Publications (5)14.4 Total impact
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Article: Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway.
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ABSTRACT: Beta cell failure is caused by loss of cell mass, mostly by apoptosis, but also by simple dysfunction (decline of glucose-stimulated insulin secretion, downregulation of specific gene expression). Apoptosis and dysfunction are caused, at least in part, by lipoglucotoxicity. The mechanisms implicated are oxidative stress, increase in the hexosamine biosynthetic pathway (HBP) flux and endoplasmic reticulum (ER) stress. Oxidative stress plays a role in glucotoxicity-induced beta cell dedifferentiation, while glucotoxicity-induced ER stress has been mostly linked to beta cell apoptosis. We sought to clarify whether ER stress caused by increased HBP flux participates in a dedifferentiating response of beta cells, in the absence of relevant apoptosis. We used INS-1E cells and murine islets. We analysed the unfolded protein response and the expression profile of beta cells by real-time RT-PCR and western blot. The signal transmission pathway elicited by ER stress was investigated by real-time RT-PCR and immunofluorescence. Glucosamine and high glucose induced ER stress, but did not decrease cell viability in INS-1E cells. ER stress caused dedifferentiation of beta cells, as shown by downregulation of beta cell markers and of the transcription factor, pancreatic and duodenal homeobox 1. Glucose-stimulated insulin secretion was inhibited. These effects were prevented by the chemical chaperone, 4-phenyl butyric acid. The extracellular signal-regulated kinase (ERK) signal transmission pathway was implicated, since its inhibition prevented the effects induced by glucosamine and high glucose. Glucotoxic ER stress dedifferentiates beta cells, in the absence of apoptosis, through a transcriptional response. These effects are mediated by the activation of ERK1/2.Diabetologia 01/2012; 55(1):141-53. · 6.81 Impact Factor -
Article: Hepatocyte nuclear factor (HNF)-4alpha-driven epigenetic silencing of the human PED gene.
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ABSTRACT: Overexpression of PED (also known as PEA15) determines insulin resistance and impaired insulin secretion and may contribute to progression toward type 2 diabetes. Recently, we found that the transcription factor hepatocyte nuclear factor (HNF)-4alpha binds to PED promoter and represses its transcription. However, the molecular details responsible for regulation of PED gene remain unclear. Here we used gain and loss of function approaches to investigate the hypothesis that HNF-4alpha controls chromatin remodelling at the PED promoter in human cell lines. HNF-4alpha production and binding induce chromatin remodelling at the -250 to 50 region of PED, indicating that remodelling is limited to two nucleosomes located at the proximal promoter. Chromatin immunoprecipitation assays also revealed concomitant HNF-4alpha-induced deacetylation of histone H3 at Lys9 and Lys14, and increased dimethylation of histone H3 at Lys9. The latter was followed by reduction of histone H3 Lys4 dimethylation. HNF-4alpha was also shown to target the histone deacetylase complex associated with silencing mediator of retinoic acid and thyroid hormone receptor, both at the PED promoter, and at GRB14 and USP21 regulatory regions, leading to a reduction of mRNA levels. Moreover, HNF-4alpha silencing and PED overexpression were accompanied by a significant reduction of hepatic glycogen content. These results show that HNF-4alpha serves as a scaffold protein for histone deacetylase activities, thereby inhibiting liver expression of genes including PED. Dysregulation of these mechanisms may lead to upregulation of the PED gene in type 2 diabetes.Diabetologia 07/2010; 53(7):1482-92. · 6.81 Impact Factor -
Article: [Pre- and post- operative chemotherapy of rectal carcinoma. Indications and results].
Minerva chirurgica 01/2004; 58(6):887-91. · 0.77 Impact Factor -
Article: Beta-hexosaminidase activity in alcoholic fatty liver and in CCl4-induced liver fibrosis of the rat.
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ABSTRACT: beta-Hexosaminidase (Hex) activity was previously found to be increased in the sera of patients with liver cirrhosis, cholestasis and acute alcohol intoxication, as well as in rats with CCl4-induced liver cirrhosis. We studied this enzymatic activity in the sera and liver tissue of rats with alcoholic fatty liver due to prolonged alcohol intake and CCl4-induced liver fibrosis in association with moderate alterations in liver function tests. Serum and liver Hex activity did not show any significant change in both experimental models. These data suggest that Hex is not an alcohol-induced enzyme, and that severe, but not moderate, liver damage can determine the increase in this lysosomal enzymatic activity.Enzyme 02/1989; 42(2):68-72. -
Article: Angiotensin-converting enzyme activity in experimental alcoholic fatty liver of the rat.
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ABSTRACT: Angiotensin-converting enzyme (ACE) activity was found increased in serum of patients with chronic alcoholism. We studied this enzymatic activity in serum and liver tissue of rats with alcoholic fatty liver due to prolonged intake of ethanol with a liquid diet, according to De Carli and Lieber. Serum and liver ACE activity did not show any significant increase in rats with alcoholic fatty liver when compared with controls, whereas gamma-glutamyltransferase activity exhibited a striking enhancement in serum and liver. Our data suggest that ACE is not an alcohol-induced enzyme in the experimental rat model.Enzyme 02/1988; 40(1):14-7.
