Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Mild iron overload in chronic hepatitis C is associated with liver fibrosis, hepatitis C virus (HCV) genotype 1b infection, and an impaired response to interferon therapy. In this study we evaluated whether polymorphisms in the hemochromatosis gene HFE and the transferrin receptor gene TFR1 are associated with these typical findings. The study considered 246 HCV-infected patients and 200 blood donors as controls, in which C282Y, H63D, and S65C mutations ( HFE) and the S142G polymorphism ( TFR1) were detected. HCV genotype, serum ferritin levels, stainable intrahepatic iron, and grade of fibrosis according to the METAVIR score (F0-F4) were determined. In HCV-infected patients, heterozygosity for the C282Y mutation in HFE was significantly associated with elevated serum ferritin levels, stainable liver iron, and advanced fibrosis or cirrhosis (F2-F4). By multivariate logistic regression analysis the odds ratio for the development of advanced fibrosis or cirrhosis (F2-F4) was 2.5 for HCV-infected patients carrying a heterozygous C282Y mutation and 4.8 for HCV-infected patients with C282Y/H63D and C282Y/S65C compound heterozygosity. Heterozygosity for the C282Y mutation in HFE contributes to iron accumulation and fibrosis progression in chronic hepatitis C.
J Mol Med (Berl) 2003 Dec
PMID:Hemochromatosis and transferrin receptor gene polymorphisms in chronic hepatitis C: impact on iron status, liver injury and HCV genotype. 1476 Aug 28

In liver fibrosis, the quiescent hepatic stellate cells (HSC) are activated to proliferate and express the activated myofibroblast phenotype, losing fat droplets and the stored vitamin A, and depositing more extracellular matrix. Therapeutic strategies for liver fibrosis are focused on HSC. Pentoxifylline (PTF), an analog of the methylxanthine, prevents the biochemical and histological changes associated with animal liver fibrosis. The aim of the present study was to investigate the phenotypic change of myofibroblasts into quiescent lipocytes by PTF and/or retinol, using a permanent cell line GRX that represents murine HSC. We studied the action of both drugs on the synthesis of neutral lipids, activity of phospholipase A2 (PLA2), release of arachidonic acid (AA) and prostaglandins synthesis. Accumulation and synthesis of neutral lipids was dependent upon association of retinol with PTF. PTF (0.5 mg/mL) alone did not induce lipid accumulation and synthesis, but in cells induced by physiologic concentration of retinol (1-2.5 microM), it increased the quantity of stored lipids. Retinol and PTF (5 microM and 0.1 mg/mL, respectively) had a synergistic effect on neutral lipid synthesis and accumulation. In higher PTF concentrations (0.5 and 0.7 mg/ml), the synthesis was stimulated but accumulation decreased. Membrane-associated PLA2 activity decreased after PTF treatment, which increased the AA release 8 fold, and significantly increased the production of PGE2, but not of PGF2. However, when in presence of retinol, we observed a slightly higher increase in PGE2 and PGF2a production. In conclusion, PTF treatment generated an excess of free AA. We propose that retinol counteracts the action of PTF on the AA release and PGs production, even though both drugs stimulated the lipocyte induction in the HSC.
Mol Cell Biochem 2003 Dec
PMID:Effect of pentoxifylline on arachidonic acid metabolism, neutral lipid synthesis and accumulation during induction of the lipocyte phenotype by retinol in murine hepatic stellate cell. 1467 80

The extracellular matrix (ECM) expression is subject to distinct changes during ontogeny, and the natural course of liver fibrosis in neonates is thought to differ from that in adults. We compared the expression and distribution of main ECM components between neonatal and adult liver fibrosis. Liver biopsies from infants with neonatal cholestasis and fibrosis were compared to adult biopsies exhibiting an equivalent stage of fibrosis. All biopsies were examined by immunohistochemistry (indirect ABC method) for the ECM proteins, collagens I, III, IV, and VI, laminin, and fibronectin. Infants (aged 1-8 months) with neonatal hepatitis (n = 3), extrahepatic biliary atresia (EHBA) (n = 5), and normal histology (n = 2) were compared with 9 adults (aged 17-70 years) with chronic hepatitis (n = 3), primary biliary cirrhosis (PBC) (n = 4), and normal histology (n = 2). Collagens I, III, and IV and fibronectin were significantly increased in neonatal hepatitis with mild fibrosis (score < or = 4) compared to adults with an equivalent fibrosis stage. This increase was particularly notable in perisinusoidal spaces. Laminin expression was increased in portal and perisinusoidal spaces both in neonatal hepatitis and extrahepatic biliary atresia with mild fibrosis. In infants with moderate to severe fibrosis (score > or = 6), only collagen I was increased in comparison to adults, whereas collagen VI expression was identical in all groups, irrespective of the degree of fibrosis. Expression of matrix proteins was not different in infants and adults without fibrosis. The increased perisinusoidal deposition of certain ECM components in infants with active hepatitis and mild fibrosis may point to an underlying difference in the mechanism or stimulus of fibrogenesis in neonates as compared to adults.
Pediatr Pathol Mol Med
PMID:Divergent patterns of extracellular matrix protein expression in neonatal versus adult liver fibrosis. 1469 30

