Realgar-Induced Neurotoxicity: Crosstalk Between the Autophagic Flux and the p62-NRF2 Feedback Loop Mediates p62 Accumulation to Promote Apoptosis.

Realgar is a traditional Chinese medicine that contains arsenic. It has been reported that the abuse of medicine-containing realgar has potential central nervous system (CNS) toxicity, but the toxicity mechanism has not been elucidated. In this study, we established an in vivo realgar exposure model and selected the end product of realgar metabolism, DMA, to treat SH-SY5Y cells in vitro. Many assays, including behavioral, analytical chemistry, and molecular biology, were used to elucidate the roles of the autophagic flux and the p62-NRF2 feedback loop in realgar-induced neurotoxicity. The results showed that arsenic could accumulate in the brain, causing cognitive impairment and anxiety-like behavior. Realgar impairs the ultrastructure of neurons, promotes apoptosis, perturbs autophagic flux homeostasis, amplifies the p62-NRF2 feedback loop, and leads to p62 accumulation. Further analysis showed that realgar promotes the formation of the Beclin1-Vps34 complex by activating JNK/c-Jun to induce autophagy and recruit p62. Meanwhile, realgar inhibits the activities of CTSB and CTSD and changes the acidity of lysosomes, leading to the inhibition of p62 degradation and p62 accumulation. Moreover, the amplified p62-NRF2 feedback loop is involved in the accumulation of p62. Its accumulation promotes neuronal apoptosis by upregulating the expression levels of Bax and cleaved caspase-9, resulting in neurotoxicity. Taken together, these data suggest that realgar can perturb the crosstalk between the autophagic flux and the p62-NRF2 feedback loop to mediate p62 accumulation, promote apoptosis, and induce neurotoxicity. Realgar promotes p62 accumulation to produce neurotoxicity by perturbing the autophagic flux and p62-NRF2 feedback loop crosstalk.

Regulatory effect of gut microbes on blood pressure.

Hypertension is an important global public health issue because of its high morbidity as well as the increased risk of other diseases. Recent studies have indicated that the development of hypertension is related to the dysbiosis of the gut microbiota in both animals and humans. In this review, we outline the interaction between gut microbiota and hypertension, including gut microbial changes in hypertension, the effect of microbial dysbiosis on blood pressure (BP), indicators of gut microbial dysbiosis in hypertension, and the microbial genera that affect BP at the taxonomic level. For example, increases in Lactobacillus, Roseburia, Coprococcus, Akkermansia, and Bifidobacterium are associated with reduced BP, while increases in Streptococcus, Blautia, and Prevotella are associated with elevated BP. Furthermore, we describe the potential mechanisms involved in the regulation between gut microbiota and hypertension. Finally, we summarize the commonly used treatments of hypertension that are based on gut microbes, including fecal microbiota transfer, probiotics and prebiotics, antibiotics, and dietary supplements. This review aims to find novel potential genera for improving hypertension and give a direction for future studies on gut microbiota in hypertension.

Habitual tea consumption and 5-year incident metabolic syndrome among older adults: a community-based cohort study.

BACKGROUND: The effect of tea consumption on metabolic syndrome (MetS) remains controversial. The objective of this study is to examine the prospective association of tea consumption with 5-year incident MetS among aged population in China. METHODS: This analysis included 3005 Chinese adults aged 60 years or older who were free of MetS at baseline examination. MetS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III. Information regarding tea consumption was collected via an interviewer-administrated questionnaire. The prospective associations between tea consumption at baseline and 5-year incident MetS, as well as its individual components, were assessed by multiple logistic regression models. RESULTS: Of the 3005 participants free of MetS at baseline, 406 participants (cumulative incidence: 13.5%) developed MetS at the 5-year follow-up examination. In multiple logistic regressions, 5-year cumulative incidence of MetS was found to be higher in those who drank tea more than 5 times per week as compared with non-habitual drinkers (OR = 1.38, 95% CI: 1.05-1.82; P = 0.02). This relationship still existed in men (OR = 1.43, 95%CI: 1.00-2.01; P = 0.05) when stratified by gender. Among the five major components of MetS, low high-density lipoprotein cholesterol was observed in men, while high body mass index, elevated blood pressure and the presence of diabetes mellitus were significant in women. CONCLUSIONS: High-frequent tea consumption increased the risk of MetS among older Chinese adults. These findings may add novel knowledge to the current studies regarding the controversial effect of tea consumption on cardiovascular and metabolic health among the aged population.

Identification of neurotoxicity markers induced by realgar exposure in the mouse cerebral cortex using lipidomics.

Realgar is a traditional Chinese medicine containing arsenic and has neurotoxicity. This study used realgar exposure mice model, neurobehavioral tests, analytical chemistry, molecular biology and nontargeted lipidomics to explore the mechanism of realgar damages the nervous system. The arsenic contained in realgar passed through the BBB and accumulated in the brain. Neurons, synapses and myelin showed abnormal changes in the cerebral cortex. The number of autophagosomes were incresed as well as levels of MDA, Lp-PLA2, and cPLA2 but the CAT level was significant reduced. Finally, the cognition and memory of mice were decreased. Nontargeted lipidomics detected 34 lipid subclasses including 1603 lipid molecules. The levels of the LPC and LPE were significantly increased. Under the condition of variable importance for the projection (VIP)>1 and P < 0.05, only 28 lipid molecules satisfied the criteria. The lipid molecular markers SM (d36:2), PE (18:2/22:6) and PE (36:3) which were filtered by receiver operating characteristic (ROC) curve (AUC>0.8 or AUC<0.2) were used to identify the neurotoxicity induced by realgar. Therefore, realgar induces neurotoxicity through exacerbating oxidative damage and lipid dysfunction. Providing research basis for the clinical diagnosis and treatment of realgar-induced neurotoxicity.

(-)-Gossypol-enriched cottonseed oil inhibits proliferation and adipogenesis of human breast pre-adipocytes.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women. Obesity is an important risk factor for developing breast cancer and is one of few risk factors that women can modify to prevent cancer. (-)-Gossypol-enriched cottonseed oil [(-)-GPCSO] contains 65% (-)-gossypol and 35% (+)-gossypol. Previous studies have demonstrated that both (-)-gossypol and (-)-GPCSO have potent anticancer activity against multiple types of cancer, including breast cancer. In addition, (-)-GPCSO reduced body weight gain and food intake in young female rats. However, the role of (-)-GPCSO on adipogenesis in human breast pre-adipocytes remains unclear. MATERIALS AND METHODS: Primary human breast pre-adipocytes were induced to differentiate in adipogenic medium in the presence of (-)-GPCSO. The proliferation of pre-adipocytes was determined with a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2-H-tetrazolium (MTS) assay. Lipid accumulation and glycerol 3-phosphate dehydrogenase (GPDH) activity were measured during adipocyte differentiation. mRNA expression of cyclin-D1, B-cell lymphoma-2 (BCL-2), Peroxisome Proliferator-Activated Receptor-γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα) and leptin was analyzed by real-time PCR. RESULTS: (-)-GPCSO inhibited proliferation of pre-adipocytes and down-regulated the expression of cyclin-D1 and BCL-2. (-)-GPCSO also significantly decreased adipogenesis, as determined by inhibition of GPDH activity, triglyceride content (TG), and down-regulation of the expression of PPARγ, C/EBPα and leptin. CONCLUSION: These findings suggest that (-)-GPCSO has the potential as a food supplement to inhibit adipogenesis, and therefore, reduce obesity.