The antifibrotic effect of TGF-β1 siRNAs in murine model of liver cirrhosis

Kim, Kyung-Hyun; Kim, Hyun-Chul; Hwang, Meeyul; Oh, Hoon-Kyu; Lee, Tae-Sung; Chang, Young‐Chae; Song, Hyun-Ok; Won, Nam-Hee; Park, Kwan‐Kyu

doi:10.1016/j.bbrc.2006.03.087

Cited by 49 publications

(56 citation statements)

References 18 publications

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“…TGF-β1 mRNA expression correlated closely with the expression of procollagen type 1 and patients with increased fibrogenic activity as determined by measuring the serum level of collagen type 3 peptide had an increased level of the cytokine (2). RNA interference using TGF-β1 siRNA showed an anti-fibrotic effect in the livers injected with carbon tetrachloride with decreased expression of type 1 collagen (15).…”

Section: Figmentioning

confidence: 83%

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The anti-fibrotic effect of green tea with a high catechin content in the galactosamine-injured rat liver

et al. 2007

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Previously, we reported that the oral administration of green tea rich in catechins restored levels of several biomarkers increasing in galactosamine-treated rats to nearly control values. These biomarkers included serum transaminase activities, serum concentrations of tumor necrosis factor-α and interleukin 1-β, and the hepatic mRNA expression of these inflammatory cytokines. In the present study, we examined possible anti-fibrotic effects of green tea in galactosamine-induced hepatitis. The results of the reverse transcription and polymerase chain reaction indicated that the increase in gene expression of the α1 chain of collagen type 1 and transforming growth factor β-1 in the injured liver 24 h post-injection of galactosamine was suppressed by the administration of green tea. Masson's trichrome staining demonstrated that the extent of fibrogenesis after 14 days was greater in the galactosamine-injured livers not treated with green tea than the treated ones. These results suggest that the drinking of green tea with a high catechin content may help to prevent and/or attenuate the development of fibrosis in hepatitis.

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Section: Figmentioning

confidence: 83%

“…Fixed liver samples were embedded in paraffin. Three-micrometer sections were cut and subjected to Masson's trichrome staining for an evaluation of liver fibrosis (15).…”

Section: Serum Transaminase Activitiesmentioning

confidence: 99%

The anti-fibrotic effect of green tea with a high catechin content in the galactosamine-injured rat liver

et al. 2007

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“…Lee et al developed poly(β-L-malic acid) (PLMA) based copolymer, Polycefin, as a platform for drug delivery ( Figure 12B) (214). PLMA can be prepared from the myxomycete Physarum polycephalum with high purity (554).…”

Section: Poly(l-malic Acid)mentioning

confidence: 99%

“…Polycefin was synthesized as a multicomponent prototype for targeted delivery of ODNs to brain tumors (214), which contained: i) biodegradable, nonimmunogenic, nontoxic PLMA as backbone; ii) morpholino ODN targeting α4 and β1 chains of laminin-8, which is specifically overexpressed in glial brain tumors via disulfide bonds; iii) monoclonal anti-transferrin receptor antibody for specific tissue targeting; iv) L-valine containing, pH-sensitive membrane disrupting unit(s), v) PEG. Polycefin was extensively characterized (214).…”

Section: Poly(l-malic Acid)mentioning

confidence: 99%

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Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Houssein

Mahato

2007

Oligonucleotides

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Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of α1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed.

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AMP‐activated protein kinase inhibits TGF‐β‐induced fibrogenic responses of hepatic stellate cells by targeting transcriptional coactivator p300

Lim¹,

Oh²,

Kim³

et al. 2011

Journal Cellular Physiology

147

121

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Liver fibrosis is a common consequence of various chronic liver injuries, including virus infection and ethanol. Activated hepatic stellate cells (HSCs) contribute to liver fibrosis through the accumulation of extracellular matrix proteins, including type I alpha collagen (COL1A). The activation of adenosine monophosphate-activated protein kinase (AMPK) modulates HSCs activation, but its underlying mechanism remains unclear. Here, we report that AMPK inhibits transforming growth factor (TGF)-β-induced fibrogenic property of HSCs by regulating transcriptional coactivator p300. We treated human (LX-2) and rat (CFSC-2G) HSC lines with TGF-β to induce fibrogenic activation of HSCs. Pharmacological activation of AMPK by treatment with 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), metformin, or adiponectin lowered TGF-β-induced expression of COL1A and myofibroblast marker alpha-smooth muscle actin (α-SMA). Transient transduction of constitutively active AMPKα (caAMPKα) was sufficient to attenuate COL1A and α-SMA expression, whereas an AMPK inhibitor considerably abrogated the inhibitory effect of AICAR on fibrogenic gene expression. Although AMPK significantly suppressed Smad-dependent transcription, it did not affect TGF-β-stimulated phosphorylation, nuclear localization, or DNA-binding activity of Smad2/3. AICAR rather attenuated TGF-β-induced Smad3 interaction with transcriptional coactivator p300 accompanying with reduction of Smad3 acetylation. Moreover, AICAR induced not only physical interaction between AMPK and p300 but also proteasomal degradation of p300 protein. Our data provide substantial evidence that AMPK could be a novel therapeutic target for treatment of liver fibrosis, by demonstrating the underlying mechanism of AMPK-induced antifibrotic function in HSCs.

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The antifibrotic effect of TGF-β1 siRNAs in murine model of liver cirrhosis

Cited by 49 publications

References 18 publications

The anti-fibrotic effect of green tea with a high catechin content in the galactosamine-injured rat liver

The anti-fibrotic effect of green tea with a high catechin content in the galactosamine-injured rat liver

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

AMP‐activated protein kinase inhibits TGF‐β‐induced fibrogenic responses of hepatic stellate cells by targeting transcriptional coactivator p300

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