@article{ChaykovskaAltervonWebskyetal.2013, author = {Chaykovska, Lyubov and Alter, Markus L. and von Websky, Karoline and Hohmann, Margarete and Tsuprykov, Oleg and Reichetzeder, Christoph and Kutil, Barbara and Kraft, Robin and Klein, Thomas and Hocher, Berthold}, title = {Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension}, series = {Journal of hypertension}, volume = {31}, journal = {Journal of hypertension}, number = {11}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0b013e3283649b4d}, pages = {2290 -- 2299}, year = {2013}, abstract = {Objective:To investigate the effects of linagliptin alone and in combination with the angiotensin II receptor blocker (ARB), telmisartan on blood pressure (BP), kidney function, heart morphology and oxidative stress in rats with renovascular hypertension.Methods:Fifty-seven male Wistar rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2k1c) method]. Animals were randomly divided into four treatment groups (n=14-18 per group) receiving: telmisartan (10mg/kg per day in drinking water), linagliptin (89ppm in chow), combination (linagliptin 89ppm+telmisartan 10mg/kg per day) or placebo. An additional group of 12 rats underwent sham surgery. BP was measured one week after surgery. Hypertensive animals entered a 16-week dosing period. BP was measured 2, 4, 8, 12 and 16 weeks after the initiation of treatment. Blood and urine were tested for assessment of kidney function and oxidative stress 6, 10, 14 and 18 weeks after surgery. Blood and urine sampling and organ harvesting were finally performed.Results:Renal stenosis caused an increase in meanSD systolic BP as compared with the sham group (157.7 +/- 29.3 vs. 106.2 +/- 20.5mmHg, respectively; P<0.001). Telmisartan alone and in combination with linagliptin, normalized SBP (111.1 +/- 24.3mmHg and 100.4 +/- 13.9mmHg, respectively; P<0.001 vs. placebo). Telmisartan alone and in combination with linagliptin significantly prevented cardiac hypertrophy, measured by heart weight and myocyte diameter. Renal function measured by cystatin C was not affected by 2k1c surgery. Telmisartan significantly increased plasma concentration of cystatin C. 2k1c surgery initiated fibrosis in both kidneys. Telmisartan promoted further fibrotic changes in the clipped kidney, as measured by protein expression of Col1a1 and histology for interstitial fibrosis and glomerulosclerosis. In non-clipped kidneys, telmisartan demonstrated antifibrotic properties, reducing Col1a1 protein expression. Plasma levels of oxidized low-density lipoprotein were higher in the placebo-treated 2k1c rats as compared to sham-operated animals. The increase was abolished by linagliptin alone (P=0.03 vs. placebo) and in combination with telmisartan (P=0.02 vs. placebo). Combination therapy also significantly reduced plasma concentration of carbonyl proteins (P=0.04 vs. placebo).Conclusion:Inhibition of type 4 dipeptidyl peptidase with linagliptin did not counter BP-lowering effects of ARB in 2k1c rats. Linagliptin reduced lipid and protein oxidation in 2k1c rats, and this effect was BP-independent.}, language = {en} } @article{CzarnockaVanDerKelenWillemsetal.2017, author = {Czarnocka, Weronika and Van Der Kelen, Katrien and Willems, Patrick and Szechynska-Hebda, Magdalena and Shahnejat-Bushehri, Sara and Balazadeh, Salma and Rusaczonek, Anna and M{\"u}ller-R{\"o}ber, Bernd and Van Breusegem, Frank and Karpinski, Stanislaw}, title = {The dual role of LESION SIMULATING DISEASE 1 as a condition-dependent scaffold protein and transcription regulator}, series = {Plant, cell \& environment : cell physiology, whole-plant physiology, community physiology}, volume = {40}, journal = {Plant, cell \& environment : cell physiology, whole-plant physiology, community physiology}, publisher = {Wiley}, address = {Hoboken}, issn = {0140-7791}, doi = {10.1111/pce.12994}, pages = {2644 -- 2662}, year = {2017}, abstract = {Since its discovery over two decades ago as an important cell death regulator in Arabidopsis thaliana, the role of LESION SIMULATING DISEASE 1 (LSD1) has been studied intensively within both biotic and abiotic stress responses as well as with respect to plant fitness regulation. However, its molecular mode of action remains enigmatic. Here, we demonstrate that nucleo-cytoplasmic LSD1 interacts with a broad range of other proteins that are engaged in various molecular pathways such as ubiquitination, methylation, cell cycle control, gametogenesis, embryo development and cell wall formation. The interaction of LSD1 with these partners is dependent on redox status, as oxidative stress significantly changes the quantity and types of LSD1-formed complexes. Furthermore, we show that LSD1 regulates the number and size of leaf mesophyll cells and affects plant vegetative growth. Importantly, we also reveal that in addition to its function as a scaffold protein, LSD1 acts as a transcriptional regulator. Taken together, our results demonstrate that LSD1 plays a dual role within the cell by acting as a condition-dependent scaffold protein and as a transcription regulator.