TY - JOUR A1 - Scholz, Nicole A1 - Guan, Chonglin A1 - Nieberler, Matthias A1 - Grotmeyer, Alexander A1 - Maiellaro, Isabella A1 - Gao, Shiqiang A1 - Beck, Sebastian A1 - Pawlak, Matthias A1 - Sauer, Markus A1 - Asan, Esther A1 - Rothemund, Sven A1 - Winkler, Jana A1 - Prömel, Simone A1 - Nagel, Georg A1 - Langenhan, Tobias A1 - Kittel, Robert J T1 - Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons JF - eLife N2 - Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in organ development, brain function and govern immunological responses. Correspondingly, this receptor family is linked to a multitude of diverse human diseases. aGPCRs have been suggested to possess mechanosensory properties, though their mechanism of action is fully unknown. Here we show that the Drosophila aGPCR Latrophilin/dCIRL acts in mechanosensory neurons by modulating ionotropic receptor currents, the initiating step of cellular mechanosensation. This process depends on the length of the extended ectodomain and the tethered agonist of the receptor, but not on its autoproteolysis, a characteristic biochemical feature of the aGPCR family. Intracellularly, dCIRL quenches cAMP levels upon mechanical activation thereby specifically increasing the mechanosensitivity of neurons. These results provide direct evidence that the aGPCR dCIRL acts as a molecular sensor and signal transducer that detects and converts mechanical stimuli into a metabotropic response. KW - Latrophilin KW - adhesion GPCR KW - dCIRL KW - sensory physiology KW - metabotropic signalling KW - mechanotransduction Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170520 VL - 6 IS - e28360 ER - TY - JOUR A1 - Godbole, Amod A1 - Lyga, Sandra A1 - Lohse, Martin J. A1 - Calebiro, Davide T1 - Internalized TSH receptors en route to the TGN induce local G\(_{S}\)-protein signaling and gene transcription JF - Nature Communications N2 - A new paradigm of G-protein-coupled receptor (GPCR) signaling at intracellular sites has recently emerged, but the underlying mechanisms and functional consequences are insufficiently understood. Here, we show that upon internalization in thyroid cells, endogenous TSH receptors traffic retrogradely to the trans-Golgi network (TGN) and activate endogenous Gs-proteins in the retromer-coated compartment that brings them to the TGN. Receptor internalization is associated with a late cAMP/protein kinase A (PKA) response at the Golgi/TGN. Blocking receptor internalization, inhibiting PKA II/interfering with its Golgi/TGN localization, silencing retromer or disrupting Golgi/TGN organization all impair efficient TSH-dependent cAMP response element binding protein (CREB) phosphorylation. These results suggest that retrograde trafficking to the TGN induces local G\(_{S}\)-protein activation and cAMP/PKA signaling at a critical position near the nucleus, which appears required for efficient CREB phosphorylation and gene transcription. This provides a new mechanism to explain the functional consequences of GPCR signaling at intracellular sites and reveals a critical role for the TGN in GPCR signaling. KW - G protein-coupled receptors KW - fluorescence imaging KW - hormone receptors KW - trans-Golgi network Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170375 VL - 8 IS - 443 ER - TY - JOUR A1 - Maurer, Jana A1 - Hupp, Sabrina A1 - Bischoff, Carolin A1 - Foertsch, Christina A1 - Mitchell, Timothy J. A1 - Chakraborty, Trinad A1 - Iliev, Asparouh I. T1 - Distinct neurotoxicity profile of listeriolysin O from \(Listeria\) \(monocytogenes\) JF - Toxins N2 - Cholesterol-dependent cytolysins (CDCs) are protein toxins that originate from Gram-positive bacteria and contribute substantially to their pathogenicity. CDCs bind membrane cholesterol and build prepores and lytic pores. Some