Background and Purpose-The identification of a neuroprotective drug for stroke remains elusive. Given that mitochondria play a key role both in maintaining cellular energetic homeostasis and in triggering the activation of cell death pathways, we evaluated the efficacy of newly identified inhibitors of cytochrome c release in hypoxia/ischemia induced cell death. We demonstrate that methazolamide and melatonin are protective in cellular and in vivo models of neuronal hypoxia. Methods-The effects of methazolamide and melatonin were tested in oxygen/glucose deprivation-induced death of primary cerebrocortical neurons. Mitochondrial membrane potential, release of apoptogenic mitochondrial factors, pro-IL-1␤ processing, and activation of caspase -1 and -3 were evaluated. Methazolamide and melatonin were also studied in a middle cerebral artery occlusion mouse model. Infarct volume, neurological function, and biochemical events were examined in the absence or presence of the 2 drugs. Results-Methazolamide and melatonin inhibit oxygen/glucose deprivation-induced cell death, loss of mitochondrial membrane potential, release of mitochondrial factors, pro-IL-1␤ processing, and activation of caspase-1 and -3 in primary cerebrocortical neurons. Furthermore, they decrease infarct size and improve neurological scores after middle cerebral artery occlusion in mice. Conclusions-We demonstrate that methazolamide and melatonin are neuroprotective against cerebral ischemia and provide evidence of the effectiveness of a mitochondrial-based drug screen in identifying neuroprotective drugs. Given the proven human safety of melatonin and methazolamide, and their ability to cross the blood-brain-barrier, these drugs are attractive as potential novel therapies for ischemic injury.

BackgroundStudies have shown that pistachios can improve blood lipid profiles in subjects with moderate hypercholesterolemia which could reduce the risk of cardiovascular disease. However, there is also a widely perceived view that eating nuts can lead to body weight gain due to their high fat content.PurposeTo investigate the impact of different dosages of pistachios on body weight, blood pressure, blood lipids, blood glucose and insulin in subjects with metabolic syndrome.MethodsNinety subjects with metabolic syndrome (consistent with 2005 International Diabetes Federation metabolic syndrome standard without diabetes) were enrolled in three endocrinology outpatient clinics in Beijing. All subjects received dietary counseling according to the guidelines of the American Heart Association Step I diet. After a 4 week run-in, subjects were randomized to consume either the recommended daily serving of 42 g pistachios (RSG), a higher daily serving of 70 g pistachio (HSG) or no pistachios (DCG) for 12 weeks.ResultsSubjects in all three groups were matched at baseline for BMI: DCG 28.03 ± 4.3; RSG 28.12 ± 3.22; and HSG 28.01 ± 4.51 kg/m2. There were no significant changes in body weight or BMI in any groups during the study nor any change from baseline at any time point in any group. During the entire study, there were no significant differences in waist-to-hip ratio among the groups or any change from baseline in any group (DCG -0.00 ± 0.03, RSG -0.01 ± 0.02 and HSG 0.01 ± 0.04). There were no significant differences detected among groups in triglycerides, fasting glucose and 2 hour postprandial glucose following a 75 gram glucose challenge. Exploratory analyses demonstrated that glucose values 2 h after a 75 gm glucose challenge were significantly lower at week 12 compared with baseline values in the HSG group (-1.13 ± 2.58 mmol/L, p = 0.02), and a similar trend was noted in the RSG group (-0.77 ± 2.07 mmol/L, p = 0.06), while no significant change was seen in the DCG group (-0.15 ± 2.27 mmol/L, p = 0.530). At the end of study, serum triglyceride levels were significantly lower compared with baseline in the RSG group (-0.38 ± 0.79 mmol/L, p = 0.018), but no significant changes were observed in the HSG or DCG groups.ConclusionDespite concerns that pistachio nut consumption may promote weight gain, the daily ingestion of either 42 g or 70 g of pistachios for 12 weeks did not lead to weight gain or an increase in waist-to-hip ratio in Chinese subjects with metabolic syndrome. In addition, pistachio consumption may improve the risk factor associated with the metabolic syndrome.

Background: Some heavy metals (e.g., arsenic, cadmium, lead, mercury) have been associated with obesity and obesity comorbidities. The analytical approach for those associations has typically focused on individual metals. There is a growing interest in evaluating the health effects of cumulative exposure to metal mixtures. Objectives: We utilized our Environmental Risk Score (ERS), a summary measure to examine the risk of exposure to multi-pollutants in epidemiologic research, to evaluate the associations of cumulative exposure to a mixture of correlated heavy metals with obesity and its comorbidities including hypertension, and type-2 diabetes mellitus (T2DM) while accounting for high degree correlations and interactions among metal mixtures components. Methods: We examined blood and urinary markers of 18 heavy metals among 9,537 adults in NHANES 2003–2014. We randomly split data into a training set for the construction of ERS (n=6,675) and a testing set for the evaluation of its statistical performance (n=2,862). ERS of heavy metal mixtures was computed for waist circumference using adaptive elastic-net (AENET) with 189 predictors including 18 main effects, 18 squared terms, and 153 pairwise interactions of heavy metals. Regression analyses with complex survey designs were performed to assess the associations of ERS with other obesity measures, hypertension and T2DM. Results: 7 main effects (blood lead, blood cadmium, blood mercury, and urinary markers of monomethylarsonic acid (MMA), barium, mercury and thallium), 4 squared terms (blood cadmium, urinary cadmium, urinary antimony and urinary tungsten), and 7 pairwise interactions (blood lead & urinary cadmium, blood lead & urinary MMA, blood lead & urinary uranium, urinary cadmium & urinary MMA, urinary dimethylarsinic acid (DMA) & urinary tungsten, urinary MMA & urinary cobalt, and urinary lead & urinary antimony) were selected by AENET for construction of ERS of waist circumference-related metal mixtures. An increase in ERS from 10th percentile to 90th percentile in the overall study population was significantly associated with 4.50 kg/m2 (95% CI: 4.06, 4.94) higher BMI, 4.16 mm (95% CI: 3.56, 4.76) higher skinfold thickness, and 4.11 kg (95% CI: 0.83, 7.40) higher total body fat, independent of age, sex, race/ethnicity, education, smoking status, physical activity and NHANES cycle (Ps < 0.05). Significant associations of ERS with both hypertension and T2DM were also observed (Ps < 0.05). Conclusions: Our study suggests that cumulative exposure to heavy metals as mixtures is associated with obesity and its related chronic conditions such as hypertension and T2DM. Additional research is needed to confirm these findings in longitudinal settings.

A152T‐variant human tau (hTau‐A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau‐A152T or wild‐type hTau (hTau‐WT), we find age‐dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau‐A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau‐A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau‐A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co‐expression of hTau‐A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau‐A152T and amyloid‐β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.