Nitric Oxide Released From Luminal S-nitroso-n-acetylcysteine Increases Gastric Mucosal Blood Flow

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Nitric oxide (NO)-mediated vasodilation plays a key role in gastric mucosal defense, and NO-donor drugs may protect against diseases associated with gastric mucosal blood flow (GMBF) deficiencies. In this study, we used the ex vivo gastric chamber method and Laser Doppler Flowmetry to characterize the effects of luminal aqueous NO-donor drug S-nitroso-N-acetylcysteine (SNAC) solution administration compared to aqueous NaNO2 and NaNO3 solutions (pH 7.4) on GMBF in Sprague-Dawley rats. SNAC solutions (600 mu M and 12 mM) led to a rapid threefold increase in GMBF, which was maintained during the incubation of the solutions with the gastric mucosa, while NaNO2 or NaNO3 solutions (12 mM) did not affect GMBF. SNAC solutions (600 mu M and 12 mM) spontaneously released NO at 37 degrees C at a constant rate of 0.3 or 14 nmol center dot mL(-1)center dot min(-1), respectively, while NaNO2 (12 mM) released NO at a rate of 0.06 nmol center dot mL(-1)center dot min(-1) and NaNO3 (12 mM) did not release NO. These results suggest that the SNAC-induced GMBF increase is due to their higher rates of spontaneous NO release compared to equimolar NaNO2 solutions. Taken together, our data indicate that oral SNAC administration is a potential approach for gastric acid-peptic disorder prevention and treatment.20341094123Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2011/50514-5, 2013/07173-8]CNPq [309390/2011-7]FAPESP [2008/57560-0

(-)-tarchonanthuslactone Exerts A Blood Glucose-increasing Effect In Experimental Type 2 Diabetes Mellitus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)A number of studies have proposed an anti-diabetic effect for tarchonanthuslactone based on its structural similarity with caffeic acid, a compound known for its blood glucose-reducing properties. However, the actual effect of tarchonanthuslactone on blood glucose level has never been tested. Here, we report that, in opposition to the common sense, tarchonanthuslactone has a glucose-increasing effect in a mouse model of obesity and type 2 diabetes mellitus. The effect is acute and non-cumulative and is present only in diabetic mice. In lean, glucose-tolerant mice, despite a slight increase in blood glucose levels, the effect was not significant.20350385049Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Institute of Chemistry/UNICAMPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [proc. 13/07607-8]FAPESP [11/50514-5, 12/09254-2, 10/08673-6, 2009/53606-8

Defective Regulation Of Pomc Precedes Hypothalamic Inflammation In Diet-induced Obesity

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Obesity is the result of a long-term positive energy balance in which caloric intake overrides energy expenditure. This anabolic state results from the defective activity of hypothalamic neurons involved in the sensing and response to adiposity. However, it is currently unknown what the earliest obesity-linked hypothalamic defect is and how it orchestrates the energy imbalance present in obesity. Using an outbred model of diet-induced obesity we show that defective regulation of hypothalamic POMC is the earliest marker distinguishing obesity-prone from obesity-resistant mice. The early inhibition of hypothalamic POMC was sufficient to transform obesity-resistant in obesity-prone mice. In addition, the post-prandial change in the blood level of beta-endorphin, a POMC-derived peptide, correlates with body mass gain in rodents and humans. Taken together, these results suggest that defective regulation of POMC expression, which leads to a change of beta-endorphin levels, is the earliest hypothalamic defect leading to obesity.6Fundacao de Amparo a Pesquisa do Estado de Sao PauloConselho Nacional de Desenvolvimento Cientifico e TecnologicoFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Interleukin-6 expression by hypothalamic microglia in multiple inflammatory contexts: a systematic review

Interleukin-6 (IL-6) is a unique cytokine that can play both pro- and anti-inflammatory roles depending on the anatomical site and conditions under which it has been induced. Specific neurons of the hypothalamus provide important signals to control food intake and energy expenditure. In individuals with obesity, a microglia-dependent inflammatory response damages the neural circuits responsible for maintaining whole-body energy homeostasis, resulting in a positive energy balance. However, little is known about the role of IL-6 in the regulation of hypothalamic microglia. In this systematic review, we asked what types of conditions and stimuli could modulate microglial IL-6 expression in murine model. We searched the PubMed and Web of Science databases and analyzed 13 articles that evaluated diverse contexts and study models focused on IL-6 expression and microglia activation, including the effects of stress, hypoxia, infection, neonatal overfeeding and nicotine exposure, lipopolysaccharide stimulus, hormones, exercise protocols, and aging. The results presented in this review emphasized the role of injury-like stimuli, under which IL-6 acts as a proinflammatory cytokine, concomitant with marked microglial activation, which drive hypothalamic neuroinflammation. Emerging evidence indicates an important correlation of basal IL-6 levels and microglial function with the maintenance of hypothalamic homeostasis. Advances in our understanding of these different contexts will lead to the development of more specific pharmacological approaches for the management of acute and chronic conditions, like obesity and metabolic diseases, without disturbing the homeostatic functions of IL-6 and microglia in the hypothalamus.2019COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informação2013/07607-

