Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron overload to the liver induces hepatic injury, eventually ending up with liver fibrosis or cirrhosis. Pathogenic mechanisms involved in liver damage are only partially known, but there is evidence for an important role of iron-induced reactive oxygen species. We have, therefore, analyzed the immunohistochemical reactivity for two major free radical scavengers, copper/zinc and manganese superoxide dismutase (Cu/Zn- and Mn-SOD's) in three situations of hepatic iron overload, and compared enzyme patterns with grades of iron deposition, grades of fibrosis, and levels of microphotometrically measured type IV collagen immunoreactivity. Cu/Zn- and Mn-SOD reactivity was detectable in hepatocytes with a heavy and a low iron burden, but Cu/Zn-SOD staining was more intense than that of Mn-SOD in the three groups analysed. There was trend for microphotometrically measured type IV collagen levels to increase with the amount of iron, and increased collagen IV was correlated with higher grades of Cu/Zn-SOD, but not of Mn-SOD, reactivity. The findings suggest that the two SOD's may be differentially expressed in states of hepatic iron overload, and that low expression of the inducible radical scavenger, Mn-SOD, may play a role in chronic iron toxicity.
 ...
PMID:Copper/zinc and manganese superoxide dismutase immunoreactivity in hepatic iron overload diseases. 857 13

In this study, we developed a double-transgenic mouse model allowing hepatocyte-specific and regulated expression of the redox-modifying enzymes copper/zinc superoxide dismutase (SOD) and glutathione peroxidase (GPX) by using a tetracycline-regulatable gene expression system. Within this system, the SOD and GPX level can be regulated deliberately by addition or removal of doxycycline hydrochloride to the drinking water. As reactive oxygen species (ROS) have been implicated in a number of pathological conditions, such as atherosclerosis, thrombosis, or liver fibrosis, processes that are also frequently associated with enhanced levels of plasminogen activator inhibitor-1 (PAI-1), it was the aim of the present study to investigate the influence of SOD and GPX overexpression on the regulation of PAI-1. PAI-1 mRNA and protein levels in tetracycline transactivator-dependent SOD-overexpressing double-transgenic mice reached values 2.5- to threefold above the normal mRNA level. By applying doxycycline, a deinduction of the PAI-1 levels was observed. By using the same protocol, PAI-1 mRNA and protein levels were enhanced in GPX double-transgenic mice, and again this response was blunted by the addition of doxycycline. These studies provide some new information regarding the role of ROS within the proteolytic processes in hepatocytes that require PAI-1.
 ...
PMID:Enhanced plasminogen activator inhibitor-1 expression in transgenic mice with hepatocyte-specific overexpression of superoxide dismutase or glutathione peroxidase. 1524 48

Liver fibrosis plays a pivotal role in liver function impairment and is a feature of chronic infection by hepatitis C virus (HCV). Ten to 20% of patients progress to cirrhosis leading to an increased risk of liver failure or hepatocellular carcinoma (HCC). Recent advances have culminated in clear evidence that fibrosis can be reversible, and in expectation that effective anti-fibrotic therapy will improve the prognosis. Among the different cellular pathways involved in fibrosis, the transforming growth factor-beta1 (TGF-beta1) signaling plays a major role. Increases of TGF-beta1 expression is associated with fibrotic diseases and this cytokine could be a target for an antifibrotic drug. Clinical results on radiation-induced fibrosis have brought some evidences that Cu-Zn SOD (SOD1) could be an anti-fibrotic drug. Its therapeutic effect could be related to a down-regulation of TGF-beta1 as proved in a well characterized pig model of radiation induced fibrosis, where the efficacy of Cu-Zn SOD has been shown in reversing fibrosis. Using 3-D skin co-culture of fibroblasts from this pig model, it was showed that SOD significantly reduces the expression of the TGFbeta1, both at the mRNA and protein level. An experimental work could be undertaken to validate the Cu-Zn SOD as an anti-fibrotic drug, using HCV core protein expressing transgenic mice. As the current anti-HCV therapy with pegylated interferon combined with ribavirin can eradicate virus and stop the progression of fibrosis, but near 50% of HCV infected patients are non responders, a controlled trial is planned for HCV infected patients non responders to this therapy with a Metavir fibrosis score reaching F = 2 or >2.
 ...
PMID:Cu-Zn super oxide dismutase as a potential antifibrotic drug for hepatitis C related fibrosis. 1629 93

