Bawei Chenxiang Wan ameliorates right ventricular hypertrophy in rats with high altitude heart disease by SIRT3-HIF1α-PDK/PDH signaling pathway improving fatty acid and glucose metabolism.

BACKGROUND: Bawei Chenxiang Wan (BCW) is among the most effective and widely used therapies for coronary heart disease and angina pectoris in Tibet. However, whether it confers protection through a right-ventricle (RV) myocardial metabolic mechanism is unknown. METHODS: Male Sprague-Dawley rats were orally administrated with BCW, which was injected concurrently with a bolus of Sugen5416, and subjected to hypoxia exposure (SuHx; 5000 m altitude) for 4 weeks. Right ventricular hypertrophy (RVH) in high-altitude heart disease (HAHD) was assessed using Fulton's index (FI; ratio of RV to left ventricle + septum weights) and heart-weight-to-body-weight ratio (HW/BW). The effect of therapeutic administration of BCW on the RVH hemodynamics was assessed through catheterization (mean right ventricular pressure and mean pulmonary artery pressure (mRVP and mPAP, respectively)). Tissue samples were used to perform histological staining, and confirmatory analyses of mRNA and protein levels were conducted to detect alterations in the mechanisms of RVH in HAHD. The protective mechanism of BCW was further verified via cell culture. RESULTS: BCW considerably reduced SuHx-associated RVH, as indicated by macro morphology, HW/BW ratio, FI, mPAP, mRVP, hypertrophy markers, heart function, pathological structure, and myocardial enzymes. Moreover, BCW can alleviate the disorder of glucose and fatty acid metabolism through upregulation of carnitine palmitoyltransferase1ɑ, citrate synthase, and acetyl-CoA and downregulation of glucose transport-4, phosphofructokinase, and pyruvate, which resulted in the reduced levels of free fatty acid and lactic acid and increased aerobic oxidation. This process may be mediated via the regulation of sirtuin 3 (SIRT3)-hypoxia-inducible factor 1α (HIF1α)-pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) signaling pathway. Subsequently, the inhibition of SIRT3 expression by 3-TYP (a selective inhibitor of SIRT3) can reverse substantially the anti-RVH effect of BCW in HAHD, as indicated by hypertrophy marker and serum myocardial enzyme levels. CONCLUSIONS: BCW prevented SuHx-induced RVH in HAHD via the SIRT3-HIF1ɑ-PDK/PDH signaling pathway to alleviate the disturbance in fatty acid and glucose metabolism. Therefore, BCW can be used as an alternative drug for the treatment of RVH in HAHD.

N-terminal Domain of Amyloid-ß Impacts Fibrillation and Neurotoxicity.

Alzheimer's disease is characterized by the presence of distinct amyloid-ß peptide (Aß) assemblies with diverse sizes, shapes, and toxicity. However, the primary determinants of Aß aggregation and neurotoxicity remain unknown. Here, the N-terminal amino acid residues of Aß42 that distinguished between humans and rats were substituted. The effects of these modifications on the ability of Aß to aggregate and its neurotoxicity were investigated using biochemical, biophysical, and cellular techniques. The Aß-derived diffusible ligand, protofibrils, and fibrils formed by the N-terminal mutational peptides, including Aß42(R5G), Aß42(Y10F), and rat Aß42, were indistinguishable by conventional techniques such as size-exclusion chromatography, negative-staining transmission electron microscopy and silver staining, whereas the amyloid fibrillation detected by thioflavin T assay was greatly inhibited in vitro. Using circular dichroism spectroscopy, we discovered that both Aß42 and Aß42(Y10F) generated protofibrils and fibrils with a high proportion of parallel ß-sheet structures. Furthermore, protofibrils formed by other mutant Aß peptides and N-terminally shortened peptides were incapable of inducing neuronal death, with the exception of Aß42 and Aß42(Y10F). Our findings indicate that the N-terminus of Aß is important for its fibrillation and neurotoxicity.

Relationship between Serum Homocysteine and Metabolic Syndrome among Patients with Schizophrenia and Bipolar Disorder: A Cross Sectional Study.

