Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis.

Non-alcoholic fatty liver disease (NAFLD) is linked to obesity and insulin resistance and is the most prevalent chronic liver disease. During the development of obesity and NAFLD, mitochondria adapt to the increased lipid load in hepatocytes by increasing the rate of fatty acid oxidation. In concert with this, reactive species (RS) generation is increased, damaging hepatocytes and inducing inflammation. Hepatic mitochondrial dysfunction is central to the pathogenesis of NAFLD via undefined mechanisms. There are no FDA approved treatments for NAFLD other than weight loss and management of glucose tolerance. Electrophilic nitro-oleic acid (NO2-OA) displays anti-inflammatory and antioxidant signaling actions, thus mitochondrial dysfunction, RS production and inflammatory responses to NO2-OA and the insulin sensitizer rosiglitazone were evaluated in a murine model of insulin resistance and NAFLD. Mice on HFD for 20 wk displayed increased adiposity, insulin resistance and hepatic lipid accumulation (steatosis) compared to mice on normal chow (NC). The HFD mice had mitochondrial dysfunction characterized by lower hepatic mitochondrial complex I, IV and V activity compared to mice on NC. Treatment with NO2-OA or rosiglitazone for the last 42 days (out of 20 wk) abrogated HFD-mediated decreases in hepatic mitochondrial complex I, IV and V activity. Notably, NO2-OA treatment normalized hepatic triglyceride levels and significantly reversed hepatic steatosis. Despite the improved glucose tolerance observed upon rosiglitazone treatment, liver weight and hepatic triglycerides were significantly increased over vehicle-treated HFD mice. These observations support that the pleiotropic signaling actions of electrophilic fatty acids limit the complex hepatic and systemic pathogenic responses instigated by obesity, without the adverse effects of thiazolidinedione drugs such as rosiglitazone.

Inibição de metaloproteinases da matriz extracelular: uma possível estratégia terapêutica na hipertensão arterial? / Inhibition of matrix metalloproteinases: a possible therapeutic strategy in arterial hypertension?

A hipertensão é um importante problema de saúde pública associado ao aumento do risco de doenças cardiovasculares. Dentre outros modelos utilizados experimentalmente para estudar a hipertensão arterial, o modelo de hipertensão 2 rins-1clipe (2R1C) está associado à significativa ativação do sistema renina-angiotensina, produzindo alterações vasculares possivelmente decorrentes do aumento do estresse oxidativo e da ativação excessiva de metaloproteinases da matriz extracelular (MMPs). As MMPs são reguladas por vários processos, e a ativação dessas proteases promove degradação excessiva dos componentes da matriz extracelular e desse modo provoca um remodelamento vascular patológico. Entre várias dessas enzimas proteolíticas, asgelatinases (MMP-2 e MMP-9) têm merecido destaque por terem um importante papel nas doenças cardiovasculares. Estudos demonstram que o aumento na atividade e nos níveis de MMP-2 pode prejudicar o relaxamento vascular dependente do endotélio e causar hipertrofia arterial, especialmente da camada média, deposição excessiva decolágeno e elastina e, desse modo, contribuir para disfunção e remodelamento vascular hipertensivo. Portanto, como as MMPs desempenham importante papel no desenvolvimento e progressão de diversas doenças cardiovasculares, a inibição dessas proteases tem sido muito estudada e valorizada como uma importante estratégia terapêutica para o tratamento dessas doenças, inclusive das consequências deletérias da hipertensão arterial.