effects of the toxins are observed in non-lytic concentrations. Two pathogens, \(Streptococcus\) \(pneumoniae\) and \(Listeria\) \(monocytogenes\), cause fatal bacterial meningitis, and both produce toxins of the CDC family—pneumolysin and listeriolysin O, respectively. It has been demonstrated that pneumolysin produces dendritic varicosities (dendrite swellings) and dendritic spine collapse in the mouse neocortex, followed by synaptic loss and astrocyte cell shape remodeling without elevated cell death. We utilized primary glial cultures and acute mouse brain slices to examine the neuropathological effects of listeriolysin O and to compare it to pneumolysin with identical hemolytic activity. In cultures, listeriolysin O permeabilized cells slower than pneumolysin did but still initiated non-lytic astrocytic cell shape changes, just as pneumolysin did. In an acute brain slice culture system, listeriolysin O produced dendritic varicosities in an NMDA-dependent manner but failed to cause dendritic spine collapse and cortical astrocyte reorganization. Thus, listeriolysin O demonstrated slower cell permeabilization and milder glial cell remodeling ability than did pneumolysin and lacked dendritic spine collapse capacity but exhibited equivalent dendritic pathology. KW - medicine KW - listeriolysin O KW - meningitis KW - acute slices KW - variocosities KW - dendritic spines Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172130 VL - 9 IS - 1 ER - TY - JOUR A1 - Weigand, Isabel A1 - Ronchi, Cristina L. A1 - Rizk-Rabin, Marthe A1 - Dalmazi, Guido Di A1 - Wild, Vanessa A1 - Bathon, Kerstin A1 - Rubin, Beatrice A1 - Calebiro, Davide A1 - Beuschlein, Felix A1 - Bertherat, Jérôme A1 - Fassnacht, Martin A1 - Sbiera, Silviu T1 - Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas JF - Scientific Reports N2 - Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion. KW - kinases KW - immunohistochemistry Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157952 VL - 7 IS - 49 ER - TY - JOUR A1 - Cheng, Cheng A1 - Othman, Eman M. A1 - Stopper, Helga A1 - Edrada-Ebel, RuAngelie A1 - Hentschel, Ute A1 - Abdelmohsen, Usama Ramadan T1 - Isolation of petrocidin A, a new cytotoxic cyclic dipeptide from the marine sponge-derived bacterium \(Streptomyces\) sp. SBT348 JF - Marine Drugs N2 - A new cyclic dipeptide, petrocidin A (\(\textbf{1}\)), along with three known compounds—2,3-dihydroxybenzoic acid (\(\textbf{2}\)), 2,3-dihydroxybenzamide (\(\textbf{3}\)), and maltol (\(\textbf{4}\))—were isolated from the solid culture of \(Streptomyces\) sp. SBT348. The strain \(Streptomyces\) sp. SBT348 had been prioritized in a strain collection of 64 sponge-associated actinomycetes based on its distinct metabolomic profile using liquid chromatography/high-resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance (NMR). The absolute configuration of all α-amino acids was determined by HPLC analysis after derivatization with Marfey’s reagent and comparison with commercially available reference amino acids. Structure elucidation was pursued in the presented study by mass spectrometry and NMR spectral data. Petrocidin A (\(\textbf{1}\)) and 2,3-dihydroxybenzamide (\(\textbf{3}\)) exhibited significant cytotoxicity towards the human promyelocytic HL-60 and the human colon adenocarcinoma HT-29 cell lines. These results demonstrated the potential of sponge-associated actinomycetes for the discovery of novel and pharmacologically active natural products. KW - biology KW - sponges KW - actinomycetes KW - streptomyces KW - cyclic dipeptide KW - cytotoxic Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172644 VL - 15 IS - 12 ER - TY - JOUR A1 - Balasubramanian, Srikkanth A1 - Othman, Eman M. A1 - Kampik, Daniel A1 - Stopper, Helga A1 - Hentschel, Ute A1 - Ziebuhr, Wilma