TY - JOUR A1 - Bankoglu, Ezgi Eyluel A1 - Tschopp, Oliver A1 - Schmitt, Johannes A1 - Burkard, Philipp A1 - Jahn, Daniel A1 - Geier, Andreas A1 - Stopper, Helga T1 - Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice JF - PLoS One N2 - Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin. KW - insulin KW - mouse models DNA damage KW - oxidative stress KW - mammalian genomics KW - fatty liver KW - micronuclei KW - insulin signaling Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146970 VL - 11 IS - 11 ER - TY - JOUR A1 - Dietrich, Christoph G. A1 - Götze, Oliver A1 - Geier, Andreas T1 - Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance JF - World Journal of Gastroenterology N2 - Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests. KW - Liver cirrhosis KW - Drug metabolism KW - Transport KW - Breath tests KW - Lipid metabolism KW - Glucose metabolism Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191136 VL - 22 IS - 1 ER - TY - JOUR A1 - Banales, Jesus M. A1 - Cardinale, Vincenzo A1 - Carpino, Guido A1 - Marzioni, Marco A1 - Andersen, Jesper B. A1 - Invernizzi, Pietro A1 - Lind, Guro E. A1 - Folseraas, Trine A1 - Forbes, Stuart J. A1 - Fouassier, Laura A1 - Geier, Andreas A1 - Calvisi, Diego F. A1 - Mertens, Joachim C. A1 - Trauner, Michael A1 - Benedetti, Antonio A1 - Maroni, Luca A1 - Vaquero, Javier A1 - Macias, Rocio I. R. A1 - Raggi, Chiara A1 - Perugorria, Maria J. A1 - Gaudio, Eugenio A1 - Boberg, Kirsten M. A1 - Marin, Jose J. G. A1 - Alvaro, Domenico T1 - Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) JF - Nature Reviews Gastroenterology & Hepatology N2 - Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted. KW - primary sclerosing cholangitis KW - growth-factor-receptor KW - biliary-tract cancer KW - epithelial-mesenchymal transition KW - fine-needle-aspiration KW - human intrahepatic cholangiocarcinoma KW - induce cyclooxygenase-2 expression KW - human cholangiocellular carcinoma KW - nucleoside transporter KW - hepatic stellate cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189077 VL - 13 IS - 5 ER - TY - JOUR A1 - Kuntzen, Thomas A1 - Kuhn, Sereina A1 - Kuntzen, Daniela A1 - Seifert, Burkhardt A1 - Müllhaupt, Beat A1 - Geier, Andreas T1 - Influence of Ribavirin Serum Levels on Outcome of Antiviral Treatment and Anemia in Hepatitis C Virus Infection JF - PLoS ONE N2 - Background Ribavirin blood levels vary considerably between patients with standard weight-based dosing. Their impact on sustained virological response (SVR) with pegylated interferon and ribavirin is controversial, but has mostly been studied before the IL28b gene polymorphism as a possible confounder was discovered. Methods The impact of serum ribavirin trough levels at week 4, at the end of treatment and of mean levels across the entire antiviral treatment with pegylated interferon and ribavirin on relapse, SVR rates and anemia was retrospectively studied by univariate and multivariable logistic regression analyses in 214 patients with HCV genotype 1–4 infection, including 88 patients with available IL28b genotyping. Results Mean ribavirin levels varied between 0.68–5.65 mg/l and significantly differed between patients with or without SVR. By multivariable regression including age, sex, HCV viral load, HCV genotype, liver fibrosis stage, prior treatments, immunosuppression and IL28b genotype, ribavirin levels consistently displayed significant influence on SVR and relapse without indication for a specific importance of higher concentrations early or late in the treatment course. Although hemoglobin decline was on average more pronounced in patients with higher ribavirin levels, hemoglobin remained relatively stable in a significant proportion of these, indicating that ribavirin levels alone are insufficient to predict anemia. Conclusion While data are scarce to draw conclusions applicable for modern DAA therapies, these results support ribavirin treatment based on serum levels instead of purely weight-based dosing in combination with pegylated interferon. KW - ribavirin serum levels KW - antiviral treatment KW - anemia KW - Hepatitis C Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166888 VL - 11 IS - 7 ER -