In silico and in vivo experiments of Huperzine A modulating the development of obstructive sleep apnea by transcriptionally regulating pyruvate carboxylase expression via retinoid X receptor alpha.

Abstract

IntroductionThis study investigated the molecular mechanism by which HuA influences the expression of pyruvate carboxylase via retinoid X receptor alpha (RXRA), thereby affecting the progression of obstructive sleep apnea (OSA).MethodsBioinformatics analysis including screening of differentially expressed genes (DEGs) and searching the downstream target genes of RXRA were conducted. Cognitive function, neuronal damage, oxidative stress, and inflammation were evaluated in chronic intermittent hypoxia (CIH) mouse models. The Morris water maze test was used to assess swimming path length, escape latency, and platform crossing times. H&E and Nissl staining was performed to evaluate pathological changes and neuronal counts in brain tissue. ELISA was utilized to measure the oxidative stress levels and inflammatory cytokines. RXRA enrichment in the pyruvate carboxylase promoter region in CIH was assessed using Chromatin Immunoprecipitation (ChIP), and the effect of RXRA on pyruvate carboxylase promoter activity was analyzed using dual-luciferase assay.ResultsRXRA was identified as a potential regulatory target gene of HuA. Pyruvate carboxylase was identified as a RXRA target gene and a significant DEG in OSA. CIH-induced cognitive impairment, neuronal damage, oxidative stress, and inflammation in mice, while such symptoms were alleviated by HuA treatment. In OSA, suppression of RXRA expression led to reduced pyruvate carboxylase expression. HuA treatment enhanced RXRA expression, thereby promoting pyruvate carboxylase expression. HuA alleviated CIH-induced cognitive impairment, neuronal damage, oxidative stress, and inflammation via the RXRA/pyruvate carboxylase axis.ConclusionIn summary, HuA alleviates CIH-induced cognitive impairment, neuronal damage, oxidative stress, and inflammation by promoting the RXRA/pyruvate carboxylase axis.