A1 - Oelschlaeger, Tobias A. A1 - Abdelmohsen, Usama R. T1 - Marine sponge-derived Streptomyces sp SBT343 extract inhibits staphylococcal biofilm formation JF - Frontiers in Microbiology N2 - Staphylococcus epidermidis and Staphylococcus aureus are opportunistic pathogens that cause nosocomial and chronic biofilm-associated infections. Indwelling medical devices and contact lenses are ideal ecological niches for formation of staphylococcal biofilms. Bacteria within biofilms are known to display reduced susceptibilities to antimicrobials and are protected from the host immune system. High rates of acquired antibiotic resistances in staphylococci and other biofilm-forming bacteria further hamper treatment options and highlight the need for new anti-biofilm strategies. Here, we aimed to evaluate the potential of marine sponge-derived actinomycetes in inhibiting biofilm formation of several strains of S. epidermidis, S. aureus, and Pseudomonas aeruginosa. Results from in vitro biofilm-formation assays, as well as scanning electron and confocal microscopy, revealed that an organic extract derived from the marine sponge-associated bacterium Streptomyces sp. SBT343 significantly inhibited staphylococcal biofilm formation on polystyrene, glass and contact lens surfaces, without affecting bacterial growth. The extract also displayed similar antagonistic effects towards the biofilm formation of other S. epidermidis and S. aureus strains tested but had no inhibitory effects towards Pseudomonas biofilms. Interestingly the extract, at lower effective concentrations, did not exhibit cytotoxic effects on mouse fibroblast, macrophage and human corneal epithelial cell lines. Chemical analysis by High Resolution Fourier Transform Mass Spectrometry (HRMS) of the Streptomyces sp. SBT343 extract proportion revealed its chemical richness and complexity. Preliminary physico-chemical characterization of the extract highlighted the heat-stable and non-proteinaceous nature of the active component(s). The combined data suggest that the Streptomyces sp. SBT343 extract selectively inhibits staphylococcal biofilm formation without interfering with bacterial cell viability. Due to absence of cell toxicity, the extract might represent a good starting material to develop a future remedy to block staphylococcal biofilm formation on contact lenses and thereby to prevent intractable contact lens-mediated ocular infections. KW - medicine KW - marine sponges KW - actinomycetes KW - Streptomyces KW - staphilococci KW - biofilms KW - contact lens Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171844 VL - 8 ER - TY - THES A1 - Montag [geb. Kukielka], Gracia Anna T1 - Rolle des Differenzierungszustandes für die Empfindlichkeit von Säugerzellen gegenüber genotoxischen Agenzien T1 - Role of the differentiation status for the sensitivity of mammalian cells to genotoxic agents N2 - In der vorliegenden Arbeit wurden die Einflüsse verschiedener genotoxischer Substanzen auf Säugertierzellen untersucht. Da ein Organismus der Ontogenese unterliegt und sich Zellen aus Stamm- und Vorläuferzellen entwickelt, gilt es diese ursprünglichen Zellen vor äußeren Einflüssen zu schützen. Da bisher kaum Untersuchungen von Zellen in verschiedenen Differenzierungsstadien durchgeführt wurden, wurden unter Verwendung vieler unterschiedlicher biologischer Endpunkte Effekte auf die Vitalität, Proliferation, Mitose und Apoptose dieser Zellen untersucht. Zudem erfolgte eine Interpretation der Ausbildung von Mikrokernen, Entstehung von DNS-Schäden und der zugrundeliegenden Reparaturmechanismen. So konnte mit Hilfe der Untersuchungen der hämatopoetischen Stammzellen und der TK6-Zellen postuliert werden, dass hämatopoetische Stammzellen weitestgehend weniger empfindlich gegenüber Zytostatika (Doxorubicin, Vinblastin, Methylmethansulfonat und Mitomycin C) sind als die lymphoblastoide Zelllinie TK6, welche in der Entwicklungshierarchie den Stammzellen folgt. Die Befürchtung, dass der Mikrokerntest in immortalisierten TK6-Zellen als Grundlage für Genotoxizitätsuntersuchungen nicht genügen würden, konnte mit Hilfe der Versuchsergebnisse dieser Arbeit widerlegt werden. Die Ergebnisse belegen, dass der Mikrokerntest in TK6-Zellen relevant ist, da TK6-Zellen empfindlicher auf genotoxische Agentien im Vergleich zu hämatopoetischen Stammzellen reagieren. Bei der Untersuchung der Leukämiezelllinie HL-60 wurden die Effekte klassischer (Vinblastin, Vincristin, Vinflunin und Vinorelbin) mit neu synthetisierten Vinca-Alkaloiden (4-Chlorochablastin, 4-Chlorochacristin, 16a, 17b und 18a) verglichen. Vinca-Alkaloide werden sehr häufig mit Nebenwirkungen, wie Neuropathien assoziiert, welche während einer Chemotherapie oftmals zu Therapieabbrüchen durch die Patienten führen. Aus diesem Grund war es erstrebenswert, neuartige Vinca-Alkaloide zu entwickeln, welche weniger Nebenwirkungen aber zugleich eine ähnliche Wirksamkeit aufweisen. Obwohl die Potenz der neuen Substanzen niedriger war als bei Vinblastin, Vincristin und Vinorelbin, zeigte ein Teil eine ähnliche Wirkung wie das Vinca-Alkaloid Vinflunin auf die Krebszelllinie HL-60 auf. Die Ergebnisse diese Arbeit können als erste Indikation in vitro genommen werden, dass sich diese Substanzen in der Krebstherapie als wirksam erweisen könnten und nach weiteren Ergebnissen in vivo als therapeutische Alternativen in Betracht gezogen werden. Auch bei der vergleichenden Untersuchung von exponentiell wachsenden mit differenzierten Zelllinien konnten Unterschiede detektiert werden. Die Zelllinie HT-22, welche selbst keine Krebszelllinie ist, zeigte nach Differenzierung zu nicht exponentiell wachsenden Zellen eine erhöhte Empfindlichkeit gegenüber dem Alkylanz Methylmethansulfonat, was auf einer verminderten Basenexzisionsreparatur beruhen könnte. Auch die differenzierte Form der Adenokarzinom-Zelllinie CaCo2 zeigte eine gesteigerte Sensitivität gegenüber dem Topoisomerase II-Inhibitor Etoposid auf, wohingegen der unselektive Topoisomerase II-Hemmer Doxorubicin keinen Effekt aufwies. Um den Sachverhalt zu klären ob die festgestellten Unterschiede auf das Enzym Topoisomerase II zurückzuführen oder zellartspezifisch waren, wurden weitere Analysen der Zelllinien HL-60 und deren differenzierten Zellart durchgeführt. Auch hier konnten signifikante Unterschiede bei der Einzelzellgelelektrophorese nach Behandlung mit Doxorubicin und Etoposid festgestellt werden. Neben den in dieser Arbeit nachgewiesenen Unterschieden bei der Reparatur zwischen den Zelltypen, könnten aber auch weitere Faktoren zu Varianzen führen und die Mutagenitätsforschung beeinflussen. Folglich ist davon auszugehen, dass zukünftige Testungen bei der pharmakologischen Substanzentwicklung in verschiedenen Zellsystemen von Nöten sind, bevor neue Substanzen zugelassen werden. Alles in allem konnte die Komplexität der Ergebnisse zwischen Zellen der verschiedenen Differenzierungsstadien in dieser Arbeit aufgezeigt werden. Deswegen sollte auch bei weiteren Forschungsvorhaben insbesondere ein Augenmerk auf den Differenzierungszustand der zu untersuchenden Zellpopulation geworfen werden. N2 - In the present study, the influences of different genotoxic substances on mammalian cells were investigated. Given that organisms develop on the basis of ontogenesis and cells develop from stem cells and progenitor cells, it is important to protect these original cells from external influences. Due to the fact so far only few studies have been carried out on cells in different differentiation stages, many different biological endpoints, like effects on