}, language = {en} } @article{EndesfelderWeicheltStraussetal.2017, author = {Endesfelder, Stefanie and Weichelt, Ulrike and Strauß, Evelyn and Schl{\"o}r, Anja and Sifringer, Marco and Scheuer, Till and B{\"u}hrer, Christoph and Schmitz, Thomas}, title = {Neuroprotection by caffeine in hyperoxia-induced neonatal brain injury}, series = {International journal of molecular sciences}, volume = {18}, journal = {International journal of molecular sciences}, publisher = {Molecular Diversity Preservation International}, address = {Basel}, issn = {1422-0067}, doi = {10.3390/ijms18010187}, pages = {24}, year = {2017}, abstract = {Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term "oxygen radical disease of prematurity". Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28-32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80\% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.}, language = {en} } @article{HaaseArlinghausTentschertetal.2011, author = {Haase, Andrea and Arlinghaus, Heinrich F. and Tentschert, Jutta and Jungnickel, Harald and Graf, Philipp and Mantion, Alexandre and Draude, Felix and Galla, Sebastian and Plendl, Johanna and Goetz, Mario E. and Masic, Admir and Meier, Wolfgang P. and Thuenemann, Andreas F. and Taubert, Andreas and Luch, Andreas}, title = {Application of Laser Postionization Secondary Neutral Mass Spectrometry/Time-of-Flight Secondary Ion Mass Spectrometry in Nanotoxicology: Visualization of Nanosilver in Human Macrophages and Cellular Responses}, series = {ACS nano}, volume = {5}, journal = {ACS nano}, number = {4}, publisher = {American Chemical Society}, address = {Washington}, issn = {1936-0851}, doi = {10.1021/nn200163w}, pages = {3059 -- 3068}, year = {2011}, abstract = {Silver nanoparticles (SNP) are the subject of worldwide commercialization because of their antimicrobial effects. Yet only little data on their mode of action exist. Further, only few techniques allow for visualization and quantification of unlabeled nanoparticles inside cells. To study SNP of different sizes and coatings within human macrophages, we introduce a novel laser postionization secondary neutral mass spectrometry (Laser-SNMS) approach and prove this method superior to the widely applied confocal Raman and transmission electron microscopy. With time-of-flight secondary ion mass spectrometry (TOF-SIMS) we further demonstrate characteristic fingerprints in the lipid pattern of the cellular membrane indicative of oxidative stress and membrane fluidity changes. Increases of protein carbonyl and heme oxygenase-1 levels in treated cells confirm the presence of oxidative stress biochemically. Intriguingly, affected phagocytosis reveals as highly sensitive end point of SNP-mediated adversity In macrophages. The cellular responses monitored are. hierarchically linked, but follow individual kinetics and are partially reversible.}, language = {en} } @article{HaaseRottMantionetal.2012, author = {Haase, Andrea and Rott, Stephanie and Mantion, Alexandre and Graf, Philipp and Plendl, Johanna and Th{\"u}nemann, Andreas F. and Meier, Wolfgang P. and Taubert, Andreas and Luch, Andreas and Reiser, Georg}, title = {Effects of silver nanoparticles on primary mixed neural cell cultures: Uptake, oxidative stress and acute calcium responses}, series = {Toxicological sciences}, volume = {126}, journal = {Toxicological sciences}, number = {2}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {1096-6080}, doi = {10.1093/toxsci/kfs003}, pages = {457 -- 468}, year = {2012}, abstract = {In the body, nanoparticles can be systemically distributed and then may affect secondary target organs, such as the central nervous system (CNS). Putative adverse effects on the CNS are rarely investigated to date. Here, we used a mixed primary cell model consisting mainly of neurons and astrocytes and a minor proportion of oligodendrocytes