Gene therapy may represent a new avenue for the development of multimodal treatment for diverse forms of cirrhosis. This study explores the potential benefits of combining adenovirus-mediated human urokinase-plasminogen activator (AdHuPA) gene delivery and biliodigestive anastomosis to enhance the therapeutic efficacy of each treatment alone for cholestatic disorders resulting in secondary biliary cirrhosis. In an experimental model of secondary biliary cirrhosis, application of 6 x 10(11) vp/kg AdHuPA adenovirus vector resulted in 25.8% liver fibrosis reduction and some improvement in liver histology. The relief of bile cholestasis by a surgical procedure (biliodigestive anastomosis) combined with AdHuPA hepatic gene delivery rendered a synergistic effect, with a substantial 56.9 to 42.9% fibrosis decrease. AdHuPA transduction resulted in clear-cut expression of human uPA protein detected by immunohistochemistry and induction of up-regulation in the expression of metalloproteinases MMP-3, MMP-9, and MMP-2. Importantly, functional hepatic tests, specifically direct bilirubin, were improved. Also, hepatic cell regeneration, rearrangement of hepatic architecture, ascites, and gastric varices improved in cirrhotic rats treated with AdHuPA but not in counterpart AdGFP cirrhotic animals. We believe this might represent a novel therapeutic strategy for human cholestatic diseases.
Mol Ther 2004 Jan
PMID:Improved effects of viral gene delivery of human uPA plus biliodigestive anastomosis induce recovery from experimental biliary cirrhosis. 1474 75

Hepatic fibrosis is a wound-healing response to chronic liver injury, which if persistent can lead to cirrhosis and liver failure. Activation of hepatic stellate cells (HSCs), leading to accumulation of extracellular matrix, is the central event of fibrogenesis. Exciting progress has been made in understanding the molecular basis of this process. Major advances include: (1) elucidation of the effects (and signalling pathways) of key cytokines on HSCs; (2) understanding the transcriptional regulation of HSC activation; (3) characterisation of matrix proteases and their inhibitors; (4) demonstration of apoptosis as an important event in the resolution of hepatic fibrosis, and identification of its mediators;(5) elucidation of the complex and dynamic interaction between HSCs and matrix; and (6) understanding the role of other cellular elements in hepatic fibrosis and their interaction with HSCs. Ongoing research with gene analysis using cDNA or oligonucleotide microarrays, or transcriptional profiling, will further increase our knowledge of the regulation of the process. Ultimately,advances in the understanding of the molecular biology of hepatic fibrosis are critical to the development of effective, targeted antifibrotic therapy that might benefit millions of patients with chronic liver disease worldwide.
Expert Rev Mol Med 2003 Feb 14
PMID:Molecular basis of hepatic fibrosis. 1498 8

Many forms of liver disease may ultimately lead to fibrosis of the liver, the most advanced state being cirrhosis. Cirrhosis is a morphologic disease that eventually results in a functional change of the liver. It is generally not accompanied by signs or symptoms early in its course, and is often diagnosed late when signs of liver failure become overt. Imaging studies may suggest cirrhosis, but only if there have been gross changes in the appearance of the liver, and this is often not the case. The only way to diagnose cirrhosis reliably has been through direct histologic examination of liver tissue. The drawback to histologic diagnosis has been the risks and discomfort associated with liver biopsy. Hesitation to perform the procedure also exists due to lack of experience of many practitioners and the low reimbursement rates for a procedure that is viewed as time consuming and potentially dangerous. The search for noninvasive modalities to assess fibrosis through biochemical and other means has begun. Several markers are currently under investigation, many of which are combined with clinical assessment and other biochemical parameters, to establish the presence of liver fibrosis. FIBROSpect II is an example of a commercially available assay that employs a combination of three markers to distinguish between no, minimal and advanced fibrosis.
Expert Rev Mol Diagn 2004 Sep
PMID:FIBROSpect II: a potential noninvasive test to assess hepatic fibrosis. 1534 53

Laboratory tests for the noninvasive diagnosis of liver fibrosis were studied extensively in the past. However, no test is yet accepted to replace liver biopsy as the gold standard. The establishment of widely accepted semiquantitative histologic scoring systems for the grading and staging of chronic liver disease (e.g., Ishak, Metavir and Scheuer) was paralleled by a significant upturn of research in circulating markers of liver fibrosis. We are now experiencing the renaissance of standard clinical chemistry markers, which are assembled to multiparameter scores (e.g., aspartate aminotransferase-to-platelet ratio index, FibroTest, Forns' index). These scores still require comprehensive evaluation in comparison with histology. Better understanding of the pathophysiology of liver fibrosis provided new options regarding circulating markers of hepatic matrix metabolism (e.g., hyaluronic acid, laminin, matrix metalloproteinase-2, aminoterminal propeptide of procollagen type III and tissue inhibitors of metalloproteinases-1). Several promising studies have been published to date. Thus, a redefinition of the role of liver biopsy is expected in the foreseeable future.
Expert Rev Mol Diagn 2004 Sep
PMID:Noninvasive diagnosis of fibrosis in chronic liver disease. 1534 64

