Aminoglycoside-driven biosynthesis of selenium-deficient Selenoprotein P

Selenoprotein biosynthesis relies on the co-translational insertion of selenocysteine in response to UGA codons. Aminoglycoside antibiotics interfere with ribosomal function and may cause codon misreading. We hypothesized that biosynthesis of the selenium (Se) transporter selenoprotein P (SELENOP) is particularly sensitive to antibiotics due to its ten in frame UGA codons. As liver regulates Se metabolism, we tested the aminoglycosides G418 and gentamicin in hepatoma cell lines (HepG2, Hep3B and Hepa1-6) and in experimental mice. In vitro, SELENOP levels increased strongly in response to G418, whereas expression of the glutathione peroxidases GPX1 and GPX2 was marginally affected. Se content of G418-induced SELENOP was dependent on Se availability, and was completely suppressed by G418 under Se-poor conditions. Selenocysteine residues were replaced mainly by cysteine, tryptophan and arginine in a codon-specific manner. Interestingly, in young healthy mice, antibiotic treatment failed to affect Selenop biosynthesis to a detectable degree. These findings suggest that the interfering activity of aminoglycosides on selenoprotein biosynthesis can be severe, but depend on the Se status, and other parameters likely including age and general health. Focused analyses with aminoglycoside-treated patients are needed next to evaluate a possible interference of selenoprotein biosynthesis by the antibiotics and elucidate potential side effects

Selenium supplementation has beneficial and detrimental effects on immunity to influenza vaccine in older adults

Background & aims: Mortality resulting from influenza (flu) virus infections occurs primarily in the elderly through declining immunity. Studies in mice have suggested beneficial effects of selenium (Se) supplementation on immunity to flu but similar evidence is lacking in humans. A dietary intervention study was therefore designed to test the effects of Se-supplementation on a variety of parameters of anti-flu immunity in healthy subjects aged 50–64 years. Methods: A 12-week randomized, double-blinded, placebo-controlled clinical trial (ClinicalTrials.gov NCT00279812) was undertaken in six groups of individuals with plasma Se levels <110 ng/mL. Four groups were given daily capsules of yeast enriched with 0 μg Se/day (SeY-0/d; n = 20), 50 μg Se/d (SeY-50/d; n = 18), 100 μg Se/d (SeY-100/d; n = 21) or 200 μg Se/d (SeY-200/d; n = 23). Two groups were given onion-containing meals with either <1 μg Se/d (SeO-0/d; n = 17) or 50 μg Se/d (SeO-50/d; n = 18). Flu vaccine was administrated at week 10 and immune parameters were assessed until week 12. Results: Primary study endpoints were changes in cellular and humoral immune responses. Supplementation with SeY and SeO affected different aspects of cellular immunity. SeY increased Tctx-ADCC cell counts in blood (214%, SeY-100/d) before flu vaccination and a dose-dependent increase in T cell proliferation (500%, SeY-50/100/200/d), IL-8 (169%, SeY-100/d) and IL-10 (317%, SeY-200/d) secretion after in vivo flu challenge. Positive effects were contrasted by lower granzyme B content of CD8 cells (55%, SeY-200/d). SeO (Se 50 μg/d) also enhanced T cell proliferation after vaccination (650%), IFN-γ (289%), and IL-8 secretion (139%), granzyme (209%) and perforin (190%) content of CD8 cells but inhibited TNF-α synthesis (42%). Onion on its own reduced the number of NKT cells in blood (38%). These effects were determined by comparison to group-specific baseline yeast or onion control groups. Mucosal flu-specific antibody responses were unaffected by Se-supplementation. Conclusion: Se-supplementation in healthy human adults with marginal Se status resulted in both beneficial and detrimental effects on cellular immunity to flu that was affected by the form of Se, supplemental dose and delivery matrix. These observations call for a thorough evaluation of the risks and benefits associated with Se-supplementation

Regulation of selenoproteins after synthetic selenocompound exposure and during the acute phase inflammatory response