to analyze the effects of well-characterized 20 and 40 nm silver nanoparticles (SNP). Similar gold nanoparticles served as control and proved inert for all endpoints tested. SNP induced a strong size-dependent cytotoxicity. Additionally, in the low concentration range (up to 10 mu g/ml of SNP), the further differentiated cultures were more sensitive to SNP treatment. For detailed studies, we used low/medium dose concentrations (up to 20 mu g/ml) and found strong oxidative stress responses. Reactive oxygen species (ROS) were detected along with the formation of protein carbonyls and the induction of heme oxygenase-1. We observed an acute calcium response, which clearly preceded oxidative stress responses. ROS formation was reduced by antioxidants, whereas the calcium response could not be alleviated by antioxidants. Finally, we looked into the responses of neurons and astrocytes separately. Astrocytes were much more vulnerable to SNP treatment compared with neurons. Consistently, SNP were mainly taken up by astrocytes and not by neurons. Immunofluorescence studies of mixed cell cultures indicated stronger effects on astrocyte morphology. Altogether, we can demonstrate strong effects of SNP associated with calcium dysregulation and ROS formation in primary neural cells, which were detectable already at moderate dosages.}, language = {en} } @article{HenkelAlfineSainetal.2018, author = {Henkel, Janin and Alfine, Eugenia and Sa{\´i}n, Juliana and J{\"o}hrens, Korinna and Weber, Daniela and Castro, Jos{\´e} Pedro and K{\"o}nig, Jeannette and Stuhlmann, Christin and Vahrenbrink, Madita and Jonas, Wenke and Kleinridders, Andr{\´e} and P{\"u}schel, Gerhard Paul}, title = {Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol}, series = {Nutrients}, volume = {10}, journal = {Nutrients}, number = {9}, publisher = {Molecular Diversity Preservation International (MDPI)}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu10091326}, pages = {1 -- 17}, year = {2018}, abstract = {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.}, language = {en} } @article{HenkelBuchheimDieckowCastroetal.2019, author = {Henkel, Janin and Buchheim-Dieckow, Katja and Castro, Jos{\´e} Pedro and Laeger, Thomas and Wardelmann, Kristina and Kleinridders, Andr{\´e} and J{\"o}hrens, Korinna and P{\"u}schel, Gerhard Paul}, title = {Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH}, series = {Nutrients}, volume = {11}, journal = {Nutrients}, number = {11}, publisher = {MDPI}, address = {Basel}, issn = {2072-6643}, doi = {10.3390/nu11112709}, pages = {15}, year = {2019}, abstract = {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.}, language = {en} } @article{KobelHoellerGleyJochinkeetal.2018, author = {Kobel-H{\"o}ller, Konstanze and Gley, Kevin and Jochinke, Janina and Heider, Kristina and Fritsch, Verena Nadin and Ha Viet Duc Nguyen, and Lischke, Timo and Radek, Renate and Baumgrass, Ria and Mutzel, Rupert and Thewes, Sascha}, title = {Calcineurin Silencing in Dictyostelium discoideum Leads to Cellular Alterations Affecting Mitochondria, Gene Expression, and Oxidative Stress Response}, series = {Protist}, volume = {169}, journal = {Protist}, number = {4}, publisher = {Elsevier GMBH}, address = {M{\"u}nchen}, issn = {1434-4610}, doi = {10.1016/j.protis.2018.04.004}, pages = {584 -- 602}, year = {2018}, abstract = {Calcineurin is involved in development and cell differentiation of the social amoeba Dictyostelium discoideum. However, since knockouts of the calcineurin-encoding genes are not possible in D. discoideum it is assumed that the phosphatase also plays a crucial role during vegetative growth of the amoebae. Therefore, we investigated the role of calcineurin during vegetative growth in D. discoideum. RNAi-silenced calcineurin mutants showed cellular alterations with an abnormal morphology of mitochondria and had increased content of mitochondrial DNA (mtDNA). In contrast, mitochondria showed no substantial functional impairment. Calcineurin-silencing led to altered expression of calcium-regulated genes as well as mitochondrially-encoded genes. Furthermore, genes related to oxidative stress were higher expressed in the mutants, which correlated to an increased resistance towards reactive oxygen species (ROS). Most of the changes observed during vegetative growth were not seen after starvation of the calcineurin mutants. We show that impairment of calcineurin led to many subtle, but in the sum crucial cellular alterations in vegetative D. discoideum cells. As these alterations were not observed after starvation we propose a dual role for calcineurin during growth and development. Our results imply that calcineurin is one player in the mutual interplay between mitochondria and ROS during vegetative growth.