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

Excessive production of extracellular matrix is responsible for clinical manifestations of fibroproliferative disorders and drugs which can inhibit excessive synthesis of type I collagen are needed for the therapy. Several dicationic diphenylfurans were synthesized and were found to bind RNA. Two of these type compounds were able to reduce synthesis of type I collagen by human fibroblasts and human activated hepatic stellate cells (HSCs). Activated HSCs are responsible for collagen production in liver fibrosis. When added at 40 microM compound 588 reduced intracellular level and secretion of procollagen alpha1(I) by 50%, while compound 654 reduced these parameters by more than 80% at 20 microM. 654 also significantly reduced secretion of fibronectin. Toxic effects were observed at 80 microM for 588 and 40 microM for 654. 654 reduced expression of a reporter gene with collagen signal peptide, while expression of the same gene without signal peptide was unaffected. Also, expression of intracellular proteins tubulin and calnexin was unchanged. 654 accumulated inside the cell in the cytoplasm and did not change the steady-state level of collagen mRNAs. Treatment of cells with proteosome inhibitor MG132 did not change the inhibitory effect of 654, suggesting that 654 acts as suppressor of translation of proteins containing a signal peptide. Most secreted proteins of fibroblasts and activated HSCs are components of extracellular matrix. Therefore inhibition of their production, as shown here for procollagen alpha1(I) and fibronectin, may be a useful property of some of diphenylfurans, making these compounds a basis for development of antifibrotic drugs.
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PMID:Inhibitory effect of dicationic diphenylfurans on production of type I collagen by human fibroblasts and activated hepatic stellate cells. 1570 83

Liver fibrosis represents a significant health problem worldwide of which no acceptable therapy exists. The most characteristic feature of liver fibrosis is excess deposition of type I collagen. A great deal of research has been performed to understand the molecular mechanisms responsible for the development of liver fibrosis. The activated hepatic stellate cell (HSC) is the primary cell type responsible for the excess production of collagen. Following a fibrogenic stimulus, HSCs change from a quiescent to an activated, collagen-producing cell. Numerous changes in gene expression are associated with HSC activation including the induction of several intracellular signaling cascades, which help maintain the activated phenotype and control the fibrogenic and proliferative state of the cell. Detailed analyses in understanding the molecular basis of collagen gene regulation have revealed a complex process offering the opportunity for multiple potential therapeutic strategies. However, further research is still needed to gain a better understanding of HSC activation and how this cell maintains its fibrogenic nature. In this review we describe many of the molecular events that occur following HSC activation and collagen gene regulation that contribute to the fibrogenic nature of these cells and provide a review of therapeutic strategies to treat this disease.
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PMID:Mechanisms of liver fibrosis. 1613 30

Catechins such as epigallocatechin-3-gallate (EGCG), epicatechin-3-gallate (ECG), and epigallocatechin (EGC) are polyphenol components of green tea. EGCG is the major component and has been reported to possess a wide range of biological properties including anti-fibrogenic activity. In hepatic fibrosis, activated hepatic stellate cells (HSCs) play a central role. In this study, we investigated the effect of catechins, including EGCG, on collagen production and collagenase activity in rat primary HSCs and activated human HSC-derived TWNT-4 cells. EGCG (50 microM) suppressed type I collagen production in rat HSCs more than ECG (50 microM) did; however, EGC (50 microM) did not show suppressive effects. EGCG also inhibited both collagen production and collagenase activity (active matrix metalloproteinase-1 [MMP-1]) in a dose-dependent manner, but did not affect the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) production in TWNT-4 cells. Real-time PCR unexpectedly revealed that EGCG enhanced the transcription of type I collagen and TIMP-1, but did not affect the transcription of alpha-smooth muscle actin (alpha-SMA), and reduced the transcription MMP-1 in TWNT-4 cells. These findings demonstrated that EGCG inhibited collagen production regardless of enhanced collagen transcription and suppressed collagenase activity, and suggested that EGCG might have therapeutic potential for liver fibrosis.
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PMID:Epigallocatechin-3-gallate, a polyphenol component of green tea, suppresses both collagen production and collagenase activity in hepatic stellate cells. 1614 4

