TY - GEN A1 - Hoffmann, Linda Sarah A1 - Kretschmer, Axel A1 - Lawrenz, Bettina A1 - Hocher, Berthold A1 - Stasch, Johannes-Peter T1 - Chronic activation of heme free Guanylate Cyclase leads to renal protection in Dahl salt-sensitive rats T2 - Postprints der Universität Potsdam : Mathematisch naturwissenschaftliche Reihe N2 - The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophasphate (cGMP)-signalling pathway is impaired under oxidative stress conditions due to oxidation and subsequent loss of the prosthetic sGC heme group as observed in particular in chronic renal failure. Thus, the pool of heme free sGC is increased under pathological conditions. sGC activators such as cinaciguat selectively activate the heme free form of sGC and target the disease associated enzyme. In this study, a therapeutic effect of long-term activation of heme free sGC by the sGC activator cinaciguat was investigated in an experimental model of salt-sensitive hypertension, a condition that is associated with increased oxidative stress, heme loss from sGC and development of chronic renal failure. For that purpose Dahl/ss rats, which develop severe hypertension upon high salt intake, were fed a high salt diet (8% NaCl) containing either placebo or cinaciguat for 21 weeks. Cinaciguat markedly improved survival and ameliorated the salt-induced increase in blood pressure upon treatment with cinaciguat compared to placebo. Renal function was significantly improved in the cinaciguat group compared to the placebo group as indicated by a significantly improved glomerular filtration rate and reduced urinary protein excretion. This was due to anti-fibrotic and antiinflammatory effects of the cinaciguat treatment. Taken together, this is the first study showing that long-term activation of heme free sGC leads to renal protection in an experimental model of hypertension and chronic kidney disease. These results underline the promising potential of cinaciguat to treat renal diseases by targeting the disease associated heme free form of sGC. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 489 KW - signal-transduction system KW - nitric-oxide KW - oxidative stress KW - independent activation KW - endothelial dysfunction KW - pulmonary-hypertension KW - cardiovascular-disease KW - therapeutic target KW - heart-failure KW - cyclic-GMP Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-408088 SN - 1866-8372 IS - 489 ER - TY - GEN A1 - Castro, José Pedro A1 - Grune, Tilman A1 - Speckmann, Bodo T1 - The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction N2 - White adipose tissue (WAT) is actively involved in the regulation of whole-body energy homeostasis via storage/release of lipids and adipokine secretion. Current research links WAT dysfunction to the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). The expansion of WAT during oversupply of nutrients prevents ectopic fat accumulation and requires proper preadipocyte-to-adipocyte differentiation. An assumed link between excess levels of reactive oxygen species (ROS), WAT dysfunction and T2D has been discussed controversially. While oxidative stress conditions have conclusively been detected in WAT of T2D patients and related animal models, clinical trials with antioxidants failed to prevent T2D or to improve glucose homeostasis. Furthermore, animal studies yielded inconsistent results regarding the role of oxidative stress in the development of diabetes. Here, we discuss the contribution of ROS to the (patho)physiology of adipocyte function and differentiation, with particular emphasis on sources and nutritional modulators of adipocyte ROS and their functions in signaling mechanisms controlling adipogenesis and functions of mature fat cells. We propose a concept of ROS balance that is required for normal functioning of WAT. We explain how both excessive and diminished levels of ROS, e.g. resulting from over supplementation with antioxidants, contribute to WAT dysfunction and subsequently insulin resistance. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 339 KW - adipogenesis KW - adipose tissue dysregulation KW - antioxidants KW - metabolic disorders KW - oxidative stress Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-398039 ER - TY - GEN A1 - Scarpeci, Telma E. A1 - Zanor, María I. A1 - Carrillo, Néstor A1 - Mueller-Roeber, Bernd A1 - Valle, Estela M. T1 - Generation of superoxide anion in chloroplasts of Arabidopsis thaliana during active photosynthesis BT - a focus on rapidly induced genes T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - The antioxidant defense system involves complex functional coordination of multiple components in different organelles within the plant cell. Here, we have studied the Arabidopsis thaliana early response to the generation of superoxide anion in chloroplasts during active photosynthesis. We exposed plants to methyl viologen (MV), a superoxide anion propagator in the light, and performed biochemical and expression profiling experiments using Affymetrix ATH1 GeneChip(R) microarrays under conditions in which photosynthesis and antioxidant enzymes were active. Data analysis identified superoxide-responsive genes that were compared with available microarray results. Examples include genes encoding proteins with unknown function, transcription factors and signal transduction components. A common GAAAAGTCAAAC motif containing the W-box consensus sequence of WRKY transcription factors, was found in the promoters of genes highly up-regulated by superoxide. Band shift assays showed that oxidative treatments enhanced the specific binding of leaf protein extracts to this motif. In addition, GUS reporter gene fused to WRKY30 promoter, which contains this binding motif, was induced by MV and H2O2. Overall, our study suggests that genes involved in signalling pathways and with unknown functions are rapidly activated by superoxide anion generated in photosynthetically active chloroplasts, as part of the early antioxidant response of Arabidopsis leaves. