Effect of calorie restriction on liver and kidney glutathione in aging emory mice

Increases in antioxidant defense capacity have been associated with increases in the health and life span of calorie restricted animals. Emory mice develop late-life cataract, a lesion associated with oxidative damage and loss of lens glutathione (GSH). The effect of calorie restriction on GSH in liver and kidney in this model has not been explored. GSH and oxidized GSH (GSSG) were measured by HPLC in liver and kidney of Emory mice fed a control diet (C; 85% calories of ad-lib fed mice) or 60% calorie intake of C (R; 40% calorie restriction relative to C mice) for up to 22 mo age. Liver GSH concentration increased significantly in C and R mice from 4.5 to 12 mo old with no difference observed between the two groups. At 22 mo of age, liver GSH was lower than that of 12 mo old in both groups. As compared with GSH at 12 mo old, this decrease was almost twice as greater in C (70%, p=0.001) than in R mice (36%, p=0.02), so that R mice had a significantly higher concentration of GSH in liver than C mice at 22 mo of age (R = 32.8+5.1, C= 22.1+8.3 imol GSH/g protein, p<0.01). Liver GSSG was similar in C and R mice at 12 mo of age (4.45+1.35 vs. 4.75+1.83 imol GSSG/g protein), but increased in R mice at 22 mo (R=5:43±1.48; C=3.22±1.02, p<0.01). Therefore, at 22 mo old, total liver glutathione (GSH+GSSG) was higher in R than in C mice. There was no significant difference in GSH, GSSG and total GSH in kidney from C and R mice at these ages. Thus, calorie restriction reduces the age-related loss of GSH antioxidant capacity in liver but not kidney of Emory mice.     

Common MEFV mutation analysis in Iranian Azeri Turkish patients with familial Mediterranean fever

OBJECTIVES: To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations among Azeri Turkish patients from northwestern Iran. METHODS: One hundred ninety unrelated patients were referred by specialists to the Molecular-Medical Genetic Center of Tabriz. A clinical diagnosis of FMF was made according to published criteria. Mutation screening of the MEFV gene was performed for the 5 most commonly known mutations, namely M694V, V726A, M680I, M694I, and E148Q, by using amplification refractory mutation system for the first 4 and by polymerase chain reaction restriction-digestion testing for E148Q. These methods may also be used as a screening tool within affected families. RESULTS: Of the unrelated patients investigated, 120 (63%) had 1 or 2 mutations. Of those with mutations, 41 were homozygous, 37 were compound heterozygous, and 42 had only 1 identifiable mutation. Of the studied alleles, the most frequent mutation was M694V (28%), followed by V726A (9%), E148Q (7%), M680I (7%), and M694I (1%) mutations. CONCLUSIONS: Our results indicate that the common Mediterranean mutations are frequent in the Azeri Turkish FMF patients but with some differences in the frequency of individual mutations. The high frequency of E148Q in Azeri Turks compared with Mediterranean ethnic groups is rather interesting. The results open the way for further investigations on patients diagnosed as having FMF and in whom no mutations or only 1 mutated allele were found.     

Prevalence and correlates of alcohol use: a population-based study in Hong Kong

Objective To estimate the prevalence and pattern of alcohol use and to analyse the socio‐demographic and biological correlates of alcohol drinking in Hong Kong Chinese. Design A population‐based cross‐sectional study conducted from December 1994 to October 1996. Setting and participants 2900 randomly selected subjects age 25–74 years who participated in the Cardiovascular Risk Factor Prevalence Study in Hong Kong. Results Alcohol consumers comprised 55.4% (95% CI: 52.8–58.0) of men and 19.4% (95% CI: 17.4–21.4) of women. The median weekly ethanol consumed by male and female drinkers were 9.6 g and 3.6 g, respectively. Beer was the main source of alcohol; 61.5% of drinkers consumed beer as their main drink. In stepwise multiple regression among drinkers, male sex, smoking, high density lipoprotein cholesterol, primary or below education, diastolic blood pressure and separated or widowed marital status were associated positively with weekly ethanol consumption. Conclusion In this representative sample of Hong Kong adults, the majority were either non‐drinkers or very light drinkers, which can be used as a benchmark to measure changes in drinking pattern in the future. The putative protective effect of alcohol on heart disease could be due to the higher level of HDL in moderate drinkers.     

Direct sulfonamidation of (hetero)aromatic C–H bonds with sulfonyl azides: a novel and efficient route to N-(hetero)aryl sulfonamides

N-Aryl sulfonamides belong to a highly important class of organosulfur compounds which are found in a number of FDA-approved drugs such as dofetilide, dronedarone, ibutilide, sotalol, sulfadiazine, sulfamethizole, vemurafenib, and many more. There is therefore continuing interest in the development of novel and convenient protocols for the preparation of these pharmaceutically important compounds. Recently, direct sulfonamidation of (hetero)aromatic C–H bonds with easily available sulfonyl azides has emerged as an attractive and powerful strategy to access N-(hetero)aryl sulfonamides where non-toxic nitrogen gas forms as the sole by-product. This review highlights recent advances and developments (2012–2020) in this fast growing research area with emphasis on the mechanistic features of the reactions.

N-Aryl sulfonamides belong to a highly important class of organosulfur compounds which are found in a number of FDA-approved drugs such as dofetilide, dronedarone, ibutilide, sotalol, sulfadiazine, sulfamethizole, vemurafenib, and many more.     

