Apolipoprotein CIII overexpression exacerbates diet-induced obesity due to adipose tissue higher exogenous lipid uptake and retention and lower lipolysis rates

Hypertriglyceridemia is a common type of dyslipidemia found in obesity. However, it is not established whether primary hyperlipidemia can predispose to obesity. Evidences have suggested that proteins primarily related to plasma lipoprotein transport, such as apolipoprotein (apo) CIII and E, may significantly affect the process of body fat accumulation. We have previously observed an increased adiposity in response to a high fat diet (HFD) in mice overexpressing apoCIII. Here, we examined the potential mechanisms involved in this exacerbated response of apoCIII mice to the HFD. We measured body energy balance, tissue capacity to store exogenous lipids, lipogenesis and lipolysis rates in non-transgenic and apoCIII overexpressing mice fed a HFD during two months. Food intake, fat excretion and whole body CO2 production were similar in both groups. However, the adipose tissue mass (45 %) and leptin plasma levels (2-fold) were significantly greater in apoCIII mice. Lipogenesis rates were similar, while exogenous lipid retention was increased in perigonadal (2-fold) and brown adipose tissues (40 %) of apoCIII mice. In addition, adipocyte basal lipolysis (55 %) and in vivo lipolysis index (30 %) were significantly decreased in apoCIII mice. A fat tolerance test evidenced delayed plasma triglyceride clearance and greater transient availability of non-esterified fatty acids (NEFA) during the post-prandial state in the apoCIII mice plasma. Thus, apoCIII overexpression resulted in increased NEFA availability to adipose uptake and decreased adipocyte lipolysis, favoring lipid enlargement of adipose depots. We propose that plasma apoCIII levels represent a new risk factor for diet-induced obesity12CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informaçãosem informação2011/50400-0; 2011/51349-

Pancreatic lesions and metabolic aggravation are prevented by low doses of sitagliptin in a rat model of type 2 diabetes

Introduction: The management of type 2 diabetes is designed to reduce disease-related complications and improve long-term outcomes. Inhibition of dipeptidyl peptidase-4 (DPP-4) activity by sitagliptin has been shown to improve glycaemic control in patients with type 2 diabetes Mellitus (T2DM) by prolonging the actions of incretin hormones, but the real impact of low-dose sitagliptin treatment on cardiometabolic risk factors and pancreatic lesions is almost unknown. This study aimed to evaluate the effects of low doses of sitagliptin on cardiovascular risk factors and histological pancreas parameters in Zucker Diabetic Fatty rats (ZDF (fa/fa)) an animal model of T2DM. Materials and Methods: Twenty weeks old diabetic obese (fa/fa) ZDF male rats were treated with vehicle or sitagliptin (10 mg/kg BW/day) during 6 weeks (n=8 each). The following parameters were assessed: glycaemia, HbA1c, insulin, lipidic profile; blood pressure. Specimens for pancreatic histopathology were stained with haematoxylin-eosin and periodic-acid-Shiff, examined by light microscopy. Endocrine and exocrine pancreas was evaluated semiquantitatively concerning inflammatory infiltrate, fibrosis, vacuolization and congestion, and scored from 0 (absent) to 3 (severe and extensive damage). Results: Sitagliptin in diabetic obese ZDF rats promoted a positive effect on dysglycaemia, dyslipidaemia and prevented the increase of blood pressure. Endocrine and exocrine pancreas presented a reduction/amelioration of fibrosis severity, inflammatory infiltrate, intra-islet vacuolation, and congestion vs the vehicle-treated diabetic rats. Conclusion: Simultaneous improvement of a sustainable glycaemic profile and of pancreatic histopathological lesions supports the favorable cardiovascular risk profile and may prove beneficial in decreasing long-term complications of T2DM.The authors are very grateful to the support of Fundação Merck Sharp & Dohm

Coenzyme Q10 or Creatine Counteract Pravastatin-Induced Liver Redox Changes in Hypercholesterolemic Mice

