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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-beta1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-beta were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-beta and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.
J Cell Mol Med
PMID:Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. 1656 23

Progression of liver fibrosis has been linked with injuries associated with hypoxia and neovascularization. Neovascularization consists of angiogenesis and vasculogenesis, representing formation of blood vessels by differentiation of endothelial progenitor cells (EPCs). We investigated antifibrogenic and regenerative effects of EPC transplantation in chronic liver injury. Rat EPCs were isolated from bone marrow cells and examined in vitro for lineage markers. Recipient rats were injected intraperitoneally with dimethylnitrosamine (DMN) three times weekly for 4 weeks, plus EPC transplantation once weekly for 4 weeks. Transplanted rats showed suppression of liver fibrogenesis. Expression of growth factors promoting liver regeneration such as hepatocyte growth factor (HGF), transforming growth factor (TGF)-alpha, epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) was increased in transplanted rats, together with hepatocyte proliferation. Normal liver function parameters such as transaminase, total bilirubin, total protein, and albumin were maintained in transplanted rats. EPC transplantation is effective not only for preventing liver fibrosis but also for promoting regeneration in chronically damaged livers. Also, recently it has been reported that green fluorescent protein-positive bone marrow cells contribute to the liver tissue repair of fibrosis model rats. EPC transplantation might become an alternative if further preclinical investigation finds it to be effective in severely cirrhotic livers.
Med Mol Morphol 2006 Mar
PMID:Angiogenic cell therapy for hepatic fibrosis. 1657 10

Both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are known to be pivotal cytokines in liver fibrosis development. The aim of our current study was to elucidate the effects of dual inhibition of PDGF and TGF-beta by combination of the clinically used imatinib mesylate (STI-571) and perindopril (an ACE-inhibitor; ACE-I), respectively, on ongoing liver fibrosis development in rats. The effects of STI-571 and ACE-I at clinically comparable low doses were examined in a rat model of CCl4-induced liver fibrogenesis. Treatment with both STI-571 and ACE-I inhibited liver fibrogenesis and suppressed activation of hepatic stellate cells (HSCs). Administration of both agents exerted a more potent inhibitory effect than administration of either single agent. Our in vitro study demonstrated that STI-571 and ACE-I suppressed PDGF receptor (PDGFR) phosphorylation and TGF-beta expression in activated HSCs, respectively. Dual suppression of PDGF and TGF-beta with a combination of clinically comparable low doses of STI-571 and ACE-I exerted a significant inhibitory effect on ongoing liver fibrosis development. Since both agents are widely used in clinical practice, this combination therapy may provide a new strategy against liver fibrosis in the future.
Int J Mol Med 2006 May
PMID:Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-beta with a combination of imatinib mesylate and ACE inhibitor in rats. 1659 78

Using a developed rat model of hepatic necrosis and subsequent fibrosis induced by a high-dose intraperitoneal injection of dimethylnitrosamine (DMN), we studied iron deposition and expression of transforming growth factor-beta(1) (TGF-beta(1)) during the development of persistent liver fibrosis. Rats were sacrificed at several timepoints from 6 h to 10 months post-injection and the livers were examined for iron content and distribution, and for expression of alpha-smooth muscle actin, ED-1, TGF-beta(1), and collagen (alpha(2))I. Morphologic evidence of acute submassive hemorrhagic necrosis peaked at 36 h; on day 3 the residual parenchyma contained activated hepatic stellate cells (HSCs) and necrotic areas contained numerous macrophages; and on day 5, necrotic tissues and erythrocytes had been phagocytosed and macrophages contained abundant iron deposits. From days 7 to 10, iron-laden macrophages and activated HSCs (myofibroblasts) populated the fibrous septa in parallel. From week 2 to month 10, closely arranged macrophages and myofibroblasts were found in central-to-central bridging fibrotic tissue. TGF-beta(1) was strongly detected in both macrophages and HSCs during development of liver fibrosis. Our data suggest that increased iron deposition may be involved in the initiation and perpetuation of rat liver fibrosis. Iron-laden macrophages may influence HSCs through the action of TGF-beta(1) in DMN-induced liver fibrosis.
Exp Mol Pathol 2006 Dec
PMID:Increased iron deposition in rat liver fibrosis induced by a high-dose injection of dimethylnitrosamine. 1697 22

