Die Wirkung von Lithium auf FGF23

Lithium ist eines der ältesten Medikamente die in der Neuropsychopharmakologie eingesetzt werden (183) und stellt noch immer eine Therapie erster Wahl als Behandlungsoption bei bipolaren affektiven Störungen dar. Lithium entfaltet seine Wirkung zumindest teilweise durch die Hemmung der Glykogensynthase-Kinase 3 (GSK-3), welche den Aquaporinkanal 2 via Adenylylcyclase oder Prostaglandin E2 reguliert (32, 184). Die Lithium- Behandlung ist zudem eine der häufigsten Ursachen für den arzneimittelinduzierten Nephrogenen Diabetes Insipidus (NDI), welcher zu renalem Wasserverlust führt. Bereits gezeigt wurde, dass Dehydratation mit einer Hemmung des Klotho-Proteins einhergeht, das als obligater Kofaktor für den Fibroblasten-Wachstumsfaktor (FGF23) dient (144, 145). FGF23 unterdrückt effektiv den Alterungsprozess. Ein Mangel an FGF23 führt zu einer Erhöhung der Serumphosphat-, Kalzium- und 1,25(OH)2D3- Konzentrationen, gefolgt von vaskulärer Kalzifikation, Abnahme der Knochendichte und Erniedrigung der Lebenserwartung (118, 158, 185, 186). Seit kurzem gibt es vermehrt Hinweise darauf, dass die Behandlung mit niedrig dosiertem Lithium einen Anti-Aging Effekt ausübt und eine positive Auswirkung auf die Lebenserwartung beim Menschen zeigt (12, 178, 180). Diese Studie beschäftigt sich mit der Frage, ob eine Lithium-Behandlung die renale Expression und den Serumspiegel von Klotho, die FGF23- Serumkonzentration, die 1,25(OH)2D3-Bildung, sowie die renale Ausscheidung und die Serumkonzentration von Phosphat- und Kalzium beeinflusst. Zu diesem Zweck wurden 10 Wochen alte C57BL/6 Mäuse (Weibchen) nach einer 14- tägigen Behandlungsperiode mit NaCl oder Lithium (LiCl) (200 mg/kg/d subkutan) untersucht. Darüber hinaus wurden 95 akut depressive Patienten rekrutiert, die eine Lithiumkarbonat-Behandlung als zusätzliche Therapie über einen Zeitraum von vier Wochen erhielten. Alle Patienten erreichten ein Serumlevel von mehr als 0.4mmol/l. Von diesen Patienten wurden Blutproben vor und nach der vierwöchigen Behandlung entnommen. Im Mausexperiment wurden zudem die Serumkonzentrationen von ADH, FGF23 sowie 1,25(OH)2D3 mittels ELISA bestimmt. Mit Hilfe der Western Blot- Technik wurde die renale Klotho-Proteinmenge und die GSK-3 Phosphorylierung analysiert. Die Urin- und Serumkonzentrationen von Phosphat und Kalzium wurden photometrisch bestimmt. Im Humanexperiment wurden die Serumkonzentrationen von FGF23, dem zirkulierenden α-Klotho, von 1,25(OH)2D3 sowie die Phosphat- und Kalziumkonzentrationen der Patienten vor der Lithiumbehandlung und vier Wochen nach der Lithiumbehandlung gemessen. Sowohl die Resultate der Maus- als auch der Humanexperimente zeigen, dass eine Behandlung mit Lithium mit einer erheblichen Erhöhung des FGF23- Serumlevels und einer signifikanten Erniedrigung des 1,25(OH)2D3 sowie der Phosphatkonzentration einhergeht. Im Mausversuch zeigte sich zusätzlich zu diesen Effekten noch eine statistisch signifikante Erniedrigung der renalen Klotho-Expression und eine Erhöhung der renalen Phosphatausscheidung. Die Lithiumbehandlung bewirkte auch eine tendenziell niedrigere Serumkalziumkonzentration bei den Mäusen. Zusammenfassend präsentiert diese Studie schlüssige Beweise, dass Lithium die FGF23-Bildung hochreguliert, ein Effekt, welcher mit einer Erniedrigung der Serum 1,25(OH)2D3- und Phosphatkonzentrationen einhergeht. Diese Effekte könnten möglicherweise der Bildung von vaskulären Kalzifikationen und dem Auftreten von altersbedingten Krankheiten entgegenwirken. Unsere Beobachtungen könnten teilweise den Mechanismus erklären, durch welchen Lithium die Überlebensrate begünstigt und eine höhere Lebensdauer beim Menschen fördert

