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      S-nitroso-N-acetylcysteine attenuates liver fibrosis in experimental nonalcoholic steatohepatitis

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          S-Nitroso-N-acetylcysteine (SNAC) is a water soluble primary S-nitrosothiol capable of transferring and releasing nitric oxide and inducing several biochemical activities, including modulation of hepatic stellate cell activation. In this study, we evaluated the antifibrotic activity of SNAC in an animal model of nonalcoholic steatohepatitis (NASH) induced in Sprague-Dawley rats fed with a choline-deficient, high trans fat diet and exposed to diethylnitrosamine for 8 weeks. The rats were divided into three groups: SNAC, which received oral SNAC solution daily; NASH, which received the vehicle; and control, which received standard diet and vehicle. Genes related to fibrosis (matrix metalloproteinases [MMP]-13, -9, and -2), transforming growth factor β-1 [TGFβ-1], collagen-1α, and tissue inhibitors of metalloproteinase [TIMP-1 and -2] and oxidative stress (heat-shock proteins [HSP]-60 and -90) were evaluated. SNAC led to a 34.4% reduction in the collagen occupied area associated with upregulation of MMP-13 and -9 and downregulation of HSP-60, TIMP-2, TGFβ-1, and collagen-1α. These results indicate that oral SNAC administration may represent a potential antifibrotic treatment for NASH.

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          Most cited references 16

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          Sirius red histophotometry and spectrophotometry of sections in the assessment of the collagen content of liver tissue and its application in growing rat liver.

          By means of staining with Sirius Red F3BA in a saturated picric acid solution, the collagen contents of rat livers with varying degrees of fibrosis have been measured quantitatively in fixed and sectioned material, using both histophotometry in situ and extraction of bound dye with colorimetric analysis. These findings have been correlated with chemical assays of the hydroxyproline content in homogenates from the same livers. It appears that a highly significant correlation exists between both section-based analysis methods and the hydroxyproline content, the Spearman-Rank correlation coefficients being virtually identical. For analysis of collagen accumulation in rat liver, both section-based methods seem to be useful and reliable, the extraction method giving the quickest results for large-scale screening, and the histophotometric method being more appropriate to take readings in selected areas. With human liver material, indications have been obtained for the existence of large sampling errors due to inhomogeneous distribution of collagen deposits. Using the extraction method, no significant changes could be observed in the volume density of collagen during postnatal growth from 1 week to 21 months in rat liver: only on the third day after birth was a higher value of collagen/total protein obtained, possibly due to a higher water content of the hepatocytes. Partial hepatectomy was found to have no influence at all on the collagen content of rat liver during the period of restorative growth or after it.
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            Mechanisms of fibrinolysis in chronic liver injury (with special emphasis on MMPs and TIMPs).

            Regeneration from liver fibrosis is characterized by four essential events: 1. eradication of pathological agents, 2. apoptosis of activated hepatic stellate cells, 3. remodeling of extracellular matrix, and 4. regeneration of parenchyma and liver function. The temporal and spatial regulation of matrix metalloproteinase (MMP) activity and expression of their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play a pivotal role in matrix remodeling during hepatic fibrogenesis and recovery. According to current knowledge, the main topics and mechanisms in regeneration from hepatic fibrosis with special emphasis on MMPs and TIMPs are presented. MMP and TIMP expression patterns during hepatic fibrogenesis and fibrolysis, specific characteristics like regulation, expression of cell types, gene expression (RNA/protein), and the underlying disease are summarized. Studies presenting a time course for MMP and TIMP expression during recovery from hepatic fibrosis were taken into consideration to point out a synchronizing behavior in the expression pattern.
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              A chemist's view of the nitric oxide story.


                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                28 June 2013
                : 7
                : 553-563
                [1 ]University of São Paulo School of Medicine, Department of Gastroenterology, Clinical Division, Hepatology Branch (LIM-07), Sao Paulo, Brazil
                [2 ]Institute of Chemistry, University of Campinas, Campinas, Sao Paulo, Brazil
                [3 ]University of Sao Paulo School of Veterinary Medicine and Animal Science, Department of Pathology, Sao Paulo, Brazil
                [4 ]University of São Paulo School of Medicine, Department of Pathology (LIM14), São Paulo, Brazil
                Author notes
                Correspondence: Marcelo G de Oliveira University of Campinas, UNICAMP, Institute of Chemistry, CP 6154, CEP 13083-970, Campinas, Sao Paulo, Brazil, Tel +55 19 3521 3132, Email mgo@ 123456iqm.unicamp.br
                Claudia Pinto Marques Souza de Oliveira Av Dr Enéas de Carvalho Aguiar no 255, Instituto Central, 9159, CEP 05403-000, Sao Paulo, Brazil, Tel +55 11 2661 6447, Email cpm@ 123456usp.br
                © 2013 Mazo et al, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Original Research


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