Assessment of hepatic damage associated with chronic hepatitis B (CHB) currently relies on measurement of serum transaminases and assessment of hepatic histology. It was determined serum hepatic function tests and the liver fibrosis biomarkers type IV collagen (CIV), amino-terminal propeptide of type I procollagen (PINP), amino-terminal propeptide of type III procollagen (PIIINP) and carboxy-terminal telopeptide of type I collagen (ICTP) were of value in monitoring the effect of lamivudine therapy for CHB. Thirty-nine patients received orally 100 mg lamivudine daily for 48 weeks. Blood samples were obtained at baseline, 24 and 48 weeks. At the end of the treatment period, the patients were then divided into four groups according to the pattern of HBs and HBe antigens. At baseline, alanine aminotransferase, aspartate aminotransferase, PIIINP and the PINP/ICTP ratio and at 24 weeks alanine aminotransferase, aspartate aminotransferase and the PINP/ICTP ratio had lower values in the complete response compared with complete failure groups. Using receiver-operated curve analysis, only the PINP/ICTP ratio at baseline (area under the curve 0.806) and ALT and the PINP/ICTP ratio at 24 weeks (areas under the curve 0.803 and 0.776, respectively) had significant diagnostic ability in detecting responders. In conclusion, the PINP/ITCP ratio is sensitive and specific in detecting responders to treatment.
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PMID:Changes in serological biomarkers of liver function and connective tissue turnover in chronic hepatitis B during lamivudine therapy. 1630 71

Liver fibrosis results from chronic damage to the liver by chronic hepatitis, alcohol, and toxic agents. A characteristic of liver fibrosis is an accumulation of extracellular matrix (ECM) protein, which distorts the hepatic architecture by forming a fibrous scar, and the subsequent development of regenerating nodules defines cirrhosis. Transforming growth factor (TGF)-beta1, one of the most powerful profibrogenic mediators, plays a major role in the development of liver cirrhosis and regulates ECM gene expression and matrix degradation. This study elucidates the changes of TGF-beta1-mediated signals during liver fibrogenesis by using RNA interference. In this experiment, the TGF-beta1 siRNAs reduced the expression of TGF-beta1 in the livers of CCl(4) injection compared with those of control group, and the expression of type I collagen and alpha-smooth muscle actin was decreased. In conclusion, this study demonstrates that TGF-beta1 siRNAs inhibit TGF-beta1 expression in the murine model of liver cirrhosis and might be a good therapeutic strategy to prevent liver cirrhosis in human.
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PMID:The antifibrotic effect of TGF-beta1 siRNAs in murine model of liver cirrhosis. 1657 72

The aim was to investigate the suppressive effect of bicyclol on hepatic fibrosis induced by dimethylnitrosamine (DMN) in mice and the mechanism of its action. Hepatic fibrosis was established by intraperitoneal injection of 8 mg kg(-1) day(-1) on three consecutive days of each week for 4 or 5 weeks. In the prophylactic experiment, bicyclol (100 and 200mg.kg(-1)) was administered by gavage in association with DMN injection. For the therapeutic experiment, mice were firstly injected with DMN for 5 weeks as in the prophylactic experiment, and then the mice in drug groups were orally administered bicyclol (100 and 200mg.kg(-1)) once daily for 5 weeks. As a result, the levels of alanine aminotransferase (ALT), total bilirubin, hydroxyproline (Hyp), prolidase, tumor necrosis factor-alpha (TNFalpha), transforming growth factor beta-1 (TGFbeta(1)), type I collagen in serum and the score of liver fibrosis all significantly increased in the hepatic fibrosis model group in comparison with those in control group. The treatment with bicyclol markedly reduced all the above criteria. Bicyclol also attenuated the decrease of body weight of mice, serum total protein and albumin. In addition, bicyclol treatment inhibited liver TGFbeta(1) and tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA expression in the prophylactic experiment. Similarly, bicyclol reduced TIMP-1 levels in liver and serum and increased collagenase activity in the liver in the therapeutic experiment. The result suggest that bicyclol attenuates DMN-induced hepatic fibrosis in mice. Its mechanisms of action may be related to the hepatoprotective and anti-inflammation properties, the down-regulation of liver TGFbeta(1) and TIMP-1 expression and the increase of net collagenase activity in liver.
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PMID:Effects of bicyclol on dimethylnitrosamine-induced liver fibrosis in mice and its mechanism of action. 1660