Selen ist ein essentielles Spurenelement, das über den Einbau als 21-ste proteinogene Aminosäure Selenocystein einer kleinen Gruppe von Selenoproteinen den Namen gibt und als Bestandteil des aktiven Zentrums dieser Proteine die enzymatische Katalyse bestimmter Reaktionen ermöglicht. In der Evolution haben sich eine komplexe Synthesemaschinerie zur Biosynthese von Selenoproteinen und besondere Regulationsmechanismen zur Kontrolle der Expressionsraten entwickelt. Selenoproteine sind von besonderer Bedeutung für den Energiestoffwechsel, die Schilddrüse und das Immunsystem. In der Klinik wird Selen als Supplement zur Unterstützung des Immunsystems und zum Ausgleich des Selenverlustes bei Sepsis eingesetzt. Allerdings sind die molekularen Mechanismen des Selenverlustes in Sepsis nicht verstanden, und es herrscht Uneinigkeit über die Wirkung verschiedener Formen selenhaltiger Supplemente. Diese beiden Punkte stehen im Zentrum meiner Arbeit. In einem murinen Sepsis- Modell wurde durch Endotoxin eine Akutphasenreaktion hervorgerufen. Es zeigte sich eine streng hierarchische Verteilung des verfügbaren Selens auf die Biosynthese der unterschiedlichen Selenoproteine, die darüber hinaus auch geschlechterspezifisch war. Der Selentransporter SePP erwies sich als stabiler Selenbiomarker und als Negativ-Akutphase-Protein, während das ER-residente Selenoprotein SepS als Positiv-Akutphase-Protein eingeordnet werden konnte. Auf molekularer Ebene konnten mit der Regulation geschwindigkeitsbestimmender Proteine des Selenmetabolismus und der Charakterisierung von Hypoxie als starker Modulator der Biosynthese wichtige Mechanismen identifiziert werden, die zu einer Verschiebung der Selenoprotein-Expression in schweren Erkrankungen beitragen. Diese Studien zur Grundlage des Selenstoffwechsels wurden durch Versuche zur Intervention mit neuen selenhaltigen Präparaten ergänzt. Hier konnte mit der Gruppe der Imidoselenocarbamate eine Substanzklasse charakterisiert werden, die therapeutisch vielversprechende Effekte spezifisch in Tumorzellen induzierte und als besonders aktive Induktoren der selenabhängigen Dejodasen wirkt, ohne dabei toxisch zu sein. Zusammenfassend wurden in dieser Arbeit somit neue klinisch relevante Regulationsmechanismen der Expression von Selenoproteinen charakterisiert und mit den Imidoselenocarbamaten eine vielversprechende Substanzklasse für eine zukünftige pharmakologische Intervention identifiziert.The view on selenium (Se) changed from a toxic substance to an essential trace element with the discovery of the 21st aminoacid selenocysteine (Sec). Se exerts its biological function as part of Sec-containing selenoproteins. Sec synthesis is mediated by a complex molecular machinery and depends on an optimal selenium status. Se is essential for cellular functions and energy metabolism, thyroid gland and immune system. Se research gained interest by being linked to several diseases through animal and clinical studies. Se is a supplement in the clinics to support the immune system and replenish loss of Se in critical illness. Still, the function of several selenoproteins and the underlying physiological mechanisms controlling Se metabolism are not completely understood or have not even been explored. The present work includes experimental studies on the role and regulation of Se and selenoproteins in inflammatory diseases. To this end, an endotoxin (LPS)-challenged mouse model with different Se status was analysed, and Se- containing carbamates were characterized in tumor and non-transformed cells. Using LPS-injected mice as sepsis model, our work highlighted a hierarchical distribution of the available Se for the biosyntheses of the selenoproteome. In addition, these regulatory principles acted in a sex-specific way. The secreted SePP proved as stabile Se biomarker in blood. In inflammation, SePP qualified as a hepatic negative acute phase protein whereas SepS was regulated as a positive acute phase protein. SepS is located in the ER membrane and is part of the protein quality control and therefore reduces cellular ER stress. The second part of my work based on the interesting phenomenon that humans in Se deficient areas are diagnosed more often with cancer than others. In fact, several studies indicate an anticarcinogenic effect of Se. The relevant selenoproteins and physiological mechanisms are unknown. Comparative studies with the chemical class of imidoselenocarbamates using tumor-derived and non- transformed cells showed different effects on translation of different selenoproteins. The specific modulation of the selenoproteome expressed reflects substance- and cell-specific effects of selenocarbamates on specific selenoproteins, but not a general activation of the selenoprotein biosynthesis machinery. Especially methyl-carrying selenocarbamates proved to be efficient modulators. Moreover, this substance class proved to be effective modulators of deiodinase activities without showing toxic effects. A further characterization of the interaction of selenocompounds with specific selenoproteins and their role in inflammation, cancer and the immune system is needed to provide a better insight into underlying mechanisms needed to optimize Se supplementation