Activin receptor-like kinase 5 (ALK5) is a type I receptor of transforming growth factor (TGF)-beta. ALK5 inhibition has been reported to attenuate the tissue fibrosis including pulmonary fibrosis, renal fibrosis and liver fibrosis. To elucidate the inhibitory mechanism of ALK5 inhibitor on pulmonary fibrosis in vivo, we performed the histopathological assessment, gene expression analysis of extracellular matrix (ECM) genes and immunohistochemistry including receptor-activated Smads (R-Smads; Smad2/3), CTGF, myofibroblast marker (alpha-smooth muscle actin; aSMA) and type I collagen deposition in the lung using Bleomycin (BLM)-induced pulmonary fibrosis model. ALK5 inhibitor, SB-525334 (10 mg/kg or 30 mg/kg) was orally administered at twice a day. Lungs were isolated 5, 7, 9 and 14 days after BLM treatment. BLM treatment led to significant pulmonary fibrotic changes accompanied by significant upregulation of ECM mRNA expressions, Smad2/3 nuclear translocation, CTGF expression, myofibroblast proliferation and type I collagen deposition. SB-525334 treatment attenuated the histopathological alterations in the lung, and significantly decreased the type I and III procollagen and fibronectin mRNA expression. Immunohistochemistry revealed that SB-525334 treatment showed significant attenuation in Smad2/3 nuclear translocation, decrease in CTGF-expressing cells, myofibroblast proliferation and type I collagen deposition. These results suggest that ALK5 inhibition attenuates R-Smads activation thereby attenuates pulmonary fibrosis.
Exp Mol Pathol 2007 Aug
PMID:Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis. 1727 78

Similar to the human immunodeficiency virus (HIV), the hepatitis B virus (HBV) replicates via reverse transcription, in this case, within infected hepatocytes. Substantial advances have been achieved in the past ten years in developing and utilizing nucleoside/nucleotide analog drugs to inhibit HBV replication. Most are chain terminators that interfere with one or more steps in the replication cycle. Four of them (lamivudine, adefovir dipivoxil, entecavir, and telbivudine), have been approved by the United States Food and Drug Administration (FDA) for the treatment of chronic hepatitis B (CHB). In clinical trials of HBeAg positive and negative CHB patients, 48-52 week of treatment with these drugs can induce a 4-7 log decrease of HBV viremia and histological improvement. Long-term suppression of active HBV replication has been found to be associated with decreased inflammation, reversal of liver fibrosis and a lower incidence of hepatocellular carcinoma. However, permanent clearance of HBV is rarely achieved with current available antiviral agents, maintenance therapy being required for continuous suppression of HBV replication. In patients on continuous therapy, drug resistant mutations develop with all four drugs. Combination therapy with different nucleos(t)ide analog drugs or nucleos(t)ide drugs and pegylated interferon needs further clinical study. Newer promising nucleotide analog drugs with more potent antiviral efficacy are also under development.
Curr Mol Med 2007 Mar
PMID:Molecular mechanisms of resistance to antiviral therapy in patients with chronic hepatitis B. 1734 70

Smad1 is an important signaling molecule for members of transforming growth factor-beta (TGF-beta) superfamily. Increased expression of Smad1 in activated hepatic stellate cells (HSCs) indicates a role of Smad1 in liver fibrosis. Therefore, understanding of Smad1 gene expression could be important to control the activation of HSCs. Current study reports the cloning and characterizing rat Smad1 5'-flanking region in liver cells. Rat Smad1 5'-flanking region was cloned by PCR method. Promoter deletional analysis and electrophoretic mobility shift assay (EMSA) were examined in hepatocyte and HSCs cell line (CFSC-8B cells), respectively. Results indicated that rat Smad1 used GC-box as its promoter and there was a transcriptional regulatory element located at the region of -163 to -56bp. EMSA demonstrated two bands on Smad1 promoter region. Smad1 promoter activity was higher in CFSC-8B cells cultured on uncoated plastic dish than that of CFSC-8B cells cultured on Matrigel-coated plastic dish. In conclusion, rat Smad1 promoter was cloned and characterized in hepatocyte and HSC cell line (CFSC-8B cells) at different culture conditions.
Mol Cell Biochem 2007 Oct
PMID:Cloning and promoter activity of rat Smad1 5'-flanking region in rat hepatic stellate cells. 1753 Jan 86