A social work study on different factors influencing youth on hope for the future

In this paper, we present an empirical study to study the effects of religious duties, communicating with parents; leisure, media planning, city planning, socio-economic and education on different factors influencing the future of youth. The proposed study of this paper designs a questionnaire and distributes it among 400 people aged 18 to 29 and the results are investigated using Pearson correlation ratios. The results of our investigation indicate that there are some positive and meaningful relationship between religious duties and their hope for future (r=44%), a positive and meaningful relationship between leisure and hope for future (31%). In addition, there is a relatively positive and somewhat meaningful relationship between city planning and hope for future (15%) and finally, a small but positive relationship between media planning and hope for the future (6%). However, there is no evidence belief that there is any meaningful relationship between education and hope for the future

Pengaruh Intensitas Cahaya dan Kemiringan Panel Terhadap Koefisien Laju Konveksi pada Pemanas Air Tenaga Surya

Indonesia sebagai salah satu negara dengan posisi geografis berada di garis khatulistiwa, membuat indonesia mendapatkan sinar matahari sepanjang tahun. Konsumsi energi di Indonesia yang meningkat dan penggunaan sumber energinya yang dapat diperbaharui belum dimanfaatkan secara optimal, maka dari itu sinar matahari sebagai energi yang terbarukan dan ramah lingkungan digunakan sebagai media pemanas air bertenaga surya. Alat pemanas air tenaga surya merupakan alat untuk memanaskan air dengan memanfaatkan sumber energi matahari melalui panel kolektor. Dengan tingginya intensitas radiasi yang diperoleh yaitu sebesar 93000 Lux alat kolektor mampu menyerap panas dengan  lebih banyak sehingga menghasilkan temperatur yang paling tinggi yaitu 64°C. Intensitas Cahaya yang tinggi akan memberikan panas yang lebih maksimal pada proses pemanasan air dalam pipa kolektor dengan optimal. Pada sudut 25° dengan naiknya kemiringan dapat membuat perpindahan panas pada air lebih baik sehingga mampu menghasilkan temperatur air output tertinggi sebesar 64°C karena pada sudut 25° performa alat akan naik sehingga air yang lebih panas pada kolektor lebih mudah untuk mencapai tangki karena massa jenis air yang berada dibagian permukaan lebih mudah untuk bergerak naik

Blunted apoptosis of erythrocytes in mice deficient in the heterotrimeric G-protein subunit Gαi2

Putative functions of the heterotrimeric G-protein subunit Gαi2-dependent signaling include ion channel regulation, cell differentiation, proliferation and apoptosis. Erythrocytes may, similar to apoptosis of nucleated cells, undergo eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure. Eryptosis may be triggered by increased cytosolic Ca2+ activity and ceramide. In the present study, we show that Gαi2 is expressed in both murine and human erythrocytes and further examined the survival of erythrocytes drawn from Gαi2-deficient mice (Gαi2−/−) and corresponding wild-type mice (Gαi2+/+). Our data show that plasma erythropoietin levels, erythrocyte maturation markers, erythrocyte counts, hematocrit and hemoglobin concentration were similar in Gαi2−/− and Gαi2+/+ mice but the mean corpuscular volume was significantly larger in Gαi2−/− mice. Spontaneous PS exposure of circulating Gαi2−/− erythrocytes was significantly lower than that of circulating Gαi2+/+ erythrocytes. PS exposure was significantly lower in Gαi2−/− than in Gαi2+/+ erythrocytes following ex vivo exposure to hyperosmotic shock, bacterial sphingomyelinase or C6 ceramide. Erythrocyte Gαi2 deficiency further attenuated hyperosmotic shock-induced increase of cytosolic Ca2+ activity and cell shrinkage. Moreover, Gαi2−/− erythrocytes were more resistant to osmosensitive hemolysis as compared to Gαi2+/+ erythrocytes. In conclusion, Gαi2 deficiency in erythrocytes confers partial protection against suicidal cell death

Blunted apoptosis of erythrocytes in mice deficient in the heterotrimeric G-protein subunit Gαi2