Poziom wiedzy studentów PWSZ Nysa na temat podstawowych zabiegów resuscytacyjnych w dobie COVID-19

Celem naszej pracy była ocena poziomu wiedzy studentów Państwowej Wyższej Szkoły Zawodowej w Nysie na temat podstawowych zabiegów resuscytacyjnych w dobie pandemii COVID-19. Anonimowe badanie ankietowe przeprowadzono wśród osób studiujących na takich kierunkach jak: ratownictwo medyczne i pielęgniarstwo, ale również: dietetyka, architektura, psychofizyczne kształtowanie człowieka, zarządzanie i inżynieria produkcji. Narzędziem badawczym był kwestionariusz przesłany drogą elektroniczną. Jako koło naukowe zrzeszające studentów ratownictwa medycznego poczuwamy się do obowiązku monitorowania poziomu wiedzy na wspomniany temat

Hypoxia reduces and redirects selenoprotein biosynthesis

Selenium deficiency constitutes a risk factor for the incidence and negative course of severe diseases including sepsis, stroke, autoimmune diseases or cancer. In this study, hypoxia is identified as a powerful stimulus to redirect selenoprotein biosynthesis causing reduced selenoprotein P expression and diminished selenium export from hepatocytes in favour of increased biosynthesis of the essential protective intracellular phospholipid hydroperoxide glutathione peroxidase GPX4. Specifically, hypoxia decreases transcript concentrations of central factors controlling selenium and selenocysteine metabolism including selenophosphate synthetase-2, phosphoseryl-tRNASerSec kinase and selenocysteine lyase, which are all proven to be rate-limiting enzymes in selenoprotein biosynthesis. These effects are paralleled by a general decline of selenoprotein expression; however, not all selenoproteins are affected to the same extent by hypoxia, and GPX4 constitutes an exception as its expression becomes slightly increased. Supplemental selenium is able to overcome the hypoxia-dependent down regulation of selenoprotein expression in our cell culture model system, supporting the concept of using selenium as an adjuvant treatment option in severe diseases. Although it remains to be tested whether these effects constitute a hepatocyte-specific response, the selenium-dependent decline of selenoprotein P biosynthesis under hypoxic conditions may explain the progressive selenium deficit developing in severe diseases.Peer Reviewe

GIS-gestuetzte Ermittlung von Abflusskonzentrationsparametern fuer ein konzeptionelles Hochwassermodell

A module for the concentration of runoff as part of a conceptual rainfall-runoff model is performed and its parameters are estimated by use of the hydrograph analysis and a certain geographical information system (GIS). The rainfall-runoff model has been developed for flood events and it reproduces the components of direct runoff, viz. surface runoff and interflow. The physically based parameters of the linear translation-diffusion model and the parameters of the single linear reservoir and their determination by a new technique of analysis form the objective of this study. Particularly, the simulation of runoff during the process of overland flow and channel flow in small watersheds. The spatial distribution of basin parameters, as slope, direction of slope, flood components and vegetation, were determined by application of digital topographical and morphometric maps, which are generated by GIS ARC/INOF. An example is given for the determination of flood components using several rainfall events in different watersheds. (orig.)SIGLEAvailable from TIB Hannover: RA 1164(126) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman