Proteomic investigation of urinary markers of carbon-tetrachloride-induced hepatic fibrosis in the Hanover Wistar rat

Smyth, Rosemary; Lane, Catherine; Ashiq, Rukhsana; Turton, John; Clarke, Christopher J.; Dare, Theo; York, Malcolm; Griffiths, William J.; Munday, Michael R.

doi:10.1007/s10565-008-9104-8

Cited by 14 publications

(9 citation statements)

References 75 publications

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“…Urine samples have been scarcely studied to identify liver fibrosis markers, and we were able to identify only one experimental report that analyzed urine samples with respect to hepatic fibrosis (Smyth et al 2009). In that study, LCN2 was identified as a marker of carbon tetrachloride-induced liver fibrosis (Smyth et al 2009). Our study has shown for the first time that urinary LCN2 levels (ULCR) are elevated in CHC patients with significant fibrosis compared to patients with no or minimal fibrosis.…”

Section: Discussionmentioning

confidence: 98%

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: 98%

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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“…In 2003, for example, it was shown that the enzymatic activity of D-DT is detectable in the epidermis of the skin and is increased after UV irradiation [26]. Other studies employing proteomics demonstrated that D-DT is elevated in the rat liver [27] and in the urine in a model of carbon tetrachloride-induced hepatic fibrosis [28], and that its expression increased after selenite induced apoptosis in HeLa cancer cells [29]. Only in the last four years studies have appeared that focused on the biological role of D-DT [30–32].…”

Section: Introductionmentioning

confidence: 99%

D-dopachrome tautomerase (D-DT or MIF-2): Doubling the MIF cytokine family

et al. 2012

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D-dopachrome tautomerase (D-DT) is a newly described cytokine and a member of the macrophage migration inhibitory factor (MIF) protein superfamily. MIF is a broadly expressed pro-inflammatory cytokine that regulates both the innate and the adaptive immune response. MIF activates the MAP kinase cascade, modulates cell migration, and counter-acts the immunosuppressive effects of glucocorticoids. For many cell types, MIF also acts as an important survival or anti-apoptotic factor. Circulating MIF levels are elevated in the serum in different infectious and autoimmune diseases, and neutralization of the MIF protein via antibodies or small molecule antagonists improves the outcome in numerous animal models of human disease. Recently, a detailed investigation of the biological role of the closely homologous protein D-DT, which is encoded by a gene adjacent to MIF, revealed an overlapping functional spectrum with MIF. The D-DT protein also is present in most tissues and circulates in serum at similar concentrations as MIF. D-DT binds the MIF cell surface receptor complex, CD74/CD44, with high affinity and induces similar cell signaling and effector functions. Furthermore, an analysis of the signaling properties of the two proteins showed that they work cooperatively, and that neutralization of D-DT in vivo significantly decreases inflammation. In this review, we highlight the similarities and differences between MIF and D-DT, which we propose to designate “MIF-2” and discuss the implication of D-DT/MIF-2 expression in MIF-based therapies.

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“…in rats the oral LD 50 of NDMA has been reported to be 40 mg/kg body weight (ATSDR, 1989). Other compounds which similarly to NDMA induce hepatic fibrosis in laboratory animals are: nitrosodiethylamine (NDEA), thioacetamide and carbon tetrachloride (George & Chandrakasan, 2000; Shimizu et al , 2001; Palacios et al , 2008; Smyth et al , 2009; Karantonis et al , 2010). The available literature suggests that NDMA-induced hepatic fibrosis in rats is a very successful and reproducible model for various clinical and toxicological studies.…”

Section: Introductionmentioning

confidence: 99%

Effect of N'-nitrosodimethylamine on red blood cell rheology and proteomic profiles of brain in male albino rats

Ahmad¹,

Fatima²,

Maheshwari³

et al. 2011

Interdisciplinary Toxicology

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We investigated the effects of N'-nitrosodimethylamine (NDMA) induced toxicity on red blood cell rheology in male rats and identified bands in proteomic profiles of brain which can be used as novel markers. Polyacrylamide gel electrophoresis (PAGE) profiles exhibited constitutive as well as induced expression of the polypeptides. Remarkably, the molecular weight range of the polypeptides (8–150 kDa) corresponded to that of the family of heat shock proteins. Our results revealed significant changes in blood parameters and showed the presence of acanthocytes, tear drop cells, spicules and cobot rings in the treated categories. Lactate dehydrogenase and esterase zymograms displayed a shift to anaerobic metabolism generating hypoxia-like conditions. This study strongly suggests that NDMA treatment causes acute toxicity leading to cell membrane destruction and alters protein profiles in rats. It is therefore recommended that caution should be exercised in using NDMA to avoid risks, and if at all necessary strategies should be designed to combat such conditions.

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Proteomic investigation of urinary markers of carbon-tetrachloride-induced hepatic fibrosis in the Hanover Wistar rat

Cited by 14 publications

References 75 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

D-dopachrome tautomerase (D-DT or MIF-2): Doubling the MIF cytokine family

Effect of N'-nitrosodimethylamine on red blood cell rheology and proteomic profiles of brain in male albino rats

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