Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid

Reif, Shimon; Aeed, Hussein; Shilo, Yael; Reich, Reuven; Kloog, Yoel; Kweon, Young Oh; Bruck, Rafael

doi:10.1016/j.jhep.2004.04.010

Cited by 49 publications

(29 citation statements)

References 43 publications

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“…hepatic ECM, is expressed in the liver injury/fibrosis models (Kossakowska et al 1998;Reif et al 2004) and CHC (Lichtinghagen et al , 2003Nunez et al 2004). However, previous studies have reported controversial associations between hepatic fibrosis and blood MMP-9 levels in CHC patients (Hayasaka et al 1996;Kuo et (A) Urinary MMP-9 and MMP-2 activities were identified in representative CHC patients and in a patient with end-stage renal disease (ESRD) as a positive control (Bolignano et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Activated MMP-9 can degrade type IV collagen, which is a major component of the basement membrane and normal hepatic ECM (Benyon and Arthur 2001;Iredale 2007;Friedman 2008). Several previous reports showed increased hepatic expression of MMP-9 in experimental cirrhosis (Kossakowska et al 1998;Reif et al 2004) and CHC Nunez et al 2004). These findings raise the possibility that MMP-9 may serve as a direct marker of hepatic fibrosis in CHC.…”

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confidence: 90%

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Increased Urinary Lipocalin-2 Reflects Matrix Metalloproteinase-9 Activity in Chronic Hepatitis C with Hepatic Fibrosis

Kim

Lee

Jeong

et al. 2010

Tohoku J. Exp. Med.

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Hepatic fibrosis is characterized by excessive accumulation of extracellular matrix. Matrix metalloproteinases (MMPs) play an important role in the remodeling of the extracellular matrix during hepatic fibrosis. Lipocalin-2 (LCN2) forms complexes with MMP-9 and can be detected in the urine of patients with several types of cancers. The objective of this study was to examine the relationship between urinary LCN2 levels and MMP-9 activity with respect to the stage of liver fibrosis in patients with chronic hepatitis C (CHC), and to assess the utility of urine LCN2 as a non-invasive marker of hepatic fibrosis. Fresh spot urine samples were prospectively collected from forty-two interferon-naive CHC patients who underwent liver biopsy. The stage of hepatic fibrosis was assessed according to the METAVIR fibrosis score; 18 patients had no or mild fibrosis (stages F0 and F1) and 24 patients showed significant fibrosis (stages F2-F4). Immunoblot analyses demonstrated co-migration of urine LCN2 and MMP-9. Gelatin zymography showed that urinary MMP-9/MMP-2 activity ratios were higher in patients with significant fibrosis (F2-F4) than in patients no or mild fibrosis (F0-F1). Urine LCN2 levels which were normalized to urine creatinine concentration (urine LCN2-to-creatinine ratio; ULCR) were higher in F2-F4 patients compared to F0-F1 patients. There was a positive correlation between ULCR and urine MMP-9/MMP-2 activity ratios (r = 0.735). ULCR and AST-to-platelet ratio index were independent predictors of significant fibrosis by multivariate analysis. The present study suggests that urinary LCN2 is a novel marker of hepatic fibrosis by reflecting urine MMP-9 activity in CHC.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

Increased Urinary Lipocalin-2 Reflects Matrix Metalloproteinase-9 Activity in Chronic Hepatitis C with Hepatic Fibrosis

Kim

Lee

Jeong

et al. 2010

Tohoku J. Exp. Med.

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“…We have previously shown that FTS is a reversible drug [19], [20], [21] with reversibility of its inhibitory effects on Ras-dependent growth in vitro [18], [19], [20] and in vivo [21] and on Ras -dependent behavior in vivo [15]. Moreover, FTS has been found to be beneficial in decreasing inflammation and fibrosis in experimentally induced liver cirrhosis and in treating and preventing inflammatory processes such as SLE, neuritis or nephritis in animal models [13], [14], [15], [22], [23].…”

Section: Introductionmentioning

confidence: 99%

The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J Mouse Model of Muscular Dystrophy

et al. 2011

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The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy2J/dy2J mouse model of merosin deficient congenital muscular dystrophy. The dy2J/dy2J mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy2J/dy2J mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy2J/dy2J mouse model of congenital muscular dystrophy.

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“…It has been proposed that increased expression of ras in cirrhotic livers might be associated with inflammation and fibrosis, besides its suggested role in the early step of hepatocarcinogenesis [4]. However the relationship between ras expression and angiogenesis during liver fibrogenesis has not been documented.…”

Section: Introductionmentioning

confidence: 99%

H-Ras Oncogene Expression and Angiogenesis in Experimental Liver Cirrhosis

Elpek

Ünal²,

Bozova³

2013

Gastroenterology Research and Practice

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Background. Proto-oncogenes, particularly ras, may not only affect cell proliferation but also contribute to angiogenesis by influencing both proangiogenic and antiangiogenic mediators. The aim of this study was to investigate whether any relationship exists between ras expression and angiogenesis during diethylnitrosamine- (DEN-) induced experimental liver fibrosis. Materials and Methods. Liver cirrhosis was induced in rats by intraperitoneal injections of DEN. The animals were sacrificed 2 weeks after the last administrations and a hepatectomy was performed. Masson's trichrome staining was used in the evaluation of the extent of liver fibrosis. The vascular density in portal and periportal areas was assessed by determining the count of CD34 labeled vessel sections. For quantitative evaluation of H-ras expression, in each section positive and negative cells were counted. Results. In fibrotic group H-ras expression was higher than that in nonfibrotic group and was more widespread in cirrhotic livers. Friedman's test showed that there was a significant correlation between H-ras expression and VD (P < 0.01). Conclusion. The results of this descriptive study reveal that H-ras expression gradually increases according to the severity of fibrosis and strongly correlates with angiogenesis.

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Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid

Cited by 49 publications

References 43 publications

Increased Urinary Lipocalin-2 Reflects Matrix Metalloproteinase-9 Activity in Chronic Hepatitis C with Hepatic Fibrosis

Increased Urinary Lipocalin-2 Reflects Matrix Metalloproteinase-9 Activity in Chronic Hepatitis C with Hepatic Fibrosis

The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J Mouse Model of Muscular Dystrophy

H-Ras Oncogene Expression and Angiogenesis in Experimental Liver Cirrhosis

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