The protective activity of nanomicelle curcumin in bisphenol A‐induced cardiotoxicity following subacute exposure in rats

Bisphenol A (BPA), an estrogenic compound, is used in manufacture of polycarbonate plastics and epoxy resins. Curcumin, the active ingredient of turmeric, is a potent protective compound against cardiac diseases. In this study the protective effect of nanomicelle curcumin on BPA‐induced subchronic cardiotoxicity in rats was evaluated. Rats were divided into 6 groups including control, nanomicelle curcumin (50 mg/kg, gavage), BPA (50 mg/kg, gavage), nanomicelle curcumin (10, 25, and 50 mg/kg) plus BPA. The treatments were continued for 4 weeks. Results revealed that BPA significantly induced histophatological injuries including focal lymphatic inflammation, nuclear degenerative changes and cytoplasmic vacuolation, increased body weight, systolic and diastolic blood pressures, malondialdehyde and Creatine phosphokinase‐MB level and decreased glutathione content in comparison with control group. In addition, in electrocardiographic graph, RR, QT, and PQ intervals were increased by BPA. Western blot analysis showed that BPA up‐regulated phosphorylated p38 (p38‐mitogen‐activated protein kinase) and JNK (c‐jun NH₂ terminal kinases), while down‐regulated phosphorylated AKT (Protein Kinase B) and ERK1/2 (extracellular signal‐regulated protein kinases 1 and 2). However, nanomicelle curcumin (50 mg/kg) significantly improved these toxic effects of BPA in rat heart tissue. The results provide evidence that nanomicelle curcumin showed preventive effects on subchronic exposure to BPA induced toxicity in the heart tissue in rats.     

Association between matrix metalloproteinase 2 (MMP2) promoter polymorphisms and the susceptibility to non-Hodgkin’s lymphoma in Egyptians

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases capable of extracellular matrix degradation. MMP2 is the key molecule that control invasion, tumor growth, and metastasis, and has been associated with poor prognosis in several tumors. Several epidemiological studies have focused on the associations between MMP2 promoter polymorphisms and cancer susceptibility; however, little is known about their role in hematological malignancies. The present study aimed to investigate the association of MMP2 ?735C/T and ?1306C/T promoter polymorphisms with B-NHL susceptibility and their clinicopathological characteristics. The study included 100 B-NHL patients and 100 healthy controls. Genotyping of MMP2 ?735C/T and MMP2 ?1306C/T was done by polymerase chain reaction restricted fragment length polymorphism (PCR-RFLP) technique. MMP2 ?735C/T heteromutant genotype (CT) was detected in 23 % of patients, and the homomutant genotype (TT) was detected in 7 % of patients. The polymorphic allele, T allele, was associated with susceptibility to B-NHL (OR?=?2.8:95 %CI?=?1.48–5.28). For MMP2 ?1306C/T, the frequencies of the polymorphic variants were 5 % for the heteromutant genotype (CT) and 3 % for the homomutant genotype (TT). The polymorphic allele, T allele, conferred almost fourfold increased risk of B-NHL (OR?=?3.8, 95 %CI?=?1.05–13.9), and the risk elevated to be almost eight folds when confined to diffuse large B-cell lymphoma (DLBCL) (OR?=?7.9, 95 %CI?=?1.67–32.27). MMP2 ?735C/T polymorphic genotypes were correlated with advanced clinical stages of the disease (stages III and IV). In conclusion, the study revealed that the variant alleles of MMP2 ?735C/T and MMP2 ?1306C/T can be considered as molecular risk factors for B-NHL among Egyptians.     

Systematic review and meta-analysis of age at menarche and risk of type 2 diabetes

The relation of early menarche with type 2 diabetes mellitus (T2DM) remains inconsistent across studies. The objective of this systematic review and meta-analysis of published population-based observational studies was to assess the association between age at menarche and T2DM risk. We searched online data bases through December 2013 and examined the reference lists of pertinent articles. Summary relative risks (RRs) with 95 % confidence intervals (CIs) were calculated with a random-effects model. A total of 14 effect estimates from 10 eligible studies (three cross-sectional and seven cohort studies) included 315,428 participants and 22,085 cases of T2DM. Compared with the highest or middle category, women in the lowest category of age at menarche had higher risk of T2DM [summary RR (95 % CI) 1.22 (1.17, 1.28)]. These results were consistent between studies that conducted in the United States and in Europe. The association between age at menarche and T2DM was slightly stronger for cohort than for cross-sectional studies. These findings strongly support an association between younger age at menarche and increased risk of T2DM. Age at menarche may help identify women with increased risk of developing T2DM.     

Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy

Patients with type 2 diabetes often present with cardiovascular complications; however, it is not clear how diabetes promotes cardiac dysfunction. In murine models, deletion of the gene encoding aryl hydrocarbon nuclear translocator (ARNT, also known as HIF1β) in the liver or pancreas leads to a diabetic phenotype; however, the role of ARNT in cardiac metabolism is unknown. Here, we determined that cardiac-specific deletion of Arnt in adult mice results in rapid development of cardiomyopathy (CM) that is characterized by accumulation of lipid droplets. Compared with hearts from ARNT-expressing mice, ex vivo analysis of ARNT-deficient hearts revealed a 2-fold increase in fatty acid (FA) oxidation as well as a substantial increase in the expression of PPARα and its target genes. Furthermore, deletion of both Arnt and Ppara preserved cardiac function, improved survival, and completely reversed the FA accumulation phenotype, indicating that PPARα mediates the detrimental effects of Arnt deletion in the heart. Finally, we determined that ARNT directly regulates Ppara expression by binding to its promoter and forming a complex with HIF2α. Together, these findings suggest that ARNT is a critical regulator of myocardial FA metabolism and that its deletion leads to CM and an increase in triglyceride accumulation through PPARα.