Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1.
ABSTRACT Silymarin reduces hepatic collagen accumulation by 35% in rats with secondary biliary cirrhosis. The aim of the present study was to explore its antifibrotic mechanism.
Thirty female adult Wistar rats were allocated to (1) bile duct occlusion, (2) bile duct occlusion and oral silymarin at 50 mg/kg per day, and (3) sham operation and oral silymarin at 50 mg/kg per day. Steady-state mRNA levels for procollagen alpha1(I), tissue inhibitor of metalloproteinases-1 (TIMP-1), and transforming growth factor (TGF) beta1 were determined by multi-probe ribonuclease protection assay.
After 6 weeks of bile duct occlusion, liver collagen content was increased 12-fold, when compared with the sham-operated controls. These animals displayed 17-, 6.5- and 16-fold higher transcript levels for procollagen alpha1(I), TIMP-1 and TGFbeta1 (P < 0.01). Silymarin downregulated elevated procollagen alpha1(I), TIMP-1 and TGFbeta1 mRNA levels by 40-60% (P < 0.01). These lowered hepatic profibrogenic transcript levels correlated with decreased serum levels of the aminoterminal propeptide of procollagen type III.
Silymarin suppresses expression of profibrogenic procollagen alpha1(I) and TIMP-1 most likely via downregulation of TGFbeta1 mRNA in rats with biliary fibrosis. The serum procollagen type III propeptide level mirrors profibrogenic mRNA expression in the liver.
SourceAvailable from: María Teresa González-Garza[Show abstract] [Hide abstract]
ABSTRACT: During chronic liver injury, hepatic stellate cells (HSC) are activated and proliferate, which causes excessive extracellular matrix (ECM) deposition, leading to scar formation and fibrosis. Medicinal plants are gaining popularity as antifibrotic agents, and are often safe, cost-effective, and versatile. This review aims to describe the protective role and mechanisms of medicinal plants in the inhibition of HSC activation and ECM deposition during the pathogenesis of liver fibrosis. A systematic literature review on the anti-fibrotic mechanisms of hepatoprotective plants was performed in PubMed, which yielded articles about twelve relevant plants. Many of these plants act via disruption of the transforming growth factor beta 1 signaling pathway, possibly through reduction in oxidative stress. This reduction could explain the inhibition of HSC activation and reduction in ECM deposition. Medicinal plants could be a source of anti-liver fibrosis compounds.Chinese Medicine 12/2014; 9(1):27. DOI:10.1186/s13020-014-0027-4 · 2.34 Impact Factor
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ABSTRACT: Aim: To investigate the effect of Viscum album, a plant used for the treatment of hepatocellular carcinoma that has immune-modulating properties, on acute hepatic injury in rats. Materials and methods: Hepatotoxicity was induced by CCl 4 orally (0.28 mL/kg). Rats received either Viscum album at 1 of 2 dose levels (0.1 or 0.2 mL/kg) once weekly subcutaneously alone or with silymarin (25 mg/kg, orally), or silymarin (25 mg/kg) once daily orally for 1 month, starting at the time of administration of CCl 4 . Liver damage was assessed by determining liver serum enzyme activities and by hepatic histopathology. Results: Viscum album administration decreased the increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), and also prevented the development of hepatic necrosis caused by CCl 4 . The effect of Viscum album was dose-dependent. Viscum album administered at 0.1 or 0.2 mL/kg caused significant reduction in the elevated plasma ALT by 51.2% and 65.6%, AST by 52.6% and 61.1%, and ALP by 27.7% and 57.6%, respectively. In comparison, the elevated serum ALT, AST, and ALP levels decreased to 48.9%, 51.8%, and 30.8% of the controls, respectively, with 25 mg/kg of silymarin. Viscum album (0.2 mL/kg) administered together with silymarin resulted in 73.1%, 67.6%, and 65.8% decreases in serum ALT, AST, and ALP levels, respectively. Histopathologic examination of the livers of rats treated with CCl 4 and administered Viscum album at 0.2 mL/kg showed marked restoration of the normal architecture of the liver tissue with minimal fibrosis. Conclusion: Results of the present study indicate that the administration of Viscum album in a model of liver injury induced by CCl 4 in rats results in less liver damage.
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ABSTRACT: Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a pre-eminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility.World Journal of Gastroenterology 12/2014; DOI:10.3748/wjg.v20.i47.00000 · 2.43 Impact Factor