vitality, proliferation, mitosis and apoptosis of these cells have been investigated. In addition, the formation of micronuclei, the development of DNA damage and the underlying repair mechanisms were interpreted. The investigations of hematopoietic stem cells and TK6 cells have shown that hematopoietic stem cells are predominantly less sensitive to cytostatic drugs (doxorubicin, vinblastine, methyl methanesulfonate and mitomycin C) than the lymphoblastoid cell line TK6, which follows the stem cells in the development hierarchy. The fear that the micronucleus test in immortalized TK6 cells would not be sufficient as a basis for genotoxicity studies could be refuted with the results of this work. The results show that the micronucleus test in TK6 cells is relevant because TK6 cells are more sensitive to genotoxic agents than hematopoietic stem cells. During the investigation of the leukemia cell line HL-60, the effects of classic vinca alkaloids (vinblastine, vincristine, vinflunine and vinorelbine) were compared with novel synthesized vinca alkaloids (4-chlorochablastine, 4-chlorochacristine, 16a, 17b and 18a). Vinca alkaloids are very often associated with side effects, such as neuropathies, which often lead to discontinuation of therapy by patients during chemotherapy. For this reason, it was desirable to develop novel vinca alkaloids with fewer side effects but similar efficacy. Although the potency on the cancer cell line HL-60 of the new substances was lower than in vinblastine, vincristine and vinorelbine, some showed a similar effect to the vinca alkaloid vinflunine. The results of this work can be taken as a first indication in vitro that these substances may prove effective in cancer therapy and will be considered as therapeutic alternatives in vivo according to further results. Differences were also detected in comparative investigations of exponentially growing with differentiated cell lines. The cell line HT-22, which itself is not a cancer cell line, showed an increased sensitivity to the alkylating agent methyl methanesulfonate after differentiation to non-exponentially growing cells, which could be due to reduced base excision repair. The differentiated form of the adenocarcinoma cell line CaCo2 also showed an increased sensitivity to the topoisomerase II inhibitor etoposide, whereas the non-selective topoisomerase II inhibitor doxorubicin had no effect. In order to clarify whether the found differences due to the enzyme topoisomerase II or were cell-type-specific, further analyses were carried out with the cell line HL-60 and their differentiated cell type. Again, significant differences in single cell gel electrophoresis after treatment with doxorubicin and etoposide were detected. In addition to the differences in repair between cell types shown in this study, other factors could also lead to variances and influence mutagenicity research. Therefore, it is reasonable to assume that future testings in different cell systems are necessary for the development of pharmacologically active substances before new substances will be approved. Altogether, the complexity of the results between cells in the different differentiation stages becomes apparent in this work, which also means that further research projects would pay particular attention to the differentiation stage of the investigated cell population. KW - Säugetiere KW - Blutstammzelle KW - Mutagenität KW - Zelldifferenzierung KW - Differenzierungszustand KW - Säugerzellen KW - genotoxische Agenzien KW - Mikrokerne KW - Einzelzellgelelektrophorese KW - differentiation status KW - mammalian cells KW - genotoxic agents KW - micronuclei KW - comet assay KW - Genotoxizität KW - Hämatopoetische Stammzellen KW - Empfindlichkeit Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164670 