Objective: This study aimed to compare the prevalence of metabolic syndrome and hyperhomocysteinemia and to specify predictors of the metabolic syndrome among patients with schizophrenia and bipolar disorder. Method : This cross sectional study was conducted on 100 patients with schizophrenia and 100 patients with bipolar disorder. The participants' metabolic syndrome was determined according to the criteria set by Third Report of the National Cholesterol Education Program-Adult Treatment Panel III. Hyperhomocysteinemia was considered as homocysteine levels higher than 15 µmol/L. Chi-square test, Fisher's exact test, student t test, Mann-Whitney test, and logistic regression were used for data analysis. Results: The prevalence of metabolic syndrome was not significantly different (P = 0.07) between patients with schizophrenia (27%) and bipolar disorder (39%). No statistically significant difference (P = 0.17) was observed between patients with schizophrenia (82%) and bipolar disorder (74%) in the prevalence of hyperhomocysteinemia. The results of multivariable logistic regression model showed a significant association of smoking and BMI with metabolic syndrome in patients with schizophrenia (OR = 3.69, 95% CI: 1.13-12.05, and OR = 1.38, 95% CI: 1.20-1.60, respectively). In patients with bipolar disorder, BMI was a significant predictor of developing metabolic syndrome (OR = 1.29, 95% CI: 1.14-1.47). Metabolic syndrome was more prevalent in women than in men in both diagnostic groups (P < 0.05). No significant difference was observed in hyperhomocysteinemia prevalence between male and female patients with schizophrenia (P = 1.00). However, hyperhomocysteinemia was more prevalent in males than in females among patients with bipolar disorder (P = 0.001). Conclusion: Findings showed a high prevalence of metabolic syndrome and hyperhomocysteinemia among patients with schizophrenia and bipolar disorder. To deal with this problem, regular monitoring and conducting early interventions are recommended to determine the metabolic risk profile and to prevent the cardiovascular diseases.

Metabolic syndrome and 10-year risk of cardiovascular events among schizophrenia inpatients treated with antipsychotics.

Background: The metabolic syndrome is highly prevalent among patients with schizophrenia. This study was conducted to determine the prevalence of metabolic syndrome and the risk of cardiovascular disease in the next 10 years among schizophrenic patients. Methods: This cross sectional study was performed on 100 Iranian patients with schizophrenia in 2016. The prevalence of metabolic syndrome was determined by adult treatment panel III criteria, and 10-year cardiovascular risk was calculated by Framingham Risk Score. SPSS software was used to perform statistical analysis. Chi-square and Fisher's exact or extended Fisher's exact tests were used to compare dichotomous variables. Also, Mann-Whitney U test was applied to compare the quantitative variables. Significance level was considered to be less than or equal to 0.05. Results: In this study, 83 participants (83%) were male and 17 (17%) were female. The prevalence of metabolic syndrome was 27% (21.7% in males and 52.9% in females, p=0.015). Among all components of metabolic syndrome, low HDL-C in men and abdominal obesity in females were the most common disorders. Based on Framingham Risk Score, 76%, 16%, and 8% of patients had low, intermediate, and high level of risk, respectively. A significant difference was observed between the level of risk among participants with and without metabolic syndrome (p=0.042). Conclusion: In this study, patients with schizophrenia showed a high prevalence of metabolic syndrome, but most of them had low risk of developing cardiovascular disease. These results suggest regular screening and early interventions to modify the risk factors of metabolic syndrome.

Carbon load in airway macrophages, DNA damage and lung function in taxi drivers exposed to traffic-related air pollution.

To evaluate the potential applicability of carbon load in airway macrophages as a marker of exposure to traffic-related air pollution (TRAP) and its association with parameters of comet assay as a marker of DNA damage, and pulmonary function tests (PFTs) in the group of taxi drivers in Iran. One hundred four male taxi drivers with at least 1-year job history were randomly selected from registered drivers in the taxi union. Airway macrophages were obtained via sputum induction, and then the area of airway macrophages occupied by carbon was measured. DNA damage was determined by comet assay. PFTs were measured by the spirometer. Most of the participants (89.4%) were non-smoker. In this study, 52.7% of non-smoker participants were able to give a sample of sputum with macrophage. Carbon content of airway macrophages was 0.2 µm2. There was no significant difference in pulmonary function and comet assay parameters in terms of smoking status. There was an inverse correlation between carbon load with each of comet assay and PFTs parameters, although not statistically significant. This study identified that long-term exposure to TRAP can be a risk factor for pulmonary disorders.