RESUMO
After intensive research on the gut-brain axis, intestinal dysbiosis is considered to be one of the important pathways of cognitive decline. Microbiota transplantation has long been thought to reverse the behavioral changes in the brain caused by colony dysregulation, but in our study, microbiota transplantation seemed to improve only behavioral brain function, and there was no reasonable explanation for the high level of hippocampal neuron apoptosis that remained. Butyric acid is one of the short-chain fatty acids of intestinal metabolites and is mainly used as an edible flavoring. It is commonly used in butter, cheese and fruit flavorings, and is a natural product of bacterial fermentation of dietary fiber and resistant starch in the colon, acting similarly to the small-molecule HDAC inhibitor TSA. The effect of butyric acid on HDAC levels in hippocampal neurons in the brain remains unclear. Therefore, this study used rats with low bacterial abundance, conditional knockout mice, microbiota transplantation, 16S rDNA amplicon sequencing, and behavioral assays to demonstrate the regulatory mechanism of short-chain fatty acids on the acetylation of hippocampal histones. The results showed that disturbance of short-chain fatty acid metabolism led to high HDAC4 expression in the hippocampus and regulated H4K8ac, H4K12ac, and H4K16ac to promote increased neuronal apoptosis. However, microbiota transplantation did not change the pattern of low butyric acid expression, resulting in maintained high HDAC4 expression in hippocampal neurons with continued neuronal apoptosis. Overall, our study shows that low levels of butyric acid in vivo can promote HDAC4 expression through the gut-brain axis pathway, leading to hippocampal neuronal apoptosis, and demonstrates that butyric acid has great potential value for neuroprotection in the brain. In this regard, we suggest that patients with chronic dysbiosis should pay attention to changes in the levels of SCFAs in their bodies, and if deficiencies occur, they should be promptly supplemented through diet and other means to avoid affecting brain health.
Assuntos
Disbiose , Microbioma Gastrointestinal , Camundongos , Ratos , Animais , Ácido Butírico/farmacologia , Ácidos Graxos Voláteis/metabolismo , Bactérias/genética , Bactérias/metabolismo , Hipocampo/metabolismo , Apoptose , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histona Desacetilases/farmacologiaRESUMO
As one of the most common liver diseases, nonalcoholic fatty liver disease (NAFLD) affects almost one-quarter of the world's population. Although the prevalence of NAFLD is continuously rising, effective medical treatments are still inadequate. Radix Polygoni Multiflori (RPM) is a traditional Chinese herbal medicine. As a processed product of RPM, prepared Radix Polygoni Multiflori (PRPM) has been reported to have antioxidant and anti-inflammatory effects. This study investigated whether PRPM treatment could significantly improve NAFLD. We used recent literature, the Herb database and the SwissADME database to isolate the active compounds of PRPM. The OMIM, DisGeNET and GeneCards databases were used to isolate NAFLD-related target genes, and GO functional enrichment and KEGG pathway enrichment analyses were conducted. Moreover, PRPM treatment in NAFLD model mice was evaluated. The results indicate that the target genes are mainly enriched in the AMPK and de novo lipogenesis signaling pathways and that PRPM treatment improves NAFLD disease in model mice. Here, we found the potential benefits of PRPM against NAFLD and demonstrated in vivo and in vitro that PRPM and its ingredient emodin downregulate phosphorylated P38/P38, phosphorylated ERK1/2 and genes related to de novo adipogenesis signaling pathways and reduce lipid droplet accumulation. In conclusion, our findings revealed a novel therapeutic role for PRPM in the treatment of NAFLD and metabolic inflammation.
Assuntos
Medicamentos de Ervas Chinesas , Emodina , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Emodina/farmacologia , Emodina/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Gotículas Lipídicas , Transdução de SinaisRESUMO
With an poorly characterized pathogenesis, Diabetic encephalopathy (DE), one of the main chronic complications of diabetes, would require further studies. Recent studies have proven that DE developing in conjunction with neuronal apoptosis, which is tightly regulated by a variety of processes and involved with histone acetylation and molecular signaling or so on. Though the histone deacetylase 4 (HDAC4), HDAC5, HDAC7, and HDAC9 form class IIa of the HDAC superfamily have been found participating in multiple neurodegenerative diseases, while JNK signaling pathway activation was hypothesized as a key cause leading to cell apoptosis, the correlation between HDAC4 and JNK signaling pathway remains unknown. Studies have found that Radix Polygoni Multiflori (RPM) contains a variety of ingredients, such as TSG and Emodin, could exert antioxidant effects, scavenge free radicals, inhibit cell apoptosis and provide neuroprotection, but the underlying mechanism has not fully elucidated yet. In the present study, we further explored the mechanism by which RPM improves the cognitive function of diabetic rats. Simultaneously, TSG and Emodin were used to stimulate HT-22 hippocampal neurons treated with high glucose. After RPM extracts or TSG, Emodin treatments, the cognitive functions of DE rats improved while the hippocampal neurons arranged tighter and increased. Meanwhile, the expression level of HAT, HDAC, HDAC4 and JNK signaling pathway and apoptosis related genes were decreased. Our finds indicates that RPM and Emodin would inhibit HDAC4 expression, curb the activation of the JNK pathway, reduce hippocampal neuron apoptosis and ultimately meliorate the cognitive function from diabetes. Additionally, the markedly inhibitory effects of the RPM and Emodin on HAT and HDAC was identified for the first time in this study, which provides a basis for future drug targeting histones acetylation development and application.