T/T, and IL-6 after 2 cycles of immunotherapy may serve as predictors of treatment efficacy in patients with hepatocellular carcinoma.
In this study, a new modified triaxial electrospinning is implemented to generate an Eudragit S100 (ES100)-based core–shell structural nanofiber (CSF), which is loaded with aspirin. The CSFs have a ...straight line morphology with a smooth surface, an estimated average diameter of 740 ± 110 nm, and a clear core–shell structure with a shell thickness of 65 nm, as disclosed by the scanning electron microscopy and transmission electron microscopy results. Compared to the monolithic composite nanofibers (MCFs) produced using traditional blended single-fluid electrospinning, aspirin presented in both of them amorously owing to their good compatibility. The CSFs showed considerable advantages over the MCFs in providing the desired drug-controlled-release profiles, although both of them released the drug in an erosion mechanism. The former furnished a longer time period of time-delayed-release and a smaller portion released during the first two-hour acid condition for protecting the stomach membranes, and also showed a longer time period of aspirin-extended-release for avoiding possible drug overdose. The present protocols provide a polymer-based process-nanostructure-performance relationship to optimize the reasonable delivery of aspirin.
Increased understanding of the functions of lactate has suggested a close relationship between lactate homeostasis and normal brain activity because of its importance as an energy source and ...signaling molecule. Here we show that lactate levels affect adult hippocampal neurogenesis. Cerebrovascular-specific deletion of PTEN causes learning and memory deficits and disrupts adult neurogenesis with accompanying lactate accumulation. Consistently, administering lactate to wild-type animals impairs adult hippocampal neurogenesis. The endothelial PTEN/Akt pathway increases monocarboxylic acid transporter 1 (MCT1) expression to enhance lactate transport across the brain endothelium. Moreover, cerebrovascular overexpression of MCT1 or deletion of Akt1 restores MCT1 expression, decreases lactate levels, and normalizes hippocampal neurogenesis and cognitive function in PTEN mutant mice. Together, these findings delineate how the brain endothelium maintains lactate homeostasis and contributes to adult hippocampal neurogenesis and cognitive functions.
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•Brain ECs maintain adult hippocampal neurogenesis by regulating lactate homeostasis•Loss of endothelial PTEN or MCT1 impairs hippocampal neurogenesis and cognition•The PTEN/Akt pathway upregulates MCT1 to transport lactate across the brain endothelium•PTEN mutant mouse phenotypes are rescued by MCT1 overexpression or Akt1 deletion
Lactate is increasingly recognized as an important signaling molecule in the brain. Wang et al. show that the PTEN/Akt pathway in endothelial cells upregulates MCT1 to enhance lactate transport across the brain endothelium, which is critical for lactate homeostasis, adult hippocampal neurogenesis, and cognitive function.
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