Hepatology : official journal of the American Association for the Study of Liver Diseases
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D-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor alpha (TNF-alpha) plays a pivotal role. We examined the effects of etoposide on GalN/LPS-induced fulminant hepatic failure. Mice were given an intraperitoneal dose of GalN (800 microg/g body weight)/LPS (100 ng/g body weight) with and without intraperitoneal etoposide (10 microg/g body weight) treatment. ⋯ Etoposide treatment reduced CPP32/caspase-3 activity in the liver, although it did not alter the serum TNF-alpha levels or hepatic TNFR1 mRNA expressions. In addition, etoposide treatment enhanced the mRNA and protein expression of Bcl-xL, an antiapoptotic molecule in the liver. The present findings suggest that etoposide prevents endotoxin-induced lethal liver injury by up-regulation of Bcl-xL, and that etoposide could be useful for the treatment of TNF-alpha-mediated liver diseases.
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Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates cell growth and differentiation. Recent evidence has suggested that PPARgamma ligands had anti-tumor effects through inhibiting cell growth and inducing cell differentiation in several types of malignant neoplasm. In the present study, we investigated: 1) the expression of PPARgamma in both human hepatoma cell lines and 5 resected human hepatocellular carcinoma (HCC) tissues; 2) the growth-inhibitory effect of troglitazone, a PPARgamma ligand, on those hepatoma cells; and 3) the molecular mechanisms of troglitazone-induced cell-cycle arrest. ⋯ However, HuH-7, lacking p21 protein expression, did not demonstrate clear arrest in the cell-cycle analysis. HLF, which was deficient in the protein product of the retinoblastoma tumor-suppressor gene (pRb), responded most profoundly to troglitazone, showing an increased expression in not only p21, but also in p27 and in p18. These findings suggested that p21, p27, and p18 might be involved in troglitazone-induced cell-cycle arrest in human hepatoma cells.
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Immune elimination of hepatitis B virus (HBV) during antiviral therapy depends on the activation of T-cell responses, which are generally impaired in chronic hepatitis B. HBV-specific T helper (Th)-cell reactivity has been assessed post-treatment in liver and peripheral blood of 18 anti-HBe-positive patients with chronic hepatitis B administered combined ribavirin/interferon alfa (IFN-alpha) therapy. The results showed that patients with undetectable HBV DNA by quantitative polymerase chain reaction under combination therapy were able to mount an HBV-specific CD4(+) Th-cell proliferative response and such T-cell reactivity is detectable 1 year after HBV DNA clearance. ⋯ However, HBV-specific IFN-gamma production in vitro in peripheral blood mononuclear cells augmented in 4 of 5 sustained responders and all 13 nonresponders, interleukin 10 (IL-10) production decreased in all 5 sustained responders but increased in 7 of 13 nonresponders. Furthermore, intrahepatic HBcAg plus HBeAg-specific Th-cell proliferation only occurred in sustained responders (2 of 3, 67%, vs. 0 of 9; P =.045) whose cells showed in vitro significantly increased productions in HBcAg/HBeAg-specific IFN-gamma and IL-12 compared with nonresponders in whom IFN-gamma and IL-12 productions decreased together with increased IL-10 secretion. In conclusion this study indicates that combined therapy with ribavirin and IFN-alpha for chronic hepatitis B not only significantly reduces viremia levels but also induces lasting CD4(+) T-cell proliferation and Th1 cytokine release at the site of infection, which may lead to sustained eradication of the HBV.
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Comparative Study
Furosemide-induced natriuresis as a test to identify cirrhotic patients with refractory ascites.
The diagnosis of refractory ascites in cirrhotic patients carries a poor prognosis and liver transplantation should always be considered in this situation. Identification of patients who will not respond to diuretic therapy usually requires several weeks of observation during which a trial of diuretics is instituted using stepwise increases in dosage in order to classify ascites as refractory. In the present study we evaluated the effect of a single dose of 80 mg intravenous furosemide on urinary sodium excretion over 8 hours in cirrhotic patients with ascites responsive to diuretic treatment (group 1; n = 14) and patients with refractory ascites (group 2; n = 15). ⋯ The effects of furosemide on 8-hour natriuresis was much higher in patients with responsive ascites as compared with patients with refractory ascites (125 +/- 46 vs. 30 +/- 16 mEq; mean +/- SD; P <.0001). A natriuresis lower than 50 mEq/8 hours was observed in all group-2 patients as compared with none from group 1. The present study shows that patients with refractory ascites can be identified quickly and accurately by using this simple furosemide-induced natriuresis test, which could be very useful to select patients for liver transplantation.