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Barbero-Becerra V.J.,Fondazione Italiana Fegato ONLUS | Barbero-Becerra V.J.,Obesity and Digestive Disease Unit | Santiago-Hernandez J.J.,Obesity and Digestive Disease Unit | Villegas-Lopez F.A.,Obesity and Digestive Disease Unit | And 3 more authors.
Current Medicinal Chemistry | Year: 2012

Metformin is an antidiabetic drug used widely in clinical practice. Its main clinical effect is to reduce blood glucose levels by improving insulin resistance. Nonalcoholic fatty liver disease is characterized by chronic liver damage and can develop into liver cirrhosis. Nonalcoholic fatty liver disease is associated with obesity and contributes to insulin resistance, and metformin is used to treat individuals with these conditions. The mechanisms underlying the clinical effects of metformin in treating nonalcoholic fatty liver disease are unclear. This article summarizes the literature on the mechanisms associated with liver glucose metabolism and the beneficial effects of metformin on this common liver disease. © 2012 Bentham Science Publishers. Source


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.5-1 | Award Amount: 7.81M | Year: 2010

Non-alcoholic fatty liver disease (NAFLD) has become one of the top concerns for the practising hepatogastroenterologist due to the obesity epidemic and its potential to progress to advanced liver disease which significantly impacts on overall and liver-related mortality. The aim of the FLIP (Fatty Liver: Inhibition of Progression) project is to understand and prevent the progression of liver disease in NAFLD. FLIP is a consortium of basic scientists and practising clinical hepatologists with an established track record and focus on research into the underlying mechanisms and management of patients with NAFLD. Therefore FLIP provides a unique opportunity to assemble the largest European cohort of patients with histologically diagnosed NAFLD with clinical and epidemiological data and with biobanks of DNA, frozen liver tissue and serum. These will be used in a wide range of collaborative inter-disciplinary research projects aimed at addressing key unanswered questions related to the mechanisms and consequences of liver injury in NAFLD and the development of novel preventive and therapeutic strategies. The main outcomes of FLIP will be new insights in the progression of liver disease in NAFLD in terms of initiating mechanisms and patients at risk, innovative diagnostic methods particularly adapted for large-scale screening and prognostic evaluation, improved implementation of lifestyle changes, collaboration with leading biotechnological or pharmaceutical companies in order to translate to the market diagnostic tests or newly identified molecular targets for pharmacological therapy. By disseminating the projects results, FLIP will further help the European Community to suggest guidelines on the management of this emerging liver disease. The long-term goal is to lay the foundations for the future of NAFLD research in Europe by creating a Collaborative Research Network on NAFLD that will continue the work initiated by the FLIP consortium.


Qaisiya M.,Fondazione Italiana Fegato ONLUS | Coda Zabetta C.D.,Fondazione Italiana Fegato ONLUS | Bellarosa C.,Fondazione Italiana Fegato ONLUS | Tiribelli C.,Fondazione Italiana Fegato ONLUS | Tiribelli C.,University of Trieste
Cellular Signalling | Year: 2014

Unconjugated bilirubin (UCB) is responsible for neonatal jaundice and high level of free bilirubin (Bf) can lead to kernicterus. Previous studies suggest that oxidative stress is a critical component of UCB-induced neurotoxicity. The Nrf2 pathway is a powerful sensor for cellular redox state and is activated directly by oxidative stress and/or indirectly by stress response protein kinases. Activated Nrf2 translocates to nucleus, binds to Antioxidant Response Element (ARE), and enhances the up-regulation of cytoprotective genes that mediate cell survival. The aim of the present study was to investigate the role of Nrf2 pathway in cell response to bilirubin mediated oxidative stress in the neuroblastoma SH-SY5Y cell line. Cells exposed to a toxic concentration of UCB (140. nM Bf) showed an increased intracellular ROS levels and enhanced nuclear accumulation of Nrf2 protein. UCB stimulated transcriptional induction of ARE-GFP reporter gene and induced mRNA expression of multiple antioxidant response genes as: xCT, Gly1, γGCL-m, γGCL-c, HO-1, NQO1, FTH, ME1, and ATF3. Nrf2 siRNA decreased UCB induced mRNA expression of HO1 (75%), NQO1 (54%), and FTH (40%). The Nrf2-related HO-1 induction was reduced to 60% in cells pre-treated with antioxidant (NAC) or specific signaling pathway inhibitors for PKC, P38α and MEK1/2 (80, 40 and 25%, respectively). In conclusion, we demonstrated that SH-SY5Y cells undergo an adaptive response against UCB-mediated oxidative stress by activation of multiple antioxidant response, in part through Nrf2 pathway. © 2013 Elsevier Inc. Source

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