}, language = {en} } @article{NicolaiWeishauptBaesleretal.2021, author = {Nicolai, Merle Marie and Weishaupt, Ann-Kathrin and Baesler, Jessica and Brinkmann, Vanessa and Wellenberg, Anna and Winkelbeiner, Nicola Lisa and Gremme, Anna and Aschner, Michael and Fritz, Gerhard and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Effects of manganese on genomic integrity in the multicellular model organism Caenorhabditis elegans}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {20}, publisher = {MDPI}, address = {Basel}, issn = {1422-0067}, doi = {10.3390/ijms222010905}, pages = {16}, year = {2021}, abstract = {Although manganese (Mn) is an essential trace element, overexposure is associated with Mn-induced toxicity and neurological dysfunction. Even though Mn-induced oxidative stress is discussed extensively, neither the underlying mechanisms of the potential consequences of Mn-induced oxidative stress on DNA damage and DNA repair, nor the possibly resulting toxicity are characterized yet. In this study, we use the model organism Caenorhabditis elegans to investigate the mode of action of Mn toxicity, focusing on genomic integrity by means of DNA damage and DNA damage response. Experiments were conducted to analyze Mn bioavailability, lethality, and induction of DNA damage. Different deletion mutant strains were then used to investigate the role of base excision repair (BER) and dePARylation (DNA damage response) proteins in Mn-induced toxicity. The results indicate a dose- and time-dependent uptake of Mn, resulting in increased lethality. Excessive exposure to Mn decreases genomic integrity and activates BER. Altogether, this study characterizes the consequences of Mn exposure on genomic integrity and therefore broadens the molecular understanding of pathways underlying Mn-induced toxicity. Additionally, studying the basal poly(ADP-ribosylation) (PARylation) of worms lacking poly(ADP-ribose) glycohydrolase (PARG) parg-1 or parg-2 (two orthologue of PARG), indicates that parg-1 accounts for most of the glycohydrolase activity in worms.}, language = {en} } @article{RohnRaschkeAschneretal.2019, author = {Rohn, Isabelle and Raschke, Stefanie and Aschner, Michael and Tuck, Simon and Kuehnelt, Doris and Kipp, Anna Patricia and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Treatment of caenorhabditis elegans with small selenium species enhances antioxidant defense systems}, series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, volume = {63}, journal = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, number = {9}, publisher = {Wiley}, address = {Hoboken}, issn = {1613-4125}, doi = {10.1002/mnfr.201801304}, pages = {9}, year = {2019}, abstract = {ScopeSmall selenium (Se) species play a key role in Se metabolism and act as dietary sources of the essential trace element. However, they are redox-active and trigger pro- and antioxidant responses. As health outcomes are strongly species-dependent, species-specific characteristics of Se compounds are tested in vivo. Methods and resultsIn the model organism Caenorhabditis elegans (C. elegans), immediate and sustained effects of selenite, selenomethionine (SeMet), and Se-methylselenocysteine (MeSeCys) are studied regarding their bioavailability, incorporation into proteins, as well as modulation of the cellular redox status. While all tested Se compounds are bioavailable, only SeMet persistently accumulates and is non-specifically incorporated into proteins. However, the protection toward chemically-induced formation of reactive species is independent of the applied Se compound. Increased thioredoxin reductase (TXNRD) activity and changes in mRNA expression levels of antioxidant proteins indicate the activation of cellular defense mechanisms. However, in txnrd-1 deletion mutants, no protective effects of the Se species are observed anymore, which is also reflected by differential gene expression data. ConclusionSe species protect against chemically-induced reactive species formation. The identified immediate and sustained systemic effects of Se species give rise to speculations on possible benefits facing subsequent periods of inadequate Se intake.}, language = {en} }