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Mechlovich D.,Institute of Technology | Amit T.,Institute of Technology | Mandel S.A.,Institute of Technology | Bar-Am O.,Institute of Technology | And 3 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

Increasing evidence suggests that oxidative stress (OS)-induced pancreatic β-cell impairments is involved in diabetes and diabetic complications. Our group has recently synthesized two multifunctional nontoxic, lipophilic, iron-chelating drugs, 5-{N-methyl-N-propargylaminomethyl}-8-hydroxyquinoline (M30) and 5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline (HLA20), for the treatment of various OS-mediated pathogeneses. These compounds contain the N-propargylamine cytoprotective moiety of the antiparkinsonian drug rasagiline (Azilect) and the iron-complexing component 8-hydroxyquinoline. The aim of this research was to evaluate the protective effect of the multifunctional iron-chelating drugs on rat insulin-producing pancreatic β-cells (INS-1E and RINm) against OS-induced cytotoxicity. We found that M30 and HLA20 markedly and dose-dependently inhibited H2O2-induced cytotoxicity, associated with decreased intracellular reactive oxygen species formation and increased catalase activity. In accordance, the catalase inhibitor 3-amino-1,2,4-triazol blocked the protective action of M30 against H 2O2-induced damage. Both compounds significantly increased the levels of the iron-responsive protein transferrin receptor indicating their iron-chelating effect. Further mechanistic studies showed that M30 and HLA20 attenuated H2O2-induced mitochondrial membrane potential loss, decreased the release of cytochrome c into the cytoplasm, and inhibited the activation of caspase-3, suggesting that these drugs may produce cytoprotective effects via the preservation of mitochondrial function. These results indicate that the novel drugs, M30 and HLA20 display significant cytoprotective activity against OS-induced cytotoxicity in insulin producing β-cells, which might be of therapeutic use in the treatment of diabetes mellitus. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics. Source


Costa Justus J.F.,Federal University of Parana | Ligocki Campos A.C.,Federal University of Parana | Figueroa A.L.C.,Diabetes and Obesity Research Laboratory | Gomis R.,Diabetes and Obesity Research Laboratory | And 6 more authors.
Metabolic Syndrome and Related Disorders | Year: 2016

Background: The circadian pattern of adipokines is blunted in obese subjects, and we tested the hypothesis that bariatric surgery could normalize the 24-hr pattern of adipokines. Therefore, this study was designed to examine the early impact of the newly designed sleeve gastrectomy with transit bipartition (SGTB) surgery on the circadian pattern of leptin, adiponectin, and resistin in morbidly obese subjects. Methods: The study group included six morbidly obese women [body mass index (BMI) 41.3 ± 1.53 kg/m2] who underwent SGTB and four lean women (BMI 18.61 ± 0.92 kg/m2). Blood from all subjects was collected before and 3 months after bariatric surgery every 6 hr throughout the 24-hr period. The circadian pattern of leptin, adiponectin, and resistin was measured by enzyme-linked immunosorbent assay or Luminex techniques. Results: Lean women exhibited rise of plasma leptin levels at nighttime, whereas obese women had an increase in the overall plasma leptin levels throughout the 24-hr period, lacking the physiological rise of nocturnal leptin levels compared to controls. Obese women had a decrease in 24-hr adiponectin levels and similar plasma resistin levels compared to controls. Three months after SGTB, obese women lost 16.0% (P < 0.005) of their initial body weight and had a decrease in overall 24-hr leptin levels. However, there was no recovery of the nocturnal rise in leptin levels 3 months after SGTB. The 24-hr adiponectin levels were still decreased after SGTB surgery compared to controls, while resistin levels were decreased only during night time after SGTB. Conclusions: These results suggested that SGTB is an efficient innovative procedure to rapidly decrease 24-hr leptin levels. However, after 3 months, SGTB was not enough to recover the physiological nocturnal rise of leptin levels present in lean subjects. © Copyright 2016, Mary Ann Liebert, Inc. Source


Bloch K.,Diabetes and Obesity Research Laboratory | Vanichkin A.,Diabetes and Obesity Research Laboratory | Damshkaln L.G.,RAS Nesmeyanov Institute of Organoelement Compounds | Lozinsky V.I.,RAS Nesmeyanov Institute of Organoelement Compounds | Vardi P.,Diabetes and Obesity Research Laboratory
Acta Biomaterialia | Year: 2010

