Thalidomide salvages lethal hepatic necroinflammation and accelerates recovery from cirrhosis in rats

Yeh, Ta‐Sen; Ho, Yu‐Pin; Huang, Shiu-Feng; Yeh, Jun-Nan; Jan, Yi-Yin; Chen, Miin‐Fu

doi:10.1016/j.jhep.2004.06.019

Cited by 31 publications

(21 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In 2003, Enomoto et al [23] reported that thalidomide prevented lipopolysaccharide-induced liver injury via the suppression of TNF-␣ production from Kupffer cells in vivo and vitro. In 2004, Yeh et al [8] demonstrated that intraperitoneal injection of thalidomide inhibited lethal hepatic necroinflammation and accelerated the recovery from rat liver cirrhosis induced by thioacetamide, and suggested thalidomide-induced suppression of TNF-␣ and TGF-␤ 1 expression on Kupffer cells as the mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

“…The effects of thalidomide on tumor necrosis factor-␣ (TNF-␣ ) release play an important role in these properties, which may depend on its selective degradation of TNF-␣ mRNA [4][5][6] . Recently, thalidomide has been found to be effective in experimental liver fibrosis, possibly via a mechanism which might be associated with the suppression of TNF-␣ production by thalidomide [7,8] . However, the definite pathway of this suppression has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-α via Inhibition of Degradation of an Inhibitor of Nuclear Factor-κB

Paul

Xiao

et al. 2006

Pathobiology

View full text Add to dashboard Cite

Background/Aims: Thalidomide inhibited tumor necrosis factor-α (TNF-α) effectively in many trials. The aim of this study was to investigate the effect of thalidomide on the expression of nuclear factor-ĸB (NF-ĸB), inhibitor of NF-ĸB (IĸB) and TNF-α in a rat model of liver cirrhosis. Methods: Liver cirrhosis was achieved by intraperitoneal injection of carbon tetrachloride thrice weekly, and thalidomide (10 or 100 mg/kg/day) was given daily by intragastric route for 8 weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), prealbumin (PA), hyaluronic acid (HA) and laminin (LN), and hydroxyproline (HYP), NF-ĸBp65, α-smooth muscle actin (α-SMA) protein and TNF-α mRNA were studied in the liver, IĸBα and TNF-α protein in the cytoplasm and NF-ĸBp65 protein in the nucleus. Results: Compared with nontreated cirrhotic rats, the histopathology of rats given thalidomide (100 mg/kg) was significantly better. Serum ALT, AST, HA and LN and HYP content in the liver were significantly decreased and PA was elevated (p < 0.01) in this group; the expression of TNF-α mRNA and protein, NF-ĸBp65 and α-SMA were significantly decreased and IĸBα protein was also elevated (p < 0.01). Conclusion: Thalidomide downregulates NF-ĸB-induced TNF-α and activates hepatic stellate cells (HSC) via inhibition of IĸB degradation to prevent liver cirrhosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-α via Inhibition of Degradation of an Inhibitor of Nuclear Factor-κB

Paul

Xiao

et al. 2006

Pathobiology

View full text Add to dashboard Cite

show abstract

“…Prolonged exposure to TAA always results in bile duct proliferation and liver cirrhosis histologically similar to that in human viral hepatitis infection (Hunter et al, 1977;Ledda-Columbano et al, 1991;Yeh et al, 2004). Because of this virtue, TAA has been widely applied to develop animal models of liver fibrosis and/or cirrhosis mimicking human nonbiliary liver diseases.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Xie¹,

Wang²,

Wang³

et al. 2012

Drug Metabolism and Disposition

View full text Add to dashboard Cite

ABSTRACT:Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.

show abstract

“…This anti-inflammatory effect is in addition with immunomodulatory properties by enhancing effect of T-lymphocyte response (20,21). Moreover, thalidomide was reported to accelerate the recovery from experimental cirrhosis in rats, probably mediated by TNF-α suppression effect in the liver (47). Ultimately, the few available clinical data generating also hypothesis supported the usefulness of thalidomide in the management of CHC.…”

Section: Discussionmentioning

confidence: 96%

Thalidomide with peginterferon alfa-2b and ribavirin in the treatment of non-responders genotype 1 chronic hepatitis C patients: proof of concept

Pardo-Yules

Gallego‐Durán²,

Eslam

et al. 2011

Rev. esp. enferm. dig.

View full text Add to dashboard Cite

Background: fewer than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after peginterferon alfa/ribavirin (Peg-IFN/RBV) therapy.Aims: thalidomide posses anti-inflammatory and immunomodulatory properties through inhibition of tumor necrosis factor and costimulatory effect on human CD8+ T cells.Methods: we started a prospective, open label trial of retreatment of very-difficult-to-treat genotype 1 chronic hepatitis C patients (CHC) patients, who had failed to respond to the (Peg-IFN/RBV), with a triple therapy consisting in these same antivirals plus thalidomide 200 mg/day (the TRITAL study).Results: none of the eleven patients fulfilling the inclusion criteria and included in the trial reached complete early virological response or sustained virological response. Viral load decline after 12 weeks of triple therapy thalidomide-based retreatment did not differ from viral dynamics during the first course. The triple therapy was well tolerated and only one patient developed mild bilateral neuropathy.Conclusions: thalidomide addition to standard therapy is tolerated and did not increase the SVR rate in very-difficult-to-treat genotype 1 CHC patients. Different schedules are warranted to improve attempting retreatment of non responder CHC patients.

show abstract

Thalidomide salvages lethal hepatic necroinflammation and accelerates recovery from cirrhosis in rats

Cited by 31 publications

References 34 publications

Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-α via Inhibition of Degradation of an Inhibitor of Nuclear Factor-κB

Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-α via Inhibition of Degradation of an Inhibitor of Nuclear Factor-κB

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Thalidomide with peginterferon alfa-2b and ribavirin in the treatment of non-responders genotype 1 chronic hepatitis C patients: proof of concept

Contact Info

Product

Resources

About