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1.
Braz. j. med. biol. res ; 48(5): 408-414, 05/2015. graf
Article Dans Anglais | LILACS | ID: lil-744374

Résumé

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.


Sujets)
Adolescent , Adulte , Femelle , Humains , Mâle , Jeune adulte , Trouble dépressif majeur/thérapie , Coûts des soins de santé/statistiques et données numériques , Accessibilité des services de santé/statistiques et données numériques , Troubles liés à une substance/rééducation et réadaptation , Diagnostic mixte (psychiatrie) , Trouble dépressif majeur/complications , Trouble dépressif majeur/économie , Enquêtes de santé , Accessibilité des services de santé/économie , Services de santé mentale/économie , Services de santé mentale/statistiques et données numériques , Troubles liés à une substance/complications , Troubles liés à une substance/économie , États-Unis
2.
Braz. j. med. biol. res ; 42(11): 1050-1057, Nov. 2009. ilus
Article Dans Anglais | LILACS | ID: lil-529105

Résumé

Sepsis involves a systemic inflammatory response of multiple endogenous mediators, resulting in many of the injurious and sometimes fatal physiological symptoms of the disease. This systemic activation leads to a compromised vascular response and endothelial dysfunction. Purine nucleotides interact with purinoceptors and initiate a variety of physiological processes that play an important role in maintaining cardiovascular function. The purpose of the present study was to investigate the effects of ATP on vascular function in a lipopolysaccharide (LPS) model of sepsis. LPS induced a significant increase in aortic superoxide production 16 h after injection. Addition of ATP to the organ bath incubation solution reduced superoxide production by the aortas of endotoxemic animals. Reactive Blue, an antagonist of the P2Y receptor, blocked the effect of ATP on superoxide production, and the nonselective P2Y agonist MeSATP inhibited superoxide production. Nitric oxide synthase (NOS) inhibition by L-NAME blocked vascular relaxation and reduced superoxide production in LPS-treated animals. In the presence of L-NAME there was no ATP effect on superoxide production. A vascular reactivity study showed that ATP increased maximal relaxation in LPS-treated animals compared to controls. The presence of ATP induced increases in Akt and endothelial NOS phosphorylated proteins in the aorta of septic animals. ATP reduces superoxide release resulting in an improved vasorelaxant response. Sepsis may uncouple NOS to produce superoxide. We showed that ATP through Akt pathway phosphorylated endothelial NOS and “re-couples” NOS function.


Sujets)
Animaux , Mâle , Rats , Adénosine triphosphate/pharmacologie , Aorte thoracique/enzymologie , Endothélium vasculaire/enzymologie , Nitric oxide synthase/biosynthèse , Nucléotides puriques/physiologie , Sepsie/enzymologie , Superoxydes/métabolisme , Aorte thoracique/physiopathologie , Endothélium vasculaire/physiopathologie , Lipopolysaccharides , Phosphorylation , Rat Wistar , Sepsie/physiopathologie
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