Involvement of glutathione transferases,Gtt1and Gtt2, with oxidative stress response generated by H2O2 during growth of Saccharomyces cerevisiae

Abstract

Both type 1 and type 2 diabetes (insulin-dependent and non-insulin dependent diabetes, respectively) are associated with increased risk for microvascular and macrovascular complications including retinopathy, neuropathy, nephropathy and atherosclerosis. Type 2 diabetes markedly increases the risk for cardiovascular morbidity and mortality, which has major public health implications. In this review, molecular mechanisms pertaining to diabetes-induced heart pathology are addressed.     

Changes in the erythrocyte glutathione concentration in the course of diabetes mellitus

Abstract

This study aims to evaluate the significance of the changes of erythrocyte reduced glutathione (GSH) in the course of diabetes mellitus including the pre-diabetes stage and cardiovascular disease co-morbidity. A total of 222 participants (female:male, 107:115) were selected and their erythrocyte GSH levels were measured. The participants were divided into four groups: (i) control; (ii) those with blood glucose level ≥5.6 mmol/l but < 6.9 mmol/l as pre-diabetes mellitus with no other pathology; (iii) diabetes without co-morbidity; and (iv) those with diabetes mellitus and cardiovascular disease. Statistical analysis was by ANOVA followed by a Fisher's LSD post hoc test. We observed that GSH concentration was significantly different between groups (P < 0.04). The Fisher's post hoc test indicated significant differences in erythrocyte GSH levels between the pre-diabetes mellitus and diabetes mellitus groups compared to control (P < 0.005 and P < 0.05, respectively). A statistically significant change (P < 0.001) involving an initial fall followed by a rise in erythrocyte GSH levels was observed when diabetes mellitus and diabetes mellitus+cardiovascular disease groups were combined and assessed with respect to period of diabetes. We conclude that oxidative stress is already present in the pre-diabetes stage as determined by the fall in GSH, representing the initial phase of oxidative stress in diabetes mellitus progression. This finding provides evidence that antioxidant markers such as GSH could be a useful tool for pre-diabetes mellitus screening.     

Phytoestrogen calycosin-7-O-β-D-glucopyranoside ameliorates advanced glycation end products-induced HUVEC damage

Vasculopathy including endothelial cell (EC) apoptosis and inflammation contributes to the high incidence of stroke and myocardial infarction in diabetic patients. The aim of the present study was to investigate the effect of calycosin-7-O-β-D-glucopyranoside (CG), a phytoestrogen, on advanced glycation end products (AGEs)-induced HUVEC damage. We observed that CG can significantly ameliorate AGEs-induced HUVEC oxidative stress and apoptosis. The ratio of SOD/MDA was significantly increased to the normal level by CG pretreatment. CG preincubation dramatically increased anti-apoptotic Bcl-2 while decreased pro-apoptotic Bax and Bad expressions as detected by immunocytochemistry. Moreover, CG ameliorated macrophage migration and adhesion to HUVEC; the monocyte chemotactic protein-1 and interleukin-6 levels in the culture supernatant were dramatically reduced by CG as determined by ELISA; the expressions of inflammatory proteins including ICAM-1, TGF-β1, and RAGE in both protein and mRNA levels were significantly reduced to the normal level by CG pretreatment as determined by immunocytochemistry and real-time RT-PCR. The intracellular investigation suggests that CG can reverse AGEs-activated ERK1/2 and NF-κB phosphorylation, in which estrogen receptors were involved in. Our results strongly indicate that CG can modulate EC dysfunction by ameliorating AGEs-induced cell apoptosis and inflammation.     

Glutathione synthesis by red blood cells in type 2 diabetes mellitus

Abstract

Oxidative stress is implicated in the pathogenesis and complications of type 2 diabetes mellitus (NIDDM). Glycoxidation may damage the enzymes that synthesise glutathione (GSH), an endogenous intracellular antioxidant. Erythrocytes (RBCs) taken from NIDDM subjects, and non-diabetic controls, were GSH-depleted using 1-chloro-2,4-dinitrobenzene, incubated in a solution containing GSH-rebuilding substrates, and sampled for GSH using a 5,5′-γ-dithiobis-(2-nitrobenzoic acid)/enzymatic recycling procedure. NIDDM subjects, on average, had the same GSH concentration and synthesising ability as non-diabetic controls, indicating normal function of the synthesis enzymes. A positive correlation between synthesis and concentration of GSH seen in non-diabetic controls did not exist in NIDDM, due to their putatively larger oxidative load. The results, to the best of our knowledge, provide the first evidence that, despite a higher oxidative load, intact RBCs from NIDDM subjects are able to synthesise GSH normally. It is hypothesised that increased rates of GSH synthesis would maintain a normal steady-state GSH concentration.     

Anti-atherosclerotic and anti-diabetic properties of probucol and related compounds

Abstract

Probucol is a diphenolic compound with anti-oxidant and anti-inflammatory properties that reduces atherosclerosis and restenosis. Unfortunately, adverse effects on blood lipoproteins and cardiac electrophysiology have curtailed its use as a drug. Compounds related to probucol that have improved efficacy without the adverse effects offer promise as novel therapies of cardiovascular disease. Recent results suggest that these compounds may be used for the prevention of type 2 diabetes, a disease that is increasing in prevalence and importance world-wide. In this review, the molecular mechanisms underlying the beneficial activities of probucol and related compounds are described.