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Berlin Brandenburg

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  • Lang, Florian  (28)
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  • 1
    Language: English
    In: American Journal of Physiology (Consolidated), 2010, Vol.299(4), p.C791(14)
    Description: The balance between GSH-levels and oxidative stress is critical for cell survival. The GSH-levels of erythrocytes are dramatically decreased during infection with Plasmodium spp. We therefore investigated the consequences of targeting GSH for erythrocyte and Plasmodium survival in vitro and in vivo using dimethylfumarate (DMF) at therapeutically established dosage. We first show that noninfected red blood cells (RBC) exposed to DMF undergo changes typical of apoptosis or eryptosis, such as cell shrinkage and cell membrane scrambling with subsequent phosphatidylserine (PS) exposure. DMF did not induce appreciable hemolysis. DMF-triggered PS exposure was mediated by intracellular GSH depletion and reversed by the antioxidative N-acetyl-L-cysteine. DMF treatment controlled intraerythrocyte DNA amplification and in vitro parasitemia of Plasmodium falciparum-infected RBC. In vivo, DMF treatment had no effect on RBC count or GSH levels in noninfected mice. Consistent with its effects on infected RBC, DMF treatment abrogated parasitemia and enhanced the survival of mice infected with Plasmodium berghei from 0% to 60%. In conclusion, DMF sensitizes the erythrocytes to the effect of Plasmodium infection on PS exposure, thus accelerating the clearance of infected erythrocytes. Accordingly, DMF treatment favorably influences the clinical course of malaria. As DMF targets mechanisms within the host cell, it is not likely to generate resistance of the pathogen. infection; erythrocytes; Plasmodium; phosphatidylserine doi: 10.1152/ajpcell.00014.2010.
    Keywords: Glutathione – Health Aspects ; Methyl Compounds – Health Aspects ; Malaria – Risk Factors ; Malaria – Prevention ; Red Blood Cells – Physiological Aspects
    ISSN: 0002-9513
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  • 2
    In: European Journal of Immunology, April 2012, Vol.42(4), pp.831-841
    Description: T‐cell activation and the subsequent transformation of activated cells into ‐cell blasts require profound changes in cell volume. However, the impact of cell volume regulation for ‐cell immunology has not been characterized. Here we studied the role of the cell‐volume regulating osmolyte transporter aut for ‐cell activation in aut‐deficient mice. T‐cell mediated recall responses were severely impaired in mice as shown with 16 melanoma rejection and hapten‐induced contact hypersensitivity. CD4 and CD8 cells were unequivocally located within peripheral lymph nodes of unprimed mice but significantly decreased in compared with mice following in vivo activation. Further analysis revealed that aut is critical for rescuing cells from activation‐induced cell death in vitro and in vivo as shown with , superantigen, and antigen‐specific activation. Consequently, reduction of CD4 and CD8 cells in mice upon antigen challenge resulted in impaired in vivo generation of ‐cell memory. These findings disclose for the first time that volume regulation in cells is an element in the regulation of adaptive immune responses and that the osmolyte transporter aut is crucial for ‐cell survival and ‐cell mediated immune reactions.
    Keywords: Activation‐Induced Cell Death ; Cell Volume Regulation ; Taurine Transporter ; T‐Cell Response
    ISSN: 0014-2980
    E-ISSN: 1521-4141
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  • 3
    Language: English
    In: Cell, 1997, Vol.91(5), pp.605-615
    Description: Invasion of human mucosal cells by N. gonorrhoeae via the binding to heparansulfate proteoglycan receptors is considered a crucial event of the infection. Using different human epithelial cells and primary fibroblasts, we show here an activation of the phosphatidylcholine-specific phospholipase C (PC-PLC) and acidic sphingomyelinase (ASM) by N. gonorrhoeae, resulting in the release of diacylglycerol and ceramide. Genetic and/or pharmacological blockade of ASM and PC-PLC cause inhibition of cellular invasion by N. gonorrhoeae. Complementation of ASM-deficient fibroblasts from Niemann-Pick disease patients restored N. gonorrhoeae-induced signaling and entry processes. The activation of PC-PLC and ASM, therefore, is an essential requirement for the entry of N. gonorrhoeae into distinct nonphagocytic human cell types including several epithelial cells and primary fibroblasts.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 4
    Language: English
    In: Cellular Physiology and Biochemistry, June 2012, Vol.29(5-6), pp.809-818
    Description: Background: Cardiac action potential repolarisation is determined by K+ currents including IKs. IKs channels are heteromeric channels composed of KCNQ1 and KCNE E-subunits. Mutations in KCNQ1 are associated with sinus bradycardia, familial atrial fibrillation (fAF) and/or short QT syndrome as a result of gain-of-function, and long QT syndrome (LQTS) due to loss-of-function in the ventricles. Here, we report that the missense mutation R231C located in S4 voltage sensor domain is associated with a combined clinical phenotype of sinus bradycardia, fAF and LQTS. We aim to understand the molecular basis of the complex clinical phenotype. Methods: We expressed and functionally analyzed the respective channels kinetics in Xenopus laevis oocytes. The molecular nature of the residue R231 was studied by homology modeling and molecular dynamics simulation. Results: As a result, the mutation reduced voltage sensitivity of channels, possibly due to neutralization of the positive charge of the arginine side chain substituted by cysteine. Modeling suggested that the charge carrying side chain of R231 is positioned suitably to transfer transmembrane voltages into conformational energy. Further, the mutation altered the functional interactions with KCNE subunits. Conclusion: The mutation acted in a E-subunit dependent manner, suggesting IKs function altered by the presence of different KCNE subunits in sinus node, atria and ventricles as the molecular basis of sinus bradycardia, fAF and LQTS in mutation carriers.
