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Diabetes is associated with a dramatic mortality rate due to its vascular complications. Chronic hyperglycemia in diabetes leads to enhanced glycation of erythrocytes and oxidative stress. Even though erythrocytes play a determining role in vascular complications, very little is known about how erythrocyte structure and functionality can be affected by glycation. Our objective was to decipher the impact of glycation on erythrocyte structure, oxidative stress parameters and capacity to interact with cultured human endothelial cells. In vitro glycated erythrocytes were prepared following incubation in the presence of different concentrations of glucose. To get insight into the in vivo relevance of our results, we compared these data to those obtained using red blood cells purified from diabetics or non-diabetics. We measured erythrocyte deformability, susceptibility to hemolysis, reactive oxygen species production and oxidative damage accumulation. Altered structures, redox status and oxidative modifications were increased in glycated erythrocytes. These modifications were associated with reduced antioxidant defence mediated by enzymatic activity. Enhanced erythrocyte phagocytosis by endothelial cells was observed when cultured with glycated erythrocytes, which was associated with increased levels of phosphatidylserine—likely as a result of an eryptosis phenomenon triggered by the hyperglycemic treatment. Most types of oxidative damage identified in in vitro glycated erythrocytes were also observed in red blood cells isolated from diabetics. These results bring new insights into the impact of glycation on erythrocyte structure, oxidative damage and their capacity to interact with endothelial cells, with a possible relevance to diabetes.

The clearance of erythrocytes may be carried out by vascular cells in atherosclerotic conditions. • Phagocytosis by endothelial cells is more pronounced with aged and glycated erythrocytes.• Endothelial phagocytosis is enhanced with T2D erythrocytes.• Interactions between erythrocytes and endothelial cells occur in vivo, in atherothrombotic/diabetic conditions.

Clinical benefit for mechanical thrombectomy (MT) in stroke was recently demonstrated in multiple large prospective studies. Acute hyperglycemia (HG) is an important risk factor of poor outcome in stroke patients, including those that underwent MT. The aim of this therapy is to achieve a complete reperfusion in a short time, given that reperfusion damage is dependent on the duration of ischemia. Here, we investigated the effects of acute HG in a mouse model of ischemic stroke induced by middle cerebral artery occlusion (MCAO). Hyperglycemic (intraperitoneal [ip] injection of glucose) and control (ip saline injection) 10-week male C57BL6 mice were subjected to MCAO (30, 90, and 180 min) followed by reperfusion obtained by withdrawal of the monofilament. Infarct volume, hemorrhagic transformation (HT), neutrophil infiltration, and neurological scores were assessed at 24 hr by performing vital staining, ELISA immunofluorescence, and behavioral test, respectively. Glucose injection led to transient HG (blood glucose = 250-390 mg/dL) that significantly increased infarct volume, HT, and worsened neurological outcome. In addition, we report that HG promoted blood-brain barrier disruption as shown by hemoglobin accumulation in the brain parenchyma and tended to increase neutrophil extravasation within the infarcted area. Acute HG increased neurovascular damage for all MCAO durations tested. HTs were observed as early as 90 min after ischemia under hyperglycemic conditions. This model mimics MT ischemia/reperfusion and allows the exploration of brain injury in hyperglycemic conditions.

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Increased oxidative stress and advanced glycation end-product (AGE) formation are major contributors to the development of type 2 diabetes. Here plasma proteins e.g. albumin can undergo glycoxidation and play a key role in diabetes onset and related pathologies. However, despite recent progress linking albumin-AGE to increased oxidative stress and downstream effects, its action in metabolic organs such as the liver remains to be elucidated. The current study therefore investigated links between oxidative perturbations and biochemical/structural modifications of plasma albumin, and subsequent downstream effects in transgenic db/db mouse livers and HepG2 cells, respectively. Our data reveal increased oxidative stress biomarkers and lipid accumulation in plasma and livers of diabetic mice, together with albumin glycoxidation. Purified mouse albumin modifications resembled those typically found in diabetic patients, i.e. degree of glycation, carbonylation, AGE levels and in terms of chemical composition. Receptor for AGE expression and reactive oxygen species production were upregulated in db/db mouse livers, together with impaired proteolytic, antioxidant and mitochondrial respiratory activities. In parallel, acute exposure of HepG2 cells to glycated albumin also elicited intracellular free radical formation. Together this study demonstrates that AGE-modified albumin can trigger damaging effects on the liver, i.e. by increasing oxidative stress, attenuating antioxidant capacity, and by impairment of hepatic proteolytic and respiratory chain enzyme activities.

Plant polyphenols may exert beneficial action against obesity-related oxidative stress and inflammation which promote insulin resistance. This study evaluated the effect of polyphenols extracted from French Curcuma longa on 3T3-L1 adipose cells exposed to H2 O2 -mediated oxidative stress. We found that Curcuma longa extract exhibited high amounts of curcuminoids identified as curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which exerted free radical-scavenging activities. Curcuma longa polyphenols improved insulin-mediated lipid accumulation and upregulated peroxisome proliferator-activated receptor-gamma gene expression and adiponectin secretion which decreased in H2 O2 -treated cells. Curcuminoids attenuated H2 O2 -enhanced production of pro-inflammatory molecules such as interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and nuclear factor κappa B. Moreover, they reduced intracellular levels of reactive oxygen species elevated by H2 O2 and modulated the expression of genes encoding superoxide dismutase and catalase antioxidant enzymes. Collectively, these findings highlight that Curcuma longa polyphenols protect adipose cells against oxidative stress and may improve obesity-related metabolic disorders. © 2016 BioFactors, 42(4):418-430, 2016.

BackgroundDespite pathophysiological relevance and promising experimental data, the usefulness of biomarkers of oxidative stress for cardiac risk prediction is unclear. The aim of our study was to investigate the prognostic value of 6 biomarkers exploring different pathways of oxidative stress for predicting adverse cardiovascular outcomes in patients with type 2 diabetes mellitus beyond established risk factors.Methods and ResultsThe SURDIAGENE (Survie, Diabete de type 2 et Genetique) prospective cohort study consecutively recruited 1468 patients with type 2 diabetes mellitus. Assays were performed at baseline, and incident cases of major adverse cardiovascular events (MACE)—first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke—were recorded during a median of 64 months. Advanced oxidation protein products, oxidative hemolysis inhibition assay, ischemia‐modified albumin, and total reductive capacity of plasma were not associated with the risk of MACE in univariate analyses. Fluorescent advanced glycation end products and carbonyls were associated with MACE (hazard ratio=1.38 per SD, 95% confidence interval 1.24‐1.54, P<0.001 and hazard ratio=1.15 per SD, 95% confidence interval 1.04‐1.27, P=0.006, respectively) in univariate analysis, but when added to a multivariate predictive model including traditional risk factors for MACE, these markers did not significantly improve c‐statistics or integrated discrimination index of the model.ConclusionsThese plasma concentrations of 6 markers, which cover a broad spectrum of oxidative processes, were not significantly associated with MACE occurrence and were not able to improve MACE risk discrimination and classification beyond classical risk factors in type 2 diabetes mellitus patients.