Polymeric scaffolds have been reported to promote angiogenesis, facilitating oxygen delivery; however, little is known about the effect of diabetes on the neo-vascularization of implanted polymeric scaffolds at subcutaneous (SC) sites. In this study we compare the effect of diabetes on scaffold vascularization following SC implantation into diabetic and non-diabetic mice. Wide pore agarose cryogel scaffolds with grafted gelatin were prepared by a two-step freezing procedure and subsequent thawing. The scaffolds were implanted subcutaneously into streptozoticin-induced diabetic mice and control, non-diabetic mice. The vascularization process was estimated using histological sections, in which endothelial cells were identified by Von Willebrand factor (vWF) and CD31 antigen staining and the pericyte layer was confirmed by α-smooth muscle actin (α-SMA) visualization. Comparative analysis showed a similar thickness of fibrous capsules around the vascularized scaffolds in both diabetic and non-diabetic animals. Intensive staining for α-SMA indicated the formation of mature blood vessels in the surrounding fibrous capsule and tissue invading the scaffold area. No statistically significant differences in capillary density and area occupied by blood vessels were found between diabetic and non-diabetic mice. In conclusion, the present study shows no adverse effects of diabetes on new blood vessel formation in SC implanted agarose cryogel scaffolds with grafted gelatin. © 2009 Acta Materialia Inc. Source


Ruano E.G.,CIBER ISCIII | Ruano E.G.,Diabetes and Obesity Research Laboratory | Canivell S.,Diabetes and Obesity Research Laboratory | Vieira E.,CIBER ISCIII | Vieira E.,Diabetes and Obesity Research Laboratory
PLoS ONE | Year: 2014

REV-ERB ALPHA has been shown to link metabolism with circadian rhythms. We aimed to identify new polymorphisms in the promoter of REV-ERB ALPHA and tested whether these polymorphisms could be associated with obesity in the Spanish population. Of the 1197 subjects included in our study, 779 were obese (BMI 34.38±3.1 kg/m2) and 418 lean (BMI 23.27±1.5 kg/m2). In the obese group, 469 of the 779 had type 2 diabetes. Genomic DNA from all the subjects was obtained from peripheral blood cells and the genotyping in the REV-ERB ALPHA promoter was analyzed by High Resolution Melting. We found six polymorphisms in the REV-ERB ALPHA promoter and identified rs939347 as a SNP with the highest frequency in the total population. We did not find any association between rs939347 and type 2 diabetes (p = 0.101), but rs939347 was associated with obesity (p = 0.036) with the genotype AA exhibiting higher frequency in the obese (5.2% in total obese vs 2.4% in lean). This association was found only in men (p = 0.031; 6.5% AA-carriers in obese men vs 1.9% AA-carriers in lean men), with no association found in the female population (p = 0.505; 4.4% AA-carriers in obese women vs 2.7% AA-carriers in lean women). Our results suggest that the REV-ERB ALPHA rs939347 polymorphism could modulate body fat mass in men. The present work supports the role of REV-ERB ALPHA in the development of obesity as well as a potential target for the treatment of obesity. © 2014 Ruano et al. Source


Bloch K.,Diabetes and Obesity Research Laboratory | Vennang J.,Diabetes and Obesity Research Laboratory | Lazard D.,Diabetes and Obesity Research Laboratory | Vardi P.,Diabetes and Obesity Research Laboratory
Histochemistry and Cell Biology | Year: 2012

Insulin-producing beta cells are known to be highly susceptible to hypoxia, which is a major factor in their destruction after pancreatic islet transplantation. However, whether the glucagon-producing pancreatic islet alpha cells are sensitive to hypoxia is not known. Our objective was to compare the sensitivity of alpha and beta cells to hypoxia. Isolated rat pancreatic islets were exposed to hypoxia (1% oxygen, 94% N 2, 5% CO 2) for 3 days. The viability of the alpha and beta cells, as well as the stimulusspecific secretion of glucagon and insulin, was evaluated. A quantitative analysis of the proportion of beta to alpha cells indicated that, under normoxic conditions, islet cells were composed mainly of beta cells (87 ± 3%) with only 13 ± 3% alpha cells. Instead, hypoxia treatment significantly increased the proportion of alpha cells (40 ± 13%) and decreased the proportion of beta cells to 60 ± 13%. Using the fluorescent TUNEL assay we found that only a few percent of beta cells and alpha cells were apoptotic in normoxia. In contrast, hypoxia induced an abundance of apoptotic beta cells (61 ± 22%) and had no effect on the level of apoptosis in alpha cells. In conclusion, this study demonstrates that hypoxia results in severe functional abnormality in both beta and alpha cells while alpha cells display significantly decreased rate of apoptosis compared to intensive apoptotic injury of beta cells. These findings have implications for the understanding of the possible role of hypoxia in the pathophysiology of diabetes. © Springer-Verlag 2012. Source

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