    Keywords: Original Paper ; Kcne ; Heart ; Arrhythmia ; Oocyte ; Kv7.1 ; Kvlqt1 ; Biology ; Chemistry
    ISSN: 1015-8987
    E-ISSN: 1421-9778
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  • 5
    Language: English
    In: Neurosignals, December 2015, Vol.23(1), pp.1-10
    Description: Background: Chorein, a protein supporting activation of phosphoinositide 3 kinase (PI3K), participates in the regulation of actin polymerization and cell survival. A loss of function mutation of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) leads to chorea-acanthocytosis (ChAc), a neurodegenerative disorder with simultaneous erythrocyte akanthocytosis. In blood platelets chorein deficiency has been shown to compromise expression of vesicle-associated membrane protein 8 (VAMP8) and thus degranulation. The present study explored whether chorein is similarly involved in VAMP8 expression and dopamine release of pheochromocytoma (PC12) cells. Methods: Chorein was down-regulated by silencing in PC12 cells. Transmission electron microscopy was employed to quantify the number of vesicles, RT-PCR to determine transcript levels, Western blotting to quantify protein expression and ELISA to determine dopamine release. Results: Chorein silencing significantly reduced the number of vesicles, VAMP8 transcript levels and VAMP8 protein abundance. Increase of extracellular K+ from 5 mM to 40 mM resulted in marked stimulation of dopamine release, an effect significantly blunted by chorein silencing. Conclusions: Chorein deficiency down-regulates VAMP8 expression, vesicle numbers and dopamine release in pheochromocytoma cells.
    Keywords: Original Paper ; Dopamine ; Exocytosis ; Degranulation ; Vesicles ; Vamp8 ; Anatomy & Physiology
    ISSN: 1424-862X
    E-ISSN: 1424-8638
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 23 November 1999, Vol.96(24), pp.13795-13800
    Description: Calcium influx through store-operated calcium release-activated calcium channels (CRAC) is required for T cell activation, cytokine synthesis, and proliferation. The CD95 (Apo-1/Fas) receptor plays a role in self-tolerance and tumor immune escape, and it mediates apoptosis in activated T cells. In this paper we show that CD95-stimulation blocks CRAC and Ca2+ influx in lymphocytes through the activation of acidic sphingomyelinase (ASM) and ceramide release. The block of Ca2+ entry is lacking in CD95-defective Ipr lymphocytes as well as in ASM-defective cells and can be restored by retransfection of ASM. C2 ceramide, C6 ceramide, and sphingosine block CRAC reversibly, whereas the inactive dihydroceramide has no effect. CD95-stimulation or the addition of ceramide prevents store-operated Ca2+ influx, activation of the transcriptional regulator NFAT, and IL-2 synthesis. The block of CRAC by sphingomyelinase metabolites adds a function to the repertoire of the CD95 receptor inhibiting T cell activation signals.
    Keywords: Biological sciences -- Biology -- Physiology -- Lymphocytes ; Physical sciences -- Chemistry -- Chemical compounds -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Antigen receptors ; Biological sciences -- Biology -- Cytology -- Antigen receptors ; Biological sciences -- Biology -- Cytology -- Antigen receptors ; Health sciences -- Medical conditions -- Diseases -- Antigen receptors ; Biological sciences -- Biology -- Cytology -- Antigen receptors ; Physical sciences -- Chemistry -- Chemical compounds -- Antigen receptors ; Physical sciences -- Chemistry -- Chemical compounds -- Antigen receptors
    ISSN: 00278424
    E-ISSN: 10916490
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  • 7
    Language: English
    In: Journal of Biological Chemistry, 08/29/1997, Vol.272(35), pp.22173-22181
    Description: In the present study, we show that Fas receptor ligation or cellular treatment with synthetic C sub(6)-ceramide results in activation or phosphorylation, respectively, of the small G-protein Rac1, Jun N-terminal kinase (JNK)/p38 kinases (p38-K), and the transcription factor GADD153. A signaling cascade from the Fas receptor via ceramide, Ras, Rac1, and JNK/p38-K to GADD153 is demonstrated employing transfection of transdominant inhibitory N17Ras, N17Rac1, c-Jun, or treatment with a specific p38-K inhibitor. The critical function of this signaling cascade is indicated by prevention of Fas- or C sub(6)-ceramide-induced apoptosis after inhibition of Ras, Rac1, or JNK/p38-K.
