Inhibition of RhoA/ROCK signalling pathway activity improves neural damage and cognitive deficits in the fluorosis model.

Excessive fluoride intake poses health risks to humans and animals. Many studies have indicated that fluoride exposure can damage the cytoskeleton and synapses, which has negative effects on the intellectual development of humans and animals. Our previous study suggested that the RhoA/ROCK signalling pathway is activated by NaF exposure in HT-22 cells and plays a vital role in cytoskeletal assembly and synaptogenesis. However, the mechanism underlying RhoA/ROCK-mediated cytoskeletal injury induced by fluoride remains unclear. In this study, Neuro-2A cells and ICR mice were used to investigate the effects of RhoA/ROCK activation inhibition on NaF-induced synaptic dysfunction and cognitive impairment. We detected the expression of GAP, RhoA, ROCK1/2, and (p)-MLC in vivo and in vitro model. The results showed that NaF exposure activated the RhoA/ROCK/MLC signalling pathway. We measured the effects of RhoA/ROCK inhibition on synaptic injury and intellectual impairment induced by NaF exposure. In vitro, Y-27632 suppressed activated RhoA/ROCK, attenuated morphological and ultrastructural damage, and decreased the survival rate and synapse-functional protein expression caused by NaF. In vivo, the results showed that the RhoA/ROCK/MLC pathway was inhibited by fasudil and improved pathological damage in the hippocampus, cognitive impairment, and decreased expression of neurofunctional proteins induced by NaF. Overall, these results suggest that fasudil and Y-27632 can reverse neurotoxicity caused by fluoride exposure. Furthermore, inhibition of RhoA/ROCK may be a future treatment for CNS injury, and more detailed studies on other neurodegenerative disease models are required to confirm its effectiveness.

Joint effect of alcohol drinking and tobacco smoking on all-cause mortality and premature death in China: A cohort study.

BACKGROUND: Tobacco smoking and alcohol drinking are associated with several diseases, and studies on the joint effects of smoking and drinking are rare. OBJECTIVE: This study investigates the joint effects of tobacco smoking and alcohol drinking on all-cause and premature mortality in a contemporary cohort. METHODS: The China Health and Retirement Longitudinal Study (CHARLS) is an ongoing nationally representative survey of subjects aged over 45 years in China that was performed every two years for a total of three waves from 2011 to 2015 in China. We used weighted logistic regression models to estimate the joint effects of tobacco smoking and alcohol drinking on all-cause and premature mortality. RESULTS: After adjusting for prespecified confounders, the odds ratios (ORs) of all-cause mortality were 1.51 (95% CI: 1.09-2.10) and 1.47 (95% CI: 1.03-2.08) in smokers and smokers/drinkers, respectively. Compared with nonsmokers/nondrinkers, the OR of smokers/drinkers for premature death was 3.14 (95% CI: 1.56-6.34). In the female subgroup, there was an approximately 5-fold (OR = 4.95; 95% CI: 2.00-12.27) odds of premature mortality for smokers/drinkers compared to nonsmokers/nondrinkers. CONCLUSION: This study found a joint effect of tobacco smoking and alcohol drinking on all-cause and premature mortality among a contemporary and nationally representative cohort in China. Our results suggested that the joint effects were more pronounced in women, but further research is needed.