Suppression of activation or proliferation, or induction of apoptosis in hepatic stellate cells (HSCs) have been proposed as therapeutic strategies against liver fibrosis. Salvia miltiorrhiza has been reported to exert antifibrotic effects in rats with hepatic fibrosis, but its mechanisms of action remain to be clarified. We have investigated the effects of salvianolic acid A (Sal A), an active principle from S. miltiorrhiza, on the proliferation-related biomarkers in a cell line of rat HSCs (HSC-T6) stimulated with platelet-derived growth factor-BB homodimer (PDGF-BB). DNA synthesis (bromodeoxyuridine (BrdU) incorporation), cell cycle related proteins and apoptosis markers were determined to evaluate the inhibitory effects of Sal A. The results showed that Sal A (1-10 microM) concentration-dependently attenuated PDGF-BB-stimulated proliferation (BrdU incorporation) in HSC-T6 cells. Sal A at 10 microM induced cell apoptosis in PDGF-BB-incubated HSCs, together with a reduction of Bcl-2 protein expression, induction of cell cycle inhibitory proteins p21 and p27, and down-regulation of cyclins D1 and E, suppression of Akt phosphorylation, reduction in PDGF receptor phosphorylation, and an increase in caspase-3 activity. Sal A exerted no direct cytotoxicity on primary hepatocytes and HSC-T6 cells under experimental concentrations. Our results suggested that Sal A inhibited PDGF-BB-activated HSC proliferation, partially through apoptosis induction.
 ...
PMID:Antiproliferative effect of salvianolic acid A on rat hepatic stellate cells. 1680 53

Activins are a closely related subgroup within the TGFbeta superfamily of growth and differentiation factors. They consist of two disulfide-linked beta subunits. Four mammalian activin beta subunits termed beta(A), beta(B), beta(C), and beta(E), respectively, have been identified. Activin A, the homodimer of two beta(A) subunits, has important regulatory functions in reproductive biology, embryonic development, inflammation, and tissue repair. Several intra- and extracellular antagonists, including the activin-binding proteins follistatin and follistatin-related protein, serve to fine-tune activin A activity. In the liver there is compelling evidence that activin A is involved in the regulation of cell number by inhibition of hepatocyte replication and induction of apoptosis. In addition, activin A stimulates extracellular matrix production in hepatic stellate cells and tubulogenesis of sinusoidal endothelial cells, and thus contributes to restoration of tissue architecture during liver regeneration. Accumulating evidence from animal models and from patient data suggests that deregulation of activin A signaling contributes to pathologic conditions such as hepatic inflammation and fibrosis, acute liver failure, and development of liver cancer. Increased production of activin A was suggested to be a contributing factor to impaired hepatocyte regeneration in acute liver failure and to overproduction of extracellular matrix in liver fibrosis. Recent evidence suggests that escape of (pre)neoplastic hepatocytes from growth control by activin A through overexpression of follistatin and reduced activin production contributes to hepatocarcinogenesis. The role of the activin subunits beta(C) and beta(E), which are both highly expressed in hepatocytes, is still quite incompletely understood. Down-regulation in liver tumors and a growth inhibitory function similar to that of beta(A) has been shown for beta(E). Contradictory results with regard to cell proliferation have been reported for beta(C). The profound involvement of the activin axis in liver biology and in the pathogenesis of severe hepatic diseases suggests activin as potential target for therapeutic interventions.
 ...
PMID:The activin axis in liver biology and disease. 1699 17

Paeonia lactiflora and Astragalus membranaceus are two popular traditional Chinese medicines, commonly used in Chinese herb prescription to treat liver disease. The extract prepared from the roots of Paeonia lactiflora and Astragalus membranaceus (PAE) demonstrated more excellent hepato-protective activity than the single herbs used individually as indicated in our preliminary studies. The present study was carried out to investigate the effects of PAE on liver fibrosis in rats induced by carbon tetrachloride (CCl(4)) and to explore its possible mechanisms. Liver fibrosis was induced in male Sprague-Dawley rats by injection with 50% CCl(4) subcutaneously twice a week for 8 weeks. At the same time, PAE (40, 80 and 160 mg/kg) was administered intragastrically. Upon pathological examination, the PAE-treated rats significantly reduced the liver damage and the symptoms of liver fibrosis. Administration of PAE decreased CCl(4)-induced elevation of serum transaminase activities, hyaluronic acid, laminin and procollagen type III levels, and contents of hydroxyproline in liver tissue by approximately 30-60%. It also restored the decrease in SOD and GSH-Px activities and inhibited the formation of lipid peroxidative products during CCl(4) treatment. Moreover, PAE (80, 160 mg/kg, ig) decreased the elevation of TGF-beta1 by 47.7% and 53.1%, respectively. In the primary cultured hepatic stellate cells (HSCs), PAE also significantly decreased [(3)H] thymidine incorporation in cells stimulated with platelet-derived growth factor-B subunit homodimer (PDGF-BB) and suppressed [(3)H] proline incorporation. These results suggested that PAE significantly inhibited the progression of hepatic fibrosis induced by CCl(4), and the inhibitory effect of PAE on hepatic fibrosis might be associated with its ability to scavenge free radicals, decrease the level of TGF-beta1 and inhibit collagen synthesis and proliferation in HSCs.
 ...
PMID:Effects and mechanisms of extract from Paeonia lactiflora and Astragalus membranaceus on liver fibrosis induced by carbon tetrachloride in rats. 1757 57