Saturated Fatty Acids Modulate Autophagy's Proteins In The Hypothalamus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Autophagy is an important process that regulates cellular homeostasis by degrading dysfunctional proteins, organelles and lipids. In this study, the hypothesis that obesity could lead to impairment in hypothalamic autophagy in mice was evaluated by examining the hypothalamic distribution and content of autophagic proteins in animal with obesity induced by 8 or 16 weeks high fat diet to induce obesity and in response to intracerebroventricular injections of palmitic acid. The results showed that chronic exposure to a high fat diet leads to an increased expression of inflammatory markers and downregulation of autophagic proteins. In obese mice, autophagic induction leads to the downregulation of proteins, such as JNK and Bax, which are involved in the stress pathways. In neuron cell-line, palmitate has a direct effect on autophagy even without inflammatory activity. Understanding the cellular and molecular bases of overnutrition is essential for identifying new diagnostic and therapeutic targets for obesity.103Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2011/14565-4, RA 2011/51205-6

A New Association of Post-T Tauri Stars Near The Sun

Observing ROSAT sources in 20 x 25 deg centered at the high latitude active star ER Eri, we found evidences for a new young nearby association (~30Myr at~60pc), the Horologium Association (HorA), formed by at least 10 probable and 6 possible members, some being Post-T Tauri stars. We examine several requirements that characterize a young association and they, together, create a strong evidence for the reality of the HorA. In fact, the Li line intensities are between those of the oldest classical T Tauri stars and the ones of the Local Association stars. The space velocities of the HorA relative to the Sun, U= -9.5+/-1.0, V = -20.9 +/- 1.1, W = -2.1 +/- 1.9, are not far from those of the Local Association. We suggest that some hotter and non-X-ray active stars, with similar space velocities, could be massive members of the HorA, among them, the nearby Be star Achernar. The maximum of the mass distribution function of the HorA is around 0.8 solar masses. At its distance, the projected size of the HorA, ~50 pc, would be larger than our surveyed area and many other members could have been missed. We also observed 3 control regions, two at northern and southern galactic latitudes and a third one in the known TW Hya Association (TWA), and the properties and distribution of their young stars strengthen the reality of the HorA. Contrary to the TWA, the only known binaries in the HorA are 2 very wide systems. The HorA is much more isolated from clouds and older than the TWA and could give some clues about the lifetime of the disks around T Tauri stars. Actually, none of the proposed members is an IRAS source indicating an advanced stage of the evolution of their accreting disks. ER Eri itself was found to be a RS CVn-like system.Comment: 25 pages, 5 eps figures, to appear in Astron.

Metal-functionalized covalent organic frameworks as precursors of supercapacitive porous N-doped graphene

Highly porous corrugated N-doped graphene exhibiting excellent supercapacitive behavior can be synthesized using metal-functionalized COFs as precursors

Insulin signalling in heart involves insulin receptor substrates-1 and - 2, activation of phosphatidylinositol 3-kinase and the JAK 2-growth related pathway

Objective: Hyperinsulinemia is a common feature of obesity and hypertension and may be associated with abnormal metabolism and growth of heart muscle and vascular wall. Most of the known actions of insulin were characterised in muscle, adipose tissue and liver. In this study we investigate the initial steps of insulin signalling in rat heart. Methods: After insulin infusion in the cava vein of male Wistar rats, the insulin receptor, insulin receptor substrates-1 and -2, phosphatidylinositol 3- kinase activity and Janus kinase (JAK) 2 engagement were studied by immunoprecipitation and immunoblot of heart extracts. Results: An insulin load induces rapid autophosphorylation of the insulin receptor which is followed by the phosphorylation of insulin receptor substrates-1 and -2. The phosphorylation of these early intracellular substrates leads to the association of the p85 subunit of phosphatidylinositol 3-kinase and subsequent activation of its catalytic p110 subunit. Besides activation of the lipid metabolising enzyme phosphatidylinositol 3-kinase, the phosphorylation of insulin receptor substrates-1 and -2 engages the intracellular kinase JAK 2 and induces JAK 2-STAT 1 complex formation. Conclusion: We demonstrate that the early steps of insulin signalling in heart include the phosphorylation-activation of the insulin receptor, engagement of insulin receptor substrates-1 and -2 with the consequent activation of phosphatidylinositol 3-kinase and the involvement of the recently discovered growth related pathway-JAK 2-STAT 1