Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor gamma-independent regulation of nucleophosmin.

UNLABELLED: Antidiabetic thiazolidinediones (TZD) have in vitro antiproliferative effect in epithelial cancers, including hepatocellular carcinoma (HCC). The effective anticancer properties and the underlying molecular mechanisms of these drugs in vivo remain unclear. In addition, the primary biological target of TZD, the ligand-dependent transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), is up-regulated in HCC and seems to provide tumor-promoting responses. The aim of our study was to evaluate whether chronic administration of TZD may affect hepatic carcinogenesis in vivo in relation to PPARgamma expression and activity. The effect of TZD oral administration for 26 weeks was tested on tumor formation in PPARgamma-expressing and PPARgamma-deficient mouse models of hepatic carcinogenesis. Proteomic analysis was performed in freshly isolated hepatocytes by differential in gel electrophoresis and mass spectrometry analysis. Identified TZD targets were confirmed in cultured PPARgamma-deficient hepatocytes. TZD administration in hepatitis B virus (HBV)-transgenic mice (TgN[Alb1HBV]44Bri) reduced tumor incidence in the liver, inhibiting hepatocyte proliferation and increasing apoptosis. PPARgamma deletion in hepatocytes of HBV-transgenic mice (Tg[HBV]CreKOgamma) did not modify hepatic carcinogenesis but increased the TZD antitumorigenic effect. Proteomic analysis identified nucleophosmin (NPM) as a TZD target in PPARgamma-deficient hepatocytes. TZD inhibited NPM expression at protein and messenger RNA levels and decreased NPM promoter activity. TZD inhibition of NPM was associated with the induction of p53 phosphorylation and p21 expression. CONCLUSION: These findings suggest that chronic administration of TZD has anticancer activity in the liver via inhibition of NPM expression and indicate that these drugs might be useful for HCC chemoprevention and treatment.

Dietary trans-resveratrol bioavailability and effect on CCl4-induced liver lipid peroxidation.

BACKGROUND AND AIM: Several in vitro studies have demonstrated the ability of pure trans-resveratrol (t-Res) to act as an anti-oxidant, but the scientific literature is lacking in in vivo studies dealing with dietary t-Res bioavailability in oxidative stress models. Our aim was to investigate the bioavailability of t-Res from dietary sources and its effect on an animal model of carbon tetrachloride (CCl4)-induced liver lipid peroxidation. METHODS: Ten rats were intragastrically administered for 14 days with a grape-stalk extract determining a daily t-Res dosage of 3 mg/kg. The control group (10 rats) was daily injected with the vehicle solvent without the t-Res extract. After 1 week, the induction of liver lipid peroxidation by CCl4 injection was carried out. Serum and liver samples, at different time intervals, were collected to evaluate t-Res content, by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectometry-mass spectometry (LC-MS-MS). Liver malondialdehyde (MDA) as marker of oxidative stress was measured. RESULTS: t-Res accumulates in the liver reaching 49.8 +/- 10.2 ng/g after 7 days and 191.8 +/- 15.3 ng/g after 14 days. No t-Res was detected in serum. The increase of MDA liver concentration due to CCl4 injection after 24 h and 1 week was reduced by 38% and a 63%, respectively, by the treatment with the t-Res extract. CONCLUSIONS: A moderate consumption of t-Res from a dietary source resulted in a time-dose-dependent liver accumulation. It was able to counteract in vivo CCl4-induced liver lipid peroxidation thus demonstrating the hepatoprotective property of t-Res.

Helicobacter pylori cag pathogenicity island is associated with reduced expression of interleukin-4 (IL-4) mRNA and modulation of the IL-4delta2 mRNA isoform in human gastric mucosa.

Interleukin-4 (IL-4) and IL-4delta2 mRNA gastric expression was evaluated in healthy subjects and patients who did not have ulcers but were infected with Helicobacter pylori with or without the cag pathogenicity island (cag PAI). IL-4 mRNA was physiologically expressed by gastric epithelium and negatively influenced by H. pylori. Also, nonepithelial cells in the lamina propria of H. pylori-infected patients expressed IL-4 mRNA, whereas IL-4delta2 mRNA was found only in cag PAI-negative patients. Thus, gastric IL-4 takes part in the local immune response to H. pylori.