Hepatic fibrosis is a common outcome of a variety of chronic liver diseases. Here we evaluated the therapeutic efficacy of hepatocyte growth factor (HGF) on liver fibrosis induced by bile duct ligation (BDL) and investigated potential mechanisms. Mice underwent BDL, followed by intravenous injections of naked HGF expression plasmid or control vector. HGF gene therapy markedly ameliorated hepatic fibrotic lesions, as demonstrated by reduced alpha-smooth muscle actin (alphaSMA) expression, attenuated deposition of type I and type III collagen, and normalized total hydroxyproline content. HGF also suppressed transforming growth factor-beta1 (TGF-beta1) expression. Interestingly, colocalization of alphaSMA and cytokeratin-19 in bile duct epithelium was observed, suggesting the possibility of biliary epithelial to myofibroblast transition after BDL. Cells that were still positive for cytokeratin-19 but actively producing type I collagen were found in the biliary epithelia and periductal region. Laminin staining revealed an impaired basement membrane of the bile duct epithelium in diseased liver. These lesions were largely prevented by HGF administration. In vitro, treatment of human biliary epithelial cells with TGF-beta1 induced alphaSMA and fibronectin expression and suppressed cytokeratin-19. HGF abolished the phenotypic conversion of biliary epithelial cells induced by TGF-beta1. These results suggest that HGF ameliorates hepatic biliary fibrosis in part by blocking bile duct epithelial to mesenchymal transition.
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PMID:Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation. 1665 17

Excessive production of extracellular matrix, predominantly type I collagen, results in liver fibrosis. Earlier we synthesized mannose 6-phosphate-bovine serum albumin (M6P-BSA) and conjugated to the type I collagen specific triplex-forming oligonucleotide (TFO) for its enhanced delivery to hepatic stellate cells (HSCs), which is the principal liver fibrogenic cell. In this report, we demonstrate a time-dependent cellular uptake of M6P-BSA-33P-TFO by HSC-T6 cells. Both cellular uptake and nuclear deposition of M6P-BSA-33P-TFO were significantly higher than those of 33P-TFO, leading to enhanced inhibition of type I collagen transcription. Following systemic administration into rats, hepatic accumulation of M6P-BSA-33P-TFO increased from 55% to 68% with the number of M6P per BSA from 14 to 27. Unlike 33P-TFO, there was no significant decrease in the hepatic uptake of (M6P)20-BSA-33P-TFO in fibrotic rats. Prior administration of excess M6P-BSA decreased the hepatic uptake of (M6P)20-BSA-33P-TFO from 66% to 40% in normal rats, and from 60% to 15% in fibrotic rats, suggesting M6P/insulin-like growth factor II (M6P/IGF II) receptor-mediated endocytosis of M6P-BSA-33P-TFO by HSCs. Almost 82% of the total liver uptake in fibrotic rats was contributed by HSCs. In conclusion, by conjugation with M6P-BSA, the TFO could be potentially used for the treatment of liver fibrosis.
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PMID:Receptor-mediated hepatic uptake of M6P-BSA-conjugated triplex-forming oligonucleotides in rats. 1670 23

The role of retinoic acid (RA) in liver fibrogenesis was previously studied in cultured hepatic stellate cells (HSCs). RA suppresses the expression of alpha2(I) collagen by means of the activities of specific nuclear receptors RARalpha, RXRbeta and their coregulators. In this study, the effects of RA in fibrogenesis were examined in carbon tetrachloride (CCl4) induced liver fibrosis in mice. Mice were treated with CCl4 or RA and CCl4, along side control groups, for 12weeks. RA reduced the amount of histologically detectable fibrosis produced by CCl4. This was accompanied by a attenuation of the CCl4 induced increase in alpha2(I) collagen mRNA and a lower (2-fold versus 3-fold) increase in liver hydroxyproline. Furthermore, RA reduced the levels of 3-nitrotyrosine (3-NT) protein adducts and thiobarbituric acid (TBA) reactive substance (TBARS) in the liver, which are formed as results of oxidative stress induced by CCl4 treatment. These in vivo findings support our previous in vitro studies in cultured HSC of the inhibitory effect of RA on type I collagen expression. The data also provide evidence that RA reduces CCl4 induced oxidative stress in liver, suggesting that the anti-fibrotic role of RA is not limited to the inhibition of type I collagen expression.
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PMID:Effects of retinoic acid on the development of liver fibrosis produced by carbon tetrachloride in mice. 1701 Nov 72

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.
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PMID:Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis. 1727 78


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