Putative functions of the heterotrimeric G-protein subunit Gαi2-dependent signaling include ion channel regulation, cell differentiation, proliferation and apoptosis. Erythrocytes may, similar to apoptosis of nucleated cells, undergo eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure. Eryptosis may be triggered by increased cytosolic Ca2+ activity and ceramide. In the present study, we show that Gαi2 is expressed in both murine and human erythrocytes and further examined the survival of erythrocytes drawn from Gαi2-deficient mice (Gαi2−/−) and corresponding wild-type mice (Gαi2+/+). Our data show that plasma erythropoietin levels, erythrocyte maturation markers, erythrocyte counts, hematocrit and hemoglobin concentration were similar in Gαi2−/− and Gαi2+/+ mice but the mean corpuscular volume was significantly larger in Gαi2−/− mice. Spontaneous PS exposure of circulating Gαi2−/− erythrocytes was significantly lower than that of circulating Gαi2+/+ erythrocytes. PS exposure was significantly lower in Gαi2−/− than in Gαi2+/+ erythrocytes following ex vivo exposure to hyperosmotic shock, bacterial sphingomyelinase or C6 ceramide. Erythrocyte Gαi2 deficiency further attenuated hyperosmotic shock-induced increase of cytosolic Ca2+ activity and cell shrinkage. Moreover, Gαi2−/− erythrocytes were more resistant to osmosensitive hemolysis as compared to Gαi2+/+ erythrocytes. In conclusion, Gαi2 deficiency in erythrocytes confers partial protection against suicidal cell death.Fil: Bissinger, Rosi. Eberhard Karls Universität Tübingen; AlemaniaFil: Lang, Elisabeth. Universitat Dusseldorf; AlemaniaFil: Ghashghaeinia, Mehrdad. Eberhard Karls Universität Tübingen; AlemaniaFil: Singh, Yogesh. Eberhard Karls Universität Tübingen; AlemaniaFil: Zelenak, Christine. Charité Medical University; AlemaniaFil: Fehrenbacher, Birgit. Eberhard Karls Universität Tübingen; AlemaniaFil: Honisch, Sabina. Eberhard Karls Universität Tübingen; AlemaniaFil: Chen, Hong. Eberhard Karls Universität Tübingen; AlemaniaFil: Fakhri, Hajar. Eberhard Karls Universität Tübingen; AlemaniaFil: Umbach, Anja T.. Eberhard Karls Universität Tübingen; AlemaniaFil: Liu, Guilai. Eberhard Karls Universität Tübingen; AlemaniaFil: Rexhepaj, Rexhep. Universitat Bonn; AlemaniaFil: Liu, Guoxing. Eberhard Karls Universität Tübingen; AlemaniaFil: Schaller, Martin. Eberhard Karls Universität Tübingen; AlemaniaFil: Mack, Andreas F.. Eberhard Karls Universität Tübingen; AlemaniaFil: Lupescu, Adrian. Eberhard Karls Universität Tübingen; AlemaniaFil: Birnbaumer, Lutz. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Lang, Florian. Eberhard Karls Universität Tübingen; AlemaniaFil: Qadri, Syed M.. Eberhard Karls Universität Tübingen; Alemania. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentin

Sgk1 Sensitive Pendrin Expression in Murine Platelets

Background: The anion exchanger pendrin (SLC26A4) is required for proper development of the inner ear, and contributes to iodide organification in thyroid glands as well as anion transport in various epithelia, such as airways and renal tubules. SLC26A4 deficiency leads to Pendred syndrome, which is characterized by hearing loss with enlarged vestibular aqueducts and variable hypothyroidism and goiter. Pendrin expression in kidney, heart, lung and thyroid is up-regulated by the mineralocorticoid deoxycorticosterone (DOCA). Platelets express anion exchangers but virtually nothing is known about the molecular identity and regulation of those carriers. Other carriers such as the Na+/H+ exchanger are regulated by the mineralocorticoid-sensitive serum and glucocorticoid inducible kinase SGK1. Methods: The present study utilized i) quantitative reverse transcription polymerase chain reaction (RT-qPCR) to quantify the transcript levels of Slc26a4 as compared to Gapdh and ii) western blotting to assess Slc26a4 protein abundance in murine platelets from gene-targeted mice lacking Sgk1 (sgk1-/-) and respective wild type animals (sgk1+/+) treated without or with a subcutaneous injection of 2.5 mg DOCA for 3 h, or in sgk1+/+ platelets with or without in vitro treatment for 1 h with 10 µg/ml DOCA. Results: Slc26a4 was expressed in platelets, and in vitro DOCA treatment increased Slc26a4 mRNA levels in platelets isolated from sgk1+/+ mice. Moreover, in vivo DOCA treatment significantly up-regulated Slc26a4 mRNA levels in platelets isolated from sgk1+/+ but not sgk1-/- mice. An increase in Sgk1 mRNA levels paralleled that of Slc26a4 mRNA levels in platelets of sgk1+/+ mice. In addition, DOCA treatment further increased Slc26a4 protein abundance in platelets isolated from sgk1+/+ mice. Conclusions: Pendrin is expressed in platelets and is presumably regulated by SGK1 and mineralocorticoids