Hypertension is an important public health problem associated with increased risk of cardiovascular disease. The experimental model of hypertension-2 kidney 1clipe (2K1C) promotes significant activation of the renin-angiotensin system, and produces vascular changes associated with increased oxidative stress and upregulation of extracellular matrix metalloproteinases (MMPs). MMPs can be regulated by several processes, and increased activation of these proteases promotes excessive degradation of extracellular matrix components, thereby causing pathological vascular remodeling. Among these proteolytic enzymes,the gelatinases (MMP-2 and MMP-9), have shown an important role in cardiovascular disease. Studies show that increased activity and levels of MMP-2 may impair the endothelium-dependent vasorelaxation and cause artery wall hypertrophy, excessive deposition of collagen and elastin, thus contributing to dysfunction and hypertensive vascular remodeling. Therefore, as the MMPs play an important role in the development and progression of various cardiovascular diseases, inhibiting these proteases has been valued as a possible therapeutic strategy in the treatment of cardiovascular diseases, including the complications associated with hypertension.

Distribution, detection of enterotoxigenic strains and antimicrobial drug susceptibility patterns of Bacteroides fragilis group in diarrheic and non-diarrheic feces from Brazilian infants

Despite the importance of gastrointestinal diseases and their global distribution, affecting millions of individuals around the world, the role and antimicrobial susceptibility patterns of anaerobic bacteria such as those in the Bacteroides fragilis group (BFG) are still unclear in young children. This study investigated the occurrence and distribution of species in the BFG and enterotoxigenic strains in the fecal microbiota of children and their antimicrobial susceptibility patterns. Diarrheic (n=110) and non-diarrheic (n=65) fecal samples from children aged 0-5 years old were evaluated. BFG strains were isolated and identified by conventional biochemical, physiological and molecular approaches. Alternatively, bacteria and enterotoxigenic strains were detected directly from feces by molecular biology. Antimicrobial drug susceptibility patterns were determined by the agar dilution method according to the guidelines for isolated bacteria. BFG was detected in 64.3 percent of the fecal samples (55 percent diarrheic and 80.4 percent non-diarrheic), and 4.6 percent were enterotoxigenic. Antimicrobial resistance was observed against ampicillin, ampicillin/sulbactam, piperacillin/tazobactam, meropenem, ceftriaxone, clindamycin and chloramphenicol. The data show that these bacteria are prevalent in fecal microbiota at higher levels in healthy children. The molecular methodology was more effective in identifying the B. fragilis group when compared to the biochemical and physiological techniques. The observation of high resistance levels stimulates thoughts about the indiscriminate use of antimicrobial drugs in early infancy. Further quantitative studies are needed to gain a better understanding of the role of these bacteria in acute diarrhea in children.

Distribution, detection of enterotoxigenic strains and antimicrobial drug susceptibility patterns of bacteroides fragilis group in diarrheic and non-diarrheic feces from brazilian infants.

Despite the importance of gastrointestinal diseases and their global distribution, affecting millions of individuals around the world, the role and antimicrobial susceptibility patterns of anaerobic bacteria such as those in the Bacteroides fragilis group (BFG) are still unclear in young children. This study investigated the occurrence and distribution of species in the BFG and enterotoxigenic strains in the fecal microbiota of children and their antimicrobial susceptibility patterns. Diarrheic (n=110) and non-diarrheic (n=65) fecal samples from children aged 0-5 years old were evaluated. BFG strains were isolated and identified by conventional biochemical, physiological and molecular approaches. Alternatively, bacteria and enterotoxigenic strains were detected directly from feces by molecular biology. Antimicrobial drug susceptibility patterns were determined by the agar dilution method according to the guidelines for isolated bacteria. BFG was detected in 64.3% of the fecal samples (55% diarrheic and 80.4% non-diarrheic), and 4.6% were enterotoxigenic. Antimicrobial resistance was observed against ampicillin, ampicillin/sulbactam, piperacillin/tazobactam, meropenem, ceftriaxone, clindamycin and chloramphenicol. The data show that these bacteria are prevalent in fecal microbiota at higher levels in healthy children. The molecular methodology was more effective in identifying the B. fragilis group when compared to the biochemical and physiological techniques. The observation of high resistance levels stimulates thoughts about the indiscriminate use of antimicrobial drugs in early infancy. Further quantitative studies are needed to gain a better understanding of the role of these bacteria in acute diarrhea in children.