Carbon tetrachloride (CCl(4)) was used to induce liver fibrosis in the rat. Using this model, we have identified changes in serum and urinary clinical chemistry parameters, and characterized histopathological lesions in the liver. Two experiments were conducted. In Experiment 1, rats were dosed at six levels of CCl(4) (0.06-0.36 ml/kg) twice weekly for 6 weeks, followed by a 6-week non-dosing recovery period (week 12). Livers were removed for histology at 6 and 12 weeks and serum parameters analysed. In Experiment 2, rats were given seven dose levels of CCl(4) (0.4-1.0 ml/kg) twice weekly for 6 weeks, followed by a 6-week recovery period (week 12); urine samples were analysed at 3, 6, 9 and 12 weeks using one-dimensional sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Liver fibrosis was evident at 6 weeks in Experiments 1 and 2, and the activity of serum enzymes (including alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase) was increased. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis (Experiment 2) revealed a protein band at 18.4 kDa in urine from rats treated with CCl(4), not present in control urine, which was identified as copper/zinc superoxide dismutase (Cu/Zn SOD). Western blotting revealed that SOD was increased in urine from rats treated with CCl(4) at 3 and 6 weeks, but not at 9 and 12 weeks. We conclude that Cu/Zn SOD is a urinary marker of hepatic necrosis, but not hepatic fibrosis.
 ...
PMID:Comprehensive characterization of serum clinical chemistry parameters and the identification of urinary superoxide dismutase in a carbon tetrachloride-induced model of hepatic fibrosis in the female Hanover Wistar rat. 1787 38

Proteomic techniques such as two-dimensional gel electrophoresis (2-DGE) and mass spectrometry have become important tools for the identification of novel biomarkers of toxicity and disease. Ideally, such biomarkers need to be sensitive and organ specific, but, recently, it has become apparent that it would be an additional benefit to be able to measure biomarkers in samples obtained using non-invasive methods. The present study is concerned with the identification of novel urinary markers of hepatic fibrosis. In a carbon-tetrachloride-induced liver fibrosis rat model, analysis of urine by 2-DGE revealed an increase in the concentration of a number of proteins in animals with hepatic fibrosis. Using in-gel trypsin digest and nano-scale liquid chromatography combined with electrospray ionisation tandem mass spectrometry, protein spots were identified as copper/zinc superoxide dismutase, D: -dopachrome tautomerase, beta-2-microglobulin and neutrophil gelatinase associated lipocalin. These proteins are known to have important roles in the inflammatory response.
 ...
PMID:Proteomic investigation of urinary markers of carbon-tetrachloride-induced hepatic fibrosis in the Hanover Wistar rat. 1877 38

Docosahexaenoic acid (DHA) regulates the lipid metabolism and inflammation that is closely associated with oxidative stress. The present study investigated the effects of DHA on the development of nonalcoholic steatohepatitis (NASH). To induce fatty liver, rats were fed choline-deficient high-fat diets (CDHF). The rats were then divided into 4 groups treated over the subsequent 6 weeks as follows: control, CDHF, CDHF+oxidative stress (NASH), and NASH+DHA (1.0 g/kg, p.o.). Rats of the control group were fed MF chow diet only. NASH rats showed severe steatohepatitis and liver fibrosis. Treatment with DHA significantly decreased the n-6/n-3 ratio in the livers and increased plasma SOD like activity compared with NASH rats. In addition, DHA attenuated the liver fibrosis during NASH development. Therefore, a higher DHA ratio in the liver of NASH rats might regulate the inflammatory response through a low n-6 ratio and diminished oxidative stress, effectively inhibiting liver fibrosis during NASH progression. These results suggested that DHA is a novel functional food for the prevention of NASH.
 ...
PMID:Effects of docosahexaenoic acid in an experimental rat model of nonalcoholic steatohepatitis. 2062 32

In eukaryotic cells amino acid deprivation triggers a response aimed to ensure cell survival in stress conditions. In the present work we analyzed the effects of amino acid deprivation on intracellular levels of reactive oxygen species (ROS) of hepatic stellate cells (HSC), a key cell type in the development of liver fibrosis. Histidine deprivation caused in the human immortalized HSC cell line LX-2 a fast decrease of intracellular ROS levels that was also observed in HSC incubated either with leucine-free or amino acid-free medium, but not with glucose-free medium. Phosphorylation of GCN2 kinase and its substrate eIF2alpha was induced by histidine deprivation. Reversion studies and activation of GCN2 by tRNA and the proteasome inhibitor MG-132 showed a correlation between GCN2 phosphorylation and diminished ROS levels. However, a lack of correlation between eIF2alpha phosphorylation and ROS levels was found using salubrinal, an inhibitor of eIF2alpha phosphorylation, suggesting a role for GCN2 unrelated to its activity as eIF2alpha kinase. LX-2 cells treated with histidine-free medium presented reduced SOD activity that could account for the decrease on ROS levels. Histidine deprivation as well as activation of GCN2 by treatment with tRNA, caused an increase in LX-2 cell viability, suggesting amino acid restriction to present a protective effect in HSC which is mediated by GCN2 activation.
 ...
PMID:Amino acid deprivation decreases intracellular levels of reactive oxygen species in hepatic stellate cells. 2079 12


1 2 3 4 5 Next >>