Cholestasis is one of the major liver diseases and results in progressive liver fibrosis and cirrhosis. In this study, the transcriptional response of the liver to common bile duct ligation in rats was examined by cDNA microarray analysis, and 134 genes for which expression was altered during long-term cholestasis were identified. Clustering analysis of these genes for multiple time-point data yielded 7 different patterns in which a large portion of the genes was classified into 3 clusters. Two clusters consisted of up-regulated genes, including genes that may be related to disruption of lipid metabolism and liver fibrosis observed in the early stage of cholestasis, and the other cluster consisted of down-regulated genes, including a gene that has been thought to be involved in the mechanism of cell protection against accumulation of bile acids. Since the expression patterns of these genes appear to reflect molecular features of cholestasis. Characterization of the genes identified in this study may shed further light on the physiological and pathological characteristics of long-term cholestasis.
Res Commun Mol Pathol Pharmacol 2004
PMID:Microarray analysis of hepatic gene expression during long-term cholestasis induced by common bile duct ligation in rats. 1756 6

Hepatic stellate cells (HSCs) are mesenchymal cells of the liver, activation of which is responsible for excessive synthesis of extracellular matrix, including type I collagen, and development of liver fibrosis. The activation of HSCs is driven by transcription factors and pair-related homeobox transcription factor Prx1 was identified as one of the transcription factors involved in this process, because transcription of collagen alpha1(I) gene is stimulated by Prx1 in HSCs and in the liver. Here, we show that expression of the RNA-binding protein RBMS3 is upregulated in the activation of HSCs and fibrotic livers. Immunoprecipitation followed by differential display identified Prx1 mRNA as one of the mRNAs interacting with RBMS3. The RBMS3 sequence-specific binding site was mapped to 60 nt located 1946 nt 3' of the stop codon of Prx1 mRNA. Ectopic expression of RBMS3 in quiescent HSCs, which express trace amounts of type I collagen, increased expression of Prx1 mRNA and collagen alpha1(I) mRNA. Expression of reporter Prx1 mRNA containing the RBMS3 binding site was higher than the mRNA lacking this site. Over-expression of RBMS3 further increased the steady-state level of the reporter mRNA-containing RBMS3 binding site, but had no effect on the mRNA lacking this site. Binding of RBMS3 to the Prx1 3' UTR increased the half-life of this mRNA, resulting in increased protein synthesis. These results suggest that RBMS3, by binding Prx1 mRNA in a sequence-specific manner, controls Prx1 expression and indirectly collagen synthesis. This is the first description of the function of RBMS3, as a key regulator of profibrotic potential of HSCs, representing a novel mechanism by which activated HSCs contribute to liver fibrosis.
J Mol Biol 2007 Aug 17
PMID:RNA-binding protein RBMS3 is expressed in activated hepatic stellate cells and liver fibrosis and increases expression of transcription factor Prx1. 1758 24

Adiponectin, a circulating adipocyte-derived secretory protein, reportedly plays an important role in liver fibrosis development, although the biological role of adiponectin in liver fibrogenesis is still controversial. Adiponectin is present in the serum as three oligometric complexes; namely, high-, middle-, and low-molecular weight (HMW, MMW, and LMW, respectively). Adiponectin exerts different biological activities in an oligomerization-dependent manner. The aim of our current study was to examine the alteration of each isoform of adiponectin and its receptors (AdipoR1, AdipoR2, and T-cadherin) during the choline-deficient L-amino acid-defined (CDAA) diet-induced rat liver fibrosis development. We also elucidated the methylation status of all receptors. The serum level of total adiponectin significantly increased during the liver fibrosis development. Among the three isoforms, only HMW adiponectin was significantly up-regulated whereas MMW and LMW were not. The expression of T-cadherin, which exclusively binds with HMW adiponectin, was significantly augmented as well. The AdipoR2 expression was markedly decreased and showed no marked difference from that of AdipoR1. No obvious methylation change was observed in all three receptors, suggesting that another mechanism is involved in the alteration of receptor gene expression. Collectively, since the specific ligand and receptor were augmented together, crosstalk between HMW adiponectin and T-cadherin may play an important role during liver fibrosis development in rats.
Int J Mol Med 2007 Nov
PMID:Crosstalk between high-molecular-weight adiponectin and T-cadherin during liver fibrosis development in rats. 1791 67


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