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 866 KW - antioxidant response KW - chloroplast KW - Hsp KW - oxidative stress KW - WRKY Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-434254 SN - 1866-8372 IS - 866 SP - 361 EP - 378 ER - TY - GEN A1 - Henkel, Janin A1 - Buchheim-Dieckow, Katja A1 - Castro, José Pedro A1 - Laeger, Thomas A1 - Wardelmann, Kristina A1 - Kleinridders, André A1 - Jöhrens, Korinna A1 - Püschel, Gerhard Paul T1 - Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Non-alcoholic fatty liver diseases (NAFLD) including the severe form with steatohepatitis (NASH) are highly prevalent ailments to which no approved pharmacological treatment exists. Dietary intervention aiming at 10% weight reduction is efficient but fails due to low compliance. Increase in physical activity is an alternative that improved NAFLD even in the absence of weight reduction. The underlying mechanisms are unclear and cannot be studied in humans. Here, a rat NAFLD model was developed that reproduces many facets of the diet-induced NAFLD in humans. The impact of endurance exercise was studied in this model. Male Wistar rats received control chow or a NASH-inducing diet rich in fat, cholesterol, and fructose. Both diet groups were subdivided into a sedentary and an endurance exercise group. Animals receiving the NASH-inducing diet gained more body weight, got glucose intolerant and developed a liver pathology with steatosis, hepatocyte hypertrophy, inflammation and fibrosis typical of NAFLD or NASH. Contrary to expectations, endurance exercise did not improve the NASH activity score and even enhanced hepatic inflammation. However, endurance exercise attenuated the hepatic cholesterol overload and the ensuing severe oxidative stress. In addition, exercise improved glucose tolerance possibly in part by induction of hepatic FGF21 production. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 807 KW - NAFLD KW - NASH KW - endurance exercise KW - FGF21 KW - glucose intolerance KW - cholesterol KW - oxidative stress Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-442384 SN - 1866-8372 IS - 807 ER - TY - JOUR A1 - Henkel, Janin A1 - Buchheim-Dieckow, Katja A1 - Castro, José Pedro A1 - Laeger, Thomas A1 - Wardelmann, Kristina A1 - Kleinridders, André A1 - Jöhrens, Korinna A1 - Püschel, Gerhard Paul T1 - Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH JF - Nutrients N2 - Non-alcoholic fatty liver diseases (NAFLD) including the severe form with steatohepatitis (NASH) are highly prevalent ailments to which no approved pharmacological treatment exists. Dietary intervention aiming at 10% weight reduction is efficient but fails due to low compliance. Increase in physical activity is an alternative that improved NAFLD even in the absence of weight reduction. The underlying mechanisms are unclear and cannot be studied in humans. Here, a rat NAFLD model was developed that reproduces many facets of the diet-induced NAFLD in humans. The impact of endurance exercise was studied in this model. Male Wistar rats received control chow or a NASH-inducing diet rich in fat, cholesterol, and fructose. Both diet groups were subdivided into a sedentary and an endurance exercise group. Animals receiving the NASH-inducing diet gained more body weight, got glucose intolerant and developed a liver pathology with steatosis, hepatocyte hypertrophy, inflammation and fibrosis typical of NAFLD or NASH. Contrary to expectations, endurance exercise did not improve the NASH activity score and even enhanced hepatic inflammation. However, endurance exercise attenuated the hepatic cholesterol overload and the ensuing severe oxidative stress. In addition, exercise improved glucose tolerance possibly in part by induction of hepatic FGF21 production. KW - NAFLD KW - NASH KW - endurance exercise KW - FGF21 KW - glucose intolerance KW - cholesterol KW - oxidative stress Y1 - 2019 U6 - https://doi.org/10.3390/nu11112709 SN - 2072-6643 VL - 11 IS - 11 PB - MDPI CY - Basel ER - TY - JOUR A1 - Henkel, Janin A1 - Alfine, Eugenia A1 - Saín, Juliana A1 - Jöhrens, Korinna A1 - Weber, Daniela A1 - Castro, José Pedro A1 - König, Jeannette A1 - Stuhlmann, Christin A1 - Vahrenbrink, Madita A1 - Jonas, Wenke A1 - Kleinridders, André A1 - Püschel, Gerhard Paul T1 - Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol JF - Nutrients N2 - While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease. KW - non-alcoholic fatty liver disease (NAFLD) KW - NASH KW - cholesterol KW - PUFA KW - inflammation KW - oxidative stress Y1 - 2018 U6 - https://doi.org/10.3390/nu10091326 SN - 2072-6643 VL - 10 IS - 9 SP - 1 EP - 17 PB - Molecular Diversity Preservation International (MDPI) CY - Basel ER - TY - GEN A1 - Henkel, Janin A1 - Alfine, Eugenia A1 - Saín, Juliana A1 - Jöhrens, Korinna A1 - Weber, Daniela A1 - Castro, José Pedro A1 - König, Jeannette A1 - Stuhlmann, Christin A1 - Vahrenbrink, Madita A1 - Jonas, Wenke A1 - Kleinridders, André A1 - Püschel, Gerhard Paul T1 - Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol T2 - Nutrients N2 - While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 479 KW - non-alcoholic fatty liver disease (NAFLD) KW - NASH KW - cholesterol KW - PUFA KW - inflammation KW - oxidative stress Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-419773 ER -