Statins are the preferred therapy to treat hypercholesterolemia. Their main action consists of inhibiting the cholesterol biosynthesis pathway. Previous studies report mitochondrial oxidative stress and membrane permeability transition (MPT) of several experimental models submitted to diverse statins treatments. The aim of the present study was to investigate whether chronic treatment with the hydrophilic pravastatin induces hepatotoxicity in LDL receptor knockout mice (LDLr-/-), a model for human familial hypercholesterolemia. We evaluated respiration and reactive oxygen production rates, cyclosporine-A sensitive mitochondrial calcium release, antioxidant enzyme activities in liver mitochondria or homogenates obtained from LDLr-/- mice treated with pravastatin for 3 months. We observed that pravastatin induced higher H2O2 production rate (40%), decreased activity of aconitase (28%), a superoxide-sensitive Krebs cycle enzyme, and increased susceptibility to Ca2+-induced MPT (32%) in liver mitochondria. Among several antioxidant enzymes, only glucose-6-phosphate dehydrogenase (G6PD) activity was increased (44%) in the liver of treated mice. Reduced glutathione content and reduced to oxidized glutathione ratio were increased in livers of pravastatin treated mice (1.5- and 2-fold, respectively). The presence of oxidized lipid species were detected in pravastatin group but protein oxidation markers (carbonyl and SH- groups) were not altered. Diet supplementation with the antioxidants CoQ10 or creatine fully reversed all pravastatin effects (reduced H2O2 generation, susceptibility to MPT and normalized aconitase and G6PD activity). Taken together, these results suggest that 1- pravastatin induces liver mitochondrial redox imbalance that may explain the hepatic side effects reported in a small number of patients, and 2- the co-treatment with safe antioxidants neutralize these side effects

Os Açores e os impérios : séculos XV a XX

[...]. Os Açores não constituem simplesmente um elo da correspondência transatlântica. Aliás, possuem uma identidade bem complexa. Com efeito, se a História evidencia muito a mundividência, apresentando as ilhas como o centro do Mundo, já a literatura ressalta muito o isolamento, resultante do afastamento dos continentes e da descontinuidade territorial, apresentando as ilhas como o fim do Mundo. Curiosamente, a política e os políticos, talvez com maior sentido do pragmatismo e da oportunidade, agem em função das circunstâncias. De facto, proclamam a projecção da universalidade, quando reivindicam mais capacidade de auto-governo, mas insistem na pobreza da ultraperifericidade, quando exigem mais contrapartidas financeiras. Apesar da divergência das perspectivas, atentemos mais na universalidade dos Açores, que historicamente influi na definição das dinâmicas do Atlântico, conferindo maior projecção à Europa

Multicenter randomized trial of cell therapy in cardiopathies – MiHeart Study

BACKGROUND: Cardiovascular diseases are the major cause of death in the world. Current treatments have not been able to reverse this scenario, creating the need for the development of new therapies. Cell therapies have emerged as an alternative for cardiac diseases of distinct causes in experimental animal studies and more recently in clinical trials. METHOD/DESIGN: We have designed clinical trials to test for the efficacy of autologous bone marrow derived mononuclear cell therapies in four different cardiopathies: acute and chronic ischemic heart disease, and Chagasic and dilated cardiomyopathy. All trials are multicenter, randomized, double-blind and placebo controlled. In each trial 300 patients will be enrolled and receive optimized therapy for their specific condition. Additionally, half of the patients will receive the autologous bone marrow cells while the other half will receive placebo (saline with 5% autologous serum). For each trial there are specific inclusion and exclusion criteria and the method for cell delivery is intramyocardial for the chronic ischemic heart disease and intracoronary for all others. Primary endpoint for all studies will be the difference in ejection fraction (determined by Simpson's rule) six and twelve months after intervention in relation to the basal ejection fraction. The main hypothesis of this study is that the patients who receive the autologous bone-marrow stem cell implant will have after a 6 month follow-up a mean increase of 5% in absolute left ventricular ejection fraction in comparison with the control group. DISCUSSION: Many phase I clinical trials using cell therapy for cardiac diseases have already been performed. The few randomized studies have yielded conflicting results, rendering necessary larger well controlled trials to test for efficacy of cell therapies in cardiopathies. The trials registration numbers at the NIH registry are the following: Chagasic cardiomyopathy (NCT00349271), dilated cardiomyopathy (NCT00333827), acute myocardial infarction (NCT00350766) and Chronic Ischemic Heart Disease (NCT00362388)