RESUMEN
Gut microbiota disturbance, autophagy dysregulation, and accumulation of hepatic bile acids (BAs) are essential features of liver injury. Therefore, regulating autophagy and BA metabolism are potential strategies for treating liver diseases. Vine tea has been seen beyond a pleasant tea in food science. Our previous study found that vine tea extract (VTE) intervention alleviated acute liver injury (ALI) by restoring gut microbiota dysbiosis. In this study, we aim to investigate the effect of VTE on carbon tetrachloride (CCl4)-induced hepatic autophagy and BA metabolism disorder in mice. The results showed that VTE effectively suppressed CCl4-induced liver fibrosis and hepatic autophagy. LC-MS/MS assay suggested that VTE affected fecal BA production by reducing the fecal BA levels and improving cholestasis in ALI mice. Besides, VTE inhibited BA synthesis, promoted BA transport in the liver, and enhanced BA reabsorption in the ileum through the farnesoid X receptor (FXR)-related signaling pathway. The hepatic expressions of Fxr and Abca1 were elevated by VTE. Finally, the depletion of gut microbiota in ALI mice had a negative impact on abnormal autophagy and BA metabolism. It was also noted that the administration of VTE did not provide any additional improvement in this regard. Overall, VTE ameliorated ALI by reversing hepatic autophagy and abnormal BA metabolism, and the beneficial effects of VTE on liver injury depended on the existence of gut microbiota.
RESUMEN
OBJECTIVE: To explore the specific pharmacological molecular mechanisms of Kai Xin San (KXS) on treating Alzheimer's disease (AD) based on network pharmacology and experimental validation. METHODS: The chemical compounds of KXS and their corresponding targets were screened using the Encyclopedia of Traditional Chinese Medicine (ETCM) database. AD-related target proteins were obtained from MalaCards database and DisGeNET databases. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis. Functional enrichment analysis predicted the potential key signaling pathways involved in the treatment of AD with KXS. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, the predicted key signaling pathway was validated experimentally. Positioning navigation and space search experiments were conducted to evaluate the cognitive improvement effect of KXS on AD rats. Western blot was used to further examine and investigate the expression of the key target proteins related to the predicted pathway. RESULTS: In total, 38 active compounds and 469 corresponding targets of KXS were screened, and 264 target proteins associated with AD were identified. The compound-target-disease and PPI networks identified key active ingredients and protein targets. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested a potential effect of KXS in the treatment of AD via the amyloid beta (A ß)-glycogen synthase kinase-3 beta (GSK3 ß)-Tau pathway. Molecular docking revealed a high binding affinity between the key ingredients and targets. In vivo, KXS treatment significantly improved cognitive deficits in AD rats induced by Aß1-42, decreased the levels of Aß, p-GSK3ß, p-Tau and cyclin-dependent kinase 5, and increased the expressions of protein phosphatase 1 alpha (PP1A) and PP2A (P<0.05 or P<0.01). CONCLUSION: KXS exerted neuroprotective effects by regulating the Aß -GSK3ß-Tau signaling pathway, which provides novel insights into the therapeutic mechanism of KXS and a feasible pharmacological strategy for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Medicamentos Herbarios Chinos , Ratas , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Glucógeno Sintasa Quinasa 3 beta , Farmacología en Red , Simulación del Acoplamiento Molecular , Glucógeno Sintasa Quinasa 3/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
Many studies have proven that autophagy plays a pivotal role in the development of depression and it also affects the expression of GLUT4 in the hypothalamus. Xiaoyaosan has been shown to exert antidepressant effects in a variety of ways, but its underlying mechanism by which Xiaoyaosan regulates autophagy as well as GLUT4 in the hypothalamus remains unclear. Thus, in this study, we established a mouse model of depression induced by chronic unpredictable mild stress (CUMS), and set up autophagy blockade as a control to explore whether Xiaoyaosan exerts antidepressant effect by affecting autophagy. We examined the effects of Xiaoyaosan on behaviors exhibited during the open field test, tail suspension test and sucrose preference test, and the changes in autophagy in hypothalamic neurons as well as changes in GLUT4 and the related indicators of glucose metabolism in CUMS-induced depressive mouse model. We found that CUMS- and 3-MA-induced mice exhibited depressive-like behavioral changes, with decreased LC3 expression and increased p62 expression, suggesting decreased levels of autophagy in the mouse hypothalamus. The expression of GLUT4 was also decreased, and it was closely related to the level of autophagy through Rab8 and Rab10. Nevertheless, after the intervention of Xiaoyaosan, the above changes were effectively reversed. These results show that Xiaoyaosan can regulate the autophagy in hypothalamic neurons and the expression of GLUT4 in depressed mice.