Liver cirrhosis is caused by a relative imbalance between synthesis and degradation of collagens. Arg-Gly-Asp (RGD) peptide is a major adhesive domain of several extracellular matrix (ECM) components, such as that involved in the binding of fibronectin to the alpha5beta1 integrin receptor. We previously reported that RGD peptide increased the expression of matrix metalloproteinase in hepatic stellate cells (HSCs) which play a major role in hepatic fibrosis. We evaluated whether RGD-peptides inhibit the progression of liver fibrosis in an animal model of carbon tetrachloride-induced hepatotoxicity. RGD peptide (GRGDS) (1 mg/kg body weight) was injected intraperitoneally (i.p.) 3 times a week for one month. The group treated with control peptide (GRGES) showed pathologically typical hepatic fibrosis, while the RGD-treated group showed minimal fibrotic changes. The liver contents of collagen and hydroxyproline in the RGD-treated group was significantly lower than that of the control group. Collagenase activity measured in liver homogenates was significantly higher in the treated group than in the control group. In an in vitro study using TWNT-4 cells derived from human HSCs, RGD peptide (100 mug/ml) reduced the expression of type I collagen and tissue inhibitor of matrix metalloproteinase-1, and increased that of matrix metalloproteinase-1. These results indicated that RGD peptides inhibited liver fibrosis associated with both decreased collagen production and increased collagenase acitivity, and suggested that RGD peptide might be useful for the therapy of hepatic fibrosis.
Int J Mol Med 2004 Dec
PMID:Arg-Gly-Asp (RGD) peptide ameliorates carbon tetrachloride-induced liver fibrosis via inhibition of collagen production and acceleration of collagenase activity. 1554 72

Liver fibrogenesis resulting from a diversity of pathological changes involves a disturbance in mineral, in particular zinc, homeostasis. The present study was undertaken to determine whether gene therapy with metallothionein (MT), a small protein critically involved in the regulation of zinc homeostasis, can improve the recovery of liver fibrosis in a mouse model. Wild-type (WT) mice treated with carbon tetrachloride in corn oil twice a week at 1 ml/kg for 4 weeks developed a reversible liver fibrosis upon removal of the chemical, correlating with a high level of hepatic MT; but those treated for 8 weeks developed an irreversible liver fibrosis along with low levels of hepatic MT. The same carbon tetrachloride treatment for 4 weeks resulted in an irreversible liver fibrosis in MT-knockout (MT-KO) mice. Adenoviral delivery of the human MT-II gene (approved symbol MT2A) through intravenous injection reversed the fibrosis along with increased hepatocyte regeneration within 3 days in both WT and MT-KO mice with irreversible fibrosis. The MT elevation was associated with increased activities of collagenases in the liver. This study indicates that MT makes a critical contribution to the reversal of chemical-induced hepatic fibrosis and has therapeutic potential for patients with certain liver fibrosis.
Mol Ther 2004 Dec
PMID:Metallothionein gene therapy for chemical-induced liver fibrosis in mice. 1556 44

Fibrosis is characterized by excessive production of extracellular matrix (ECM) components, predominantly type 1 collagen. Earlier we developed an antigene approach, using a type alpha1(I) promoter specific TFO to inhibit collagen gene expression. In this report, biodistribution and hepatic cellular and subcellular localization of the 25-mer antiparallel phosphorothioate triplex-forming oligonucleotide (APS TFO) were determined after intravenous injection into rats. TFOs distributed to all the major organs, with higher uptake in the liver, kidney, and spleen. The plasma concentration versus time profile of the (33)P-TFO was biphasic, with 4.36 min as t(1/2)(alpha) of distribution and 34.6 min as t(1/2)(beta) of elimination. TFO concentrations in the liver increased nonlinearly with increase in its dose from 0.2 to 50 mg/kg, but decreased when injected into fibrotic rats. Competition studies with polyinosinic acid (polyI) and dextran sulfate suggested the involvement of scavenger receptors in the hepatic uptake of the TFO. Intrahepatic cellular distribution by Kupffer, endothelial, and hepatic stellate cells (HSCs) accounted for almost 70% of the liver uptake of (33)P-TFO, while only 30% was associated with hepatocytes. The level of liver nuclei-associated TFO was much lower relative to that found in the cytoplasm at 2 and 4 h postinjection. TFO, however, inhibited collagen expression as evidenced by Sirius red staining of the liver section of fibrotic rats. In conclusion, systemic delivery of the TFO against type alpha1(I) collagen gene promoter may be used for the treatment of liver fibrosis.
Mol Pharm
PMID:Biodistribution and hepatic uptake of triplex-forming oligonucleotides against type alpha1(I) collagen gene promoter in normal and fibrotic rats. 1593 81


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