    Keywords: Apoptosis ; Apoptosis ; Fas Antigen ; Ceramide ; Rac1 Protein ; Jnk Protein ; P38 Protein ; Gadd153 Protein ; Fas Antigen ; Gadd153 Protein ; Jnk Protein ; Rac1 Protein ; Ceramide ; P38 Protein;
    ISSN: 0021-9258
    E-ISSN: 1083-351X
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  • 8
    Language: English
    In: Journal of Biological Chemistry, 10/18/1996, Vol.271(42), pp.26389-26394
    Description: Fas induces apoptosis in lymphocytes via a poorly defined intracellular signaling mechanism. We and others have previously demonstrated the involvement and significance of a signaling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in apoptosis (Gulbins, E., Bissonette, R., Mahboubi, A., Nishioka, W., Brunner, T., Baier G., Baier-Bitterlich, G., Byrd, C., Lang, F., Kolesnick, R., Altman, A., and Green, D. (1995) Immunity 2, 341; Cifone, M. G., DeMaria, R., Roncali, P., Rippo, M. R., Azuma, M., Lanier, L. L., Santoni, A., and Testi, R. (1994) J. Exp. Med. 180, 1547-1552; Gill, B. M., Nishikata, H., Chan, G., Delovitch, T. L., and Ochi, A. (1994) Immunol. Rev. 142, 113-126). Here, we demonstrate an activation of the small G-proteins Rac 1 and Rac 2 after Fas receptor triggering. Expression of a transdominant inhibitory Ras mutant (N17Ras) prevents Rac 1 and Rac 2 stimulation, suggesting a signaling cascade from the Fas receptor via Ras to Rac 1 and Rac 2. Genetic and pharmacological inhibition of Ras or Rac 1 and Rac 2 stimulation blocks Fas-induced apoptosis, pointing to an important function of a Ras and Rac protein-regulated signaling pathway in Fas-mediated programmed cell death.
    Keywords: Chemistry ; Anatomy & Physiology;
    ISSN: 0021-9258
    E-ISSN: 1083-351X
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  • 9
    Language: English
    In: Apoptosis, 2018, Vol.23(11), pp.641-650
    Description: The transcription factor p53 suppresses tumor growth by inducing nucleated cell apoptosis and cycle arrest. Because of its influence on primitive erythroid cell differentiation and survival, p53 is an important determinant of erythropoiesis. However, the impact of p53 on the fate of erythrocytes, cells lacking nucleus and mitochondria, during their post-maturation phase in the circulation remained elusive. Erythrocyte survival may be compromised by suicidal erythrocyte death or eryptosis, which is hallmarked by phosphatidylserine translocation and stimulated by increase of cytosolic Ca 2+ concentration. Here, we comparatively examined erythrocyte homeostasis in p53-mutant mice ( Trp53 tm1Tyj /J) and in corresponding WT mice (C57BL/6J) by analyzing eryptosis and erythropoiesis. To this end, spontaneous cell membrane phosphatidylserine exposure and cytosolic Ca 2+ concentration were higher in erythrocytes drawn from Trp53 tm1Tyj /J mice than from WT mice. Eryptosis induced by glucose deprivation, a pathophysiological cell stressor, was slightly, but significantly more prominent in erythrocytes drawn from Trp53 tm1Tyj /J mice as compared to WT mice. The loss of erythrocytes by eryptosis was fully compensated by enhanced erythropoiesis in Trp53 tm1Tyj /J mice, as reflected by increased reticulocytosis and abundance of erythroid precursor cells in the bone marrow. Accordingly, erythrocyte number, packed cell volume and hemoglobin were similar in Trp53 tm1Tyj /J and WT mice. Taken together, functional p53 deficiency enhances the turnover of circulating erythrocytes by parallel increase of eryptosis and stimulated compensatory erythropoiesis.
    Keywords: Phosphatidylserine ; Eryptosis ; Calcium ; P53 ; Erythropoiesis
    ISSN: 1360-8185
    E-ISSN: 1573-675X
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  • 10
    In: Scientific Reports, 2016, Vol.6
    Description: 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 Ca(2+) 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 Ca(2+) 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.
    Keywords: Eryptosis ; Erythrocytes -- Cytology ; Gtp-Binding Protein Alpha Subunit, Gi2 -- Metabolism;
    E-ISSN: 2045-2322
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