RESUMEN
The precise mechanisms underlying the inhibitory effects of SIRT3, a mitochondrial sirtuin protein, on hepatocellular carcinoma (HCC) development, as well as its impact on mitochondrial respiration, remain poorly understood. We assessed sirtuins 3 (SIRT3) levels in HCC tissues and Huh7 cells cultured under hypoxic condition. We investigated the effects of SIRT3 on cell proliferation, glycolytic metabolism, mitochondrial respiration, mitophagy, and mitochondrial biogenesis in Huh7 cells. Besides, we explored the potential mechanisms regulating SIRT3 expression in hypoxically cultured Huh7 cells. Gradual reduction in SIRT3 expressions were observed in both adjacent tumor tissues and tumor tissues. Similarly, SIRT3 expressions were diminished in Huh7 cells cultured under hypoxic condition. Forced expression of SIRT3 attenuated the growth of hypoxically cultured Huh7 cells. SIRT3 overexpression led to a decrease in extracellular acidification rate while increasing oxygen consumption rate. SIRT3 downregulated the levels of hexokinase 2 and pyruvate kinase M2. Moreover, SIRT3 enhanced mitophagy signaling, as indicated by mtKeima, and upregulated key proteins involved in various mitophagic pathways while reducing intracellular reactive oxygen species levels. Furthermore, SIRT3 increased proxisome proliferator-activated receptor-gamma coactivator 1α levels and the amount of mitochondrial DNA in Huh7 cells. Notably, ß-catenin expressions were elevated in Huh7 cells cultured under hypoxic condition. Antagonists and agonists of ß-catenin respectively upregulated and downregulated SIRT3 expressions in hypoxically cultured Huh7 cells. The modulationsof glycolysis and mitochondrial respiration represent the primary mechanism through which SIRT3, suppressed by ß-catenin, inhibits HCC cell proliferation.
RESUMEN
BACKGROUND: Emerging evidence has linked daytime napping with the risk of cardiovascular events. Cardiac arrhythmias are considered an early clinical stage for cardiovascular diseases. However, whether napping frequency is associated with incident arrhythmias remains unknown. OBJECTIVE: This study aimed to prospectively investigate the association between napping frequency and cardiac arrhythmias. METHODS: Daytime napping frequency was self-reported in response to touchscreen questionnaires. The primary outcomes were incident arrhythmias including atrial fibrillation/flutter (AF/Af), ventricular arrhythmia, and bradyarrhythmia. Cox regression analysis was conducted on the basis of 491,117 participants free of cardiac arrhythmias from the UK Biobank. The 2-sample mendelian randomization (MR) and 1-sample MR were used to ensure a causal effect of genetically predicted daytime napping on the risk of arrhythmias. RESULTS: During a median follow-up of 11.91 years, 28,801 incident AF/Af cases, 4132 incident ventricular arrhythmias, and 11,616 incident bradyarrhythmias were documented. Compared with never/rarely napping, usually napping was significantly associated with higher risks of AF/Af (hazard ratio, 1.141; 95% CI, 1.083-1.203) and bradyarrhythmia (hazard ratio, 1.138; 95% CI, 1.049-1.235) but not ventricular arrhythmia after adjustment for various covariates. The 2-sample MR and 1-sample MR analysis showed that increased daytime napping frequency was likely to be a potential causal risk factor for AF/Af in FinnGen (odds ratio, 1.626; 95% CI, 1.061-2.943) and bradyarrhythmia in the UK Biobank (odds ratio, 1.005; 95% CI, 1.002-1.008). CONCLUSION: The results of this study add to the burgeoning evidence of an association between daytime napping frequency and an increased risk of cardiac arrhythmias including AF/Af, ventricular arrhythmia, and bradyarrhythmia.
