Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen α1(I) and TIMP-1

Jia, Jidong; Bauer, Michael; Cho, Jae Jin; Ruehl, Martin; Milani, Stefano; Boigk, G.; Riecken, E. O.; Schuppan, Detlef

doi:10.1016/s0168-8278(01)00148-9

Cited by 142 publications

(107 citation statements)

References 34 publications

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“…Therefore the present study was conducted using a herbal extract combination, SLG, each with distinct inhibitory effects against HSC activation or hepatic fibrogenesis. Silymarin, an extract from milk thistle (Silybum marianum) was included in the in vivo study for comparison with SLG, as it has a long history of usage by patients with liver diseases (Schuppan et al, 1999;Saller et al, 2001) and has been reported in the literature to exert antifibrotic effects in bileduct-obstructed and DMN-intoxicated rats (Boigk et al, 1997;Jia et al, 2001;Hsu et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Antifibrotic effects of a herbal combination regimen on hepatic fibrotic rats

Lin

Hsu²,

Chiu

et al. 2007

Phytotherapy Research

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Liver fibrosis has been characterized as chronic inflammatory processes involving multiple molecular pathogenetic pathways. This therapeutic study investigated whether a combination regimen of Salvia miltiorrhiza (S), Ligusticum chuanxiong (L) and Glycyrrhiza glabra (G) exerted in vivo antifibrotic effects on rats with hepatic fibrosis. Fibrosis was induced in rats by dimethylnitrosamine (DMN) administration for 4 weeks. Fibrotic rats were randomly assigned to one of the three groups: control, SLG (50 mg/kg) or silymarin (50 mg/kg), each given by gavage twice daily for 3 weeks starting 1 week after DMN injection. The results showed that fibrosis scores of livers from DMN-treated rats with SLG (1.13 ± ± ± ± ± 0.13) were significantly reduced in comparison with DMN-treated rats receiving vehicle (1.63 ± ± ± ± ± 0.18). Moreover, the hepatic collagen content of DMN rats was significantly reduced by either SLG or silymarin treatment. The double immunohistochemical staining results also showed that α α α α α-SMA positive cells with NFκ κ κ κ κB nuclear translocation were decreased in the fibrotic livers by SLG and silymarin treatments. The mRNA expression levels of TGF-β β β β β 1, α α α α α -SMA, collagen1α α α α α2, iNOS and ICAM-1 genes were attenuated by SLG and silymarin treatment. The results showed that SLG exerted antifibrotic effects in rats with DMN-induced hepatic fibrosis.

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Section: Discussionmentioning

confidence: 99%

Antifibrotic effects of a herbal combination regimen on hepatic fibrotic rats

Lin

Hsu²,

Chiu

et al. 2007

Phytotherapy Research

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“…In similar experiments, there was a reduction of collagen and pro-collagen III contents after biliary obstruction in the rat by 30% with 50 mg/kg/day although not at the level of 25 mg/kg/day of silymarin (Mourelle et al, 1989;Boigk et al, 1997). Silymarin suppressed the expression of pro-fibrogenic procollagen-α1(I) and TIMP-1 most likely via down-regulation of TGF-β1 mRNA in the rats with biliary fibrosis (Jia et al 2001). Silymarin, administered during three years, retarded the development of alcohol-induced hepatic fibrosis in baboons (Lieber et al, 2003).…”

Section: Antifibrotic Activitymentioning

confidence: 99%

Milk thistle in liver diseases: past, present, future

Abenavoli

Capasso²,

Milić

et al. 2010

Phytotherapy Research

502

350

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Silybum marianum or milk thistle (MT) is the most well‐researched plant in the treatment of liver disease. The active complex of MT is a lipophilic extract from the seeds of the plant and is composed of three isomer flavonolignans (silybin, silydianin, and silychristin) collectively known as silymarin. Silybin is a component with the greatest degree of biological activity and makes up 50% to 70% of silymarin. Silymarin is found in the entire plant but it is concentrated in the fruit and seeds. Silymarin acts as an antioxidant by reducing free radical production and lipid peroxidation, has antifibrotic activity and may act as a toxin blockade agent by inhibiting binding of toxins to the hepatocyte cell membrane receptors. In animals, silymarin reduces liver injury caused by acetaminophen, carbon tetrachloride, radiation, iron overload, phenylhydrazine, alcohol, cold ischaemia and Amanita phalloides. Silymarin has been used to treat alcoholic liver disease, acute and chronic viral hepatitis and toxin‐induced liver diseases. Copyright © 2010 John Wiley & Sons, Ltd.

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“…The major mechanism of its hepatoprotective activity is the inhibition of hepatic NF-κB activation. In addition, silymarin has antifibrotic activity in rodents and inhibits the expression of pro-collagen-α1(I) and tissue inhibitor of metalloproteinase-1 via downregulation of TGF-β1 mRNA [196] . Silymarin acts as antioxidant; it reduces free radical production and lipid peroxidation and markedly increases the expression of superoxide dismutase in lymphocytes of patients with alcoholic cirrhosis [197,198] .…”

Section: Therapeutic Optionsmentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

413

339

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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 preeminent 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. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen α1(I) and TIMP-1

Cited by 142 publications

References 34 publications

Antifibrotic effects of a herbal combination regimen on hepatic fibrotic rats

Antifibrotic effects of a herbal combination regimen on hepatic fibrotic rats

Milk thistle in liver diseases: past, present, future

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

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