Down-Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by Glycogen Synthase Kinase GSK3ß

Background: The Na+,Cl- coupled creatine transporter CreaT (SLC6A8) is expressed in a variety of tissues including the brain. Genetic defects of CreaT lead to mental retardation with seizures. The present study explored the regulation of CreaT by the ubiquitously expressed glycogen synthase kinase GSK3ß, which contributes to the regulation of neuroexcitation. GSK3ß is phosphorylated and thus inhibited by PKB/Akt. Moreover, GSK3ß is inhibited by the antidepressant lithium. The present study thus further tested for the effects of PKB/Akt and of lithium. Methods: CreaT was expressed in Xenopus laevis oocytes with or without wild-type GSK3ß or inactive K85RGSK3ß. CreaT and GSK3ß were further expressed without and with additional expression of wild type PKB/Akt. Creatine transport in those oocytes was quantified utilizing dual electrode voltage clamp. Results: Electrogenic creatine transport was observed in CreaT expressing oocytes but not in water-injected oocytes. In CreaT expressing oocytes, co-expression of GSK3ß but not of K85RGSK3ß, resulted in a significant decrease of creatine induced current. Kinetic analysis revealed that GSK3ß significantly decreased the maximal creatine transport rate. Exposure of CreaT and GSK3ß expressing oocytes for 24 hours to Lithium was followed by a significant increase of the creatine induced current. The effect of GSK3ß on CreaT was abolished by co-expression of PKB/Akt. Conclusion: GSK3ß down-regulates the creatine transporter CreaT, an effect reversed by treatment with the antidepressant Lithium and by co-expression of PKB/Akt

Impact of Annexin A 7 Deficiency on FGF23 Plasma Concentrations

Background/Aims: The release of fibroblast growth factor FGF23, a powerful regulator of 1,25(OH)2D3 formation and mineral metabolism, is stimulated by store-operated Ca2+ entry (SOCE), which is accomplished by the pore forming Ca2+ release activated channel protein Orai1. Regulators of Orai1 and thus FGF23 release include serum & glucocorticoid inducible kinase SGK1, a kinase up-regulated by glucocorticosteroids. Some effects of glucocorticoids require the presence of annexin A7, such as suppression of prostaglandin E2 in gastric glands. The present study thus explored whether annexin A7 impacts on FGF23 plasma levels. Methods: Comparisons were made between gene targeted mice lacking functional annexin A7 (Anx7-/-) and their wild type littermates (Anx7+/+). Serum C-terminal-FGF23, intact FGF23, 1,25(OH)2D3 and PTH concentrations were measured by ELISA or EIA. The serum and urinary phosphate concentrations were measured by colorimetry, the serum Ca2+ concentration and the urinary Ca2+ concentration by flame photometry. Results: Serum C-terminal FGF23 levels and corticosterone levels were significantly higher and serum 1,25(OH)2 D3 and PTH levels were significantly lower in Anx7-/- than in Anx7+/+ mice. Water intake was slightly but significantly higher in Anx7-/- mice than in Anx7+/+ mice. No significant difference was observed between Anx7-/- and Anx7+/+ mice in urinary fluid excretion, plasma Ca2+ concentration, plasma phosphate concentration and urinary Ca2+ output. The urinary phosphate output was significantly lower in Anx7-/- mice than in Anx7+/+ mice. Conclusion: Annexin A7 deficiency upregulates FGF23 plasma levels, an effect paralleled by increased corticosterone plasma levels, as well as decreased 1,25(OH)2 D3 and PTH plasma levels