ER - TY - JOUR A1 - Werner, Rudolf A1 - Wakabayashi, Hiroshi A1 - Bauer, Jochen A1 - Schütz, Claudia A1 - Zechmeister, Christina A1 - Hayakawa, Nobuyuki A1 - Javadi, Mehrbod S. A1 - Lapa, Constantin A1 - Jahns, Roland A1 - Ergün, Süleyman A1 - Jahns, Valerie A1 - Higuchi, Takahiro T1 - Longitudinal \(^{18}\)F-FDG PET imaging in a Rat Model of Autoimmune Myocarditis JF - European Heart Journal Cardiovascular Imaging N2 - Aims: Although mortality rate is very high, diagnosis of acute myocarditis remains challenging with conventional tests. We aimed to elucidate the potential role of longitudinal 2-Deoxy-2-\(^{18}\)F-fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography (PET) inflammation monitoring in a rat model of experimental autoimmune myocarditis. Methods and results: Autoimmune myocarditis was induced in Lewis rats by immunizing with porcine cardiac myosin emulsified in complete Freund’s adjuvant. Time course of disease was assessed by longitudinal \(^{18}\)F-FDG PET imaging. A correlative analysis between in- and ex vivo \(^{18}\)F-FDG signalling and macrophage infiltration using CD68 staining was conducted. Finally, immunohistochemistry analysis of the cell-adhesion markers CD34 and CD44 was performed at different disease stages determined by longitudinal \(^{18}\)F-FDG PET imaging. After immunization, myocarditis rats revealed a temporal increase in 18F-FDG uptake (peaked at week 3), which was followed by a rapid decline thereafter. Localization of CD68 positive cells was well correlated with in vivo \(^{18}\)F-FDG PET signalling (R\(^2\) = 0.92) as well as with ex vivo 18F-FDG autoradiography (R\(^2\) = 0.9, P < 0.001, respectively). CD44 positivity was primarily observed at tissue samples obtained at acute phase (i.e. at peak 18F-FDG uptake), while CD34-positive staining areas were predominantly identified in samples harvested at both sub-acute and chronic phases (i.e. at \(^{18}\)F-FDG decrease). Conclusion: \(^{18}\)F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis. KW - positron emission tomography KW - Myokarditis KW - myocarditis KW - inflammation KW - 18F-FDG KW - PET KW - personalized treatment Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165601 SN - 2047-2404 ER - TY - JOUR A1 - Schihada, Hannes A1 - Vandenabeele, Sylvie A1 - Zabel, Ulrike A1 - Frank, Monika A1 - Lohse, Martin J. A1 - Maiellaro, Isabella T1 - A universal bioluminescence resonance energy transfer sensor design enables high-sensitivity screening of GPCR activation dynamics JF - Communications Biology N2 - G-protein-coupled receptors (GPCRs) represent one of the most important classes of drug targets. The discovery of new GCPR therapeutics would greatly benefit from the development of a generalizable high-throughput assay to directly monitor their activation or de-activation. Here we screened a variety of labels inserted into the third intracellular loop and the C-terminus of the alpha(2 Lambda)-adrenergic receptor and used fluorescence (FRET) and bioluminescence resonance energy transfer (BRET) to monitor ligand-binding and activation dynamics. We then developed a universal intramolecular BRET receptor sensor design to quantify efficacy and potency of GPCR ligands in intact cells and real time. We demonstrate the transferability of the sensor design by cloning beta(2)-adrenergic and PTH1-receptor BRET sensors and monitored their efficacy and potency. For all biosensors, the Z factors were well above 0.5 showing the suitability of such design for microtiter plate assays. This technology will aid the identification of novel types of GPCR ligands. KW - Fluorescence resonance energy transfer KW - G protein-coupled receptors KW - High-throughput screening Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228592 VL - 1 IS - 105 ER - TY - THES A1 - Cirkel, Nanett Christin T1 - Beeinflussung des oxidativen Stress-Status in einem Rattenmodell: Effekt von Selenmangel auf Niere und Leber T1 - Influenceability of Oxidative Stress for a Rat Model: Effect of Selenium Deficiency on Kidney and Liver N2 - Das Spurenelement Selen und Vitamin E reduzieren reaktive Sauerstoff Spezies (ROS). Bei Mangel dieser wichtigen Stoffe erhöht sich die Konzentration an ROS und der oxidative Stress steigt. Unter erhöhten ROS entstehen vermehrt DNA-Schäden und Lipidperoxidationen. Das ROS Wasserstoffperoxid wird zu Wasser über das Enzym Gluthationperxoidase reduziert. Dessen Aktivität steigert Selen um den Faktor 100-1.000. Das Aktivitätsmaximum des Enzyms liegt bei einer täglichen Selenaufnahme von 60-80 Mikrogramm/Tag. Dadurch wird die Menge an ROS reduziert und der oxidative Stress in der Zelle nimmt ab. Vitamin E fungiert als Radikalfänger. Sein Derivat alpha- Tocopherol besitzt die höchste antioxidative Wirkung und kann Lipidperoxidationen unterbrechen. Die vorliegende Arbeit untersucht Auswirkungen von oxidativem Stress, den ein Mangel von Selen und Vitamin E in der Nahrung bei 6 Monate und 12 Monate alten Tieren auf Leber und Niere verursacht. Der Nachweis von oxidativem Stress erfolgte über sogenannte Hitzeschockproteine HSP70 und Hämoxygenase 1. HSP 70 wird auch unter physiologischen Bedingungen exprimiert. Es wirkt als Chaperon und ist u.a. für die korrekte Faltung und Stabilisierung von Proteinen zuständig. Die Versuche zeigten, dass im Alter in der Niere die HSP70 Konzentration ansteigt und die Zelle unter vermehrtem oxidativen Stress leidet. Entsprechende Literaturergebnisse wurden bestätigt. Die Hämoxygenase 1 (HO-1) ist ein Schlüsselenzym, das vermehrt bei oxidativem Stress gebildet wird. Hoch reaktionsfreudige und freie Blutbestandteile katalysiert die Hämoxygenase. Einen Abfall der HO- 1 Konzentration zeigten Untersuchungen von Leber und Niere bei Selen, - Vitamin E Mangel und höherem Lebensalter. Gründe für die verminderte Expression sind noch wenig erforscht. Die vermehrte Anreicherung von Superoxidanionradikalen wurde in den Geweben von Leber und Niere über Dihydroethidium (DHE) Färbung nachgewiesen. Die Hypothese wurde bestätigt, dass bei Selen, -Vitamin E Mangelnahrung und höherem Alter vermehrter oxidativer Stress entsteht. Selenmangel begünstigt die Entstehung verschiedener Krankheiten, z.B. Krebs, koronale Herzerkrankung und vor allem die Keshan-Krankheit, die den Herzmuskel befällt. Selen nimmt positiven Einfluss auf Körperfunktionen: Fertilität, embryonalen Entwicklung und Entwicklung eines Neugeborenen. Einige Fragen bleiben ungeklärt: Welche physiologischen Entwicklungsprozesse fördert Selen? Nimmt Selen eine wichtige Funktion bei der Befruchtung der Eizelle ein? Wie beeinflusst Selen die Entwicklung des Gehirns? Dem Spurenelement Selen kommen offensichtlich neben seiner Bedeutung zur Minderung des oxidativen Stresses noch weitere wichtige Funktionen zu, die bisher wenig untersucht wurden. N2 - The trace element Selenium and vitamin E reduce reactive oxygen species (ROS). Under increased ROS concentration occur augmented DNA damage and lipid peroxidation. Selenium and vitamin E deficiency in nutrition of rats of 6 and 12 months causes oxidative stress in kidney and liver. Oxidative stress has been proved by heat shock protein HSP70 and Heme Oxygenase-1 (HO-1). By higher age HSP70 concentration in kidney rises and the cells suffer from increased oxidative stress. Selenium and vitamin E deficiency as well as higher age cause a decrease in concentration of HO-1 in liver and kidney, which is increasingly synthesized by oxidative stress. KW - Oxidativer Stress KW - Selenmangel KW - Vitamin E Mangel Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-163631 ER -