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Berlin Brandenburg

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  • 1
    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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  • 2
    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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  • 3
    Language: English
    In: Cellular Physiology and Biochemistry, February 2011, Vol.27(1), pp.45-54
    Description: The preclinical compounds Bay 11-7082 and parthenolide trigger apoptosis, an effect contributing to their antiinflammatory action. The substances interfere with the activation and nuclear translocation of nuclear factor NFĸB, by inhibiting NFĸB directly (parthenolide) or by interfering with the inactivation of the NFĸB inhibitory protein IĸB-α (Bay 11-7082). Beyond that, the substances may be effective in part by nongenomic effects. Similar to apoptosis of nucleated cells, erythrocytes may undergo apoptosis-like cell death (eryptosis) characterized by cell membrane scrambling with phosphatidylserine exposure, and cell shrinkage. Thus, erythrocytes allow the study of nongenomic mechanisms contributing to suicidal cell death, e.g. Ca2+ leakage or glutathione depletion. The present study utilized Western blotting to search for NFĸB and IĸB-α expression in erythrocytes, FACS analysis to determine cytosolic Ca2+ (Fluo3 fluorescence), phosphatidylserine exposure (annexin V binding), and cell volume (forward scatter), as well as an enzymatic method to determine glutathione levels. As a result, both NFĸB and IĸB-α are expressed in erythrocytes. Targeting the NFĸB pathway by Bay 11-7082 (IC50 ≈ 10 µM) and parthenolide (IC50 ≈ 30 µM) triggered suicidal erythrocyte death as shown by annexin V binding and decrease of forward scatter. Bay 11-7082 treatment further increased intracellular Ca2+ and led to depletion of reduced glutathione. The effects of Bay 11-7082 and parthenolide on annexin V binding could be fully reversed by the antioxidant N-acetylcysteine. In conclusion, the pharmacological inhibitors of NFĸB, Bay 11-7082 and parthenolide, interfere with the survival of erythrocytes involving mechanisms other than disruption of NFĸB-dependent gene expression.
    Keywords: Original Paper ; Cell Volume ; Eryptosis ; Calcium ; Phosphatidylserine Exposure ; Glutathione ; N-Acetylcysteine ; Biology ; Chemistry
    ISSN: 1015-8987
    E-ISSN: 1421-9778
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  • 4
    Language: English
    In: Cellular Physiology and Biochemistry, 2003, Vol.13(6), pp.337-346
    Description: In nucleated cells cellular taurine is released prior to DNA fragmentation and the breakdown of phosphatidylserine asymmetry within the plasma membrane. Similar to what is seen in nucleated cells, phosphatidylserine asymmetry is also abolished in erythrocytes exposed to osmotic shock or oxidative stress. The present study has been performed to explore the sensitivity of erythrocytes from a taurine transporter knockout mouse (taut-/-) against osmotic shock and oxidative stress. Erythrocyte cell volume was estimated from forward scatter and breakdown of phosphatidylserine asymmetry was identified by determination of annexin binding using FACS analysis. Erythrocytes from taut-/- mice were compared to erythrocytes from wild type littermates (taut+/ +). Plasma concentration and erythrocyte content of taurine was significantly lower in taut-/- than in taut+/ + mice, but the intraerythrocyte taurine concentration did not exceed the plasma concentration. Hyperosmotic shock (exposure to 700 mOsm) and oxidative stress (exposure to 0.1 mM tert-butyl-hydroperoxide) significantly decreased the cell volume and increased the number of annexin binding sites of erythrocytes from both, taut-/- and taut+/ + mice. However, decrease of cell volume and increase of annexin binding was significantly blunted in erythrocytes from taut-/- mice as compared to their taut+/ + littermates. Stimulation of erythropoiesis by prior hemorrhage did not abrogate the difference between taut+/ + and taut-/- erythrocytes. The present observations point to a decreased sensitivity of mature erythrocytes from taut-/- mice to osmotic shock and oxidative stress, rendering them more resistant to apoptosis.
    Keywords: Original Paper ; Biology ; Chemistry
    ISSN: 1015-8987
    E-ISSN: 1421-9778
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  • 5
    Language: English
    In: Oncology, December 2003, Vol.65(3), pp.211-217
    Description: Purpose: A phase II trial was performed to determine the antitumor efficacy and tolerance of combined docetaxel and cisplatin with or without hematopoietic growth factor support in patients with advanced gastroesophageal cancer. Patients and Methods: Thirty-seven patients with histologically confirmed metastatic gastroesophageal cancer were entered in this trial. Treatment consisted of 4-weekly courses of docetaxel 50 mg/m2 and cisplatin 50 mg/m2 both given on day 1 and 15. Depending on absolute neutrophil counts on the days of scheduled chemotherapeutic drug administration (1,000–2,000/µl), a 5-day course of human granulocyte colony-stimulating factor (G-CSF) 5 µg/kg/day was given subcutaneously; in addition, if hemoglobin was 〈12.0 mg/dl, erythropoietin 10,000 IU was administered subcutaneously 3 times per week. Results: The confirmed overall response rate (intent-to-treat) was 46%, including 4 complete responses (11%) and 13 partial responses (35%). Eleven patients (30%) had stable disease and 9 (24%) progressed while on treatment. The median time to response was 3 months, the median time to progression was 7 months and the median overall survival time was 11.5 months with 16 (43%) patients currently alive. Hematologic toxicity was common, though WHO grade 4 neutropenia occurred only in 3 patients. Nonhematologic adverse reaction were usually mild to moderate; grade 3 toxicities included alopecia in 5 patients (14%), infection in 1 (3%), neutrotoxicity in 2 (5%) and anaphylaxis in 1 patient. Conclusion: Our data suggest that the combination of docetaxel and cisplatin with or without G-CSF and/or erythropoietin has a promising therapeutic index in patients with advanced gastroesophageal cancer.
    Keywords: Clinical Study ; Palliative Chemotherapy ; Advanced Gastric Cancer ; Docetaxel ; Cisplatin ; Granulocyte Colony-Stimulating Factor ; Erythropoietin ; Medicine
    ISSN: 0030-2414
    E-ISSN: 1423-0232
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  • 6
    Language: English
    In: Cellular Physiology and Biochemistry, 1996, Vol.6(3), pp.185-194
    Description: Acridine orange has been utilized to test for an effect of cell swelling and glutamate on pH in acidic intracellular compartments of retinal ganglion cells. Alkalinization of these compartments is reflected by an increase in acridine orange fluorescence intensity at 〉 530 nm. NH4C1 (500 µM) and chloroquine (100 µM), weak bases known to alkalinize acidic compartments, expectedly increased acridine orange fluorescence. A similar effect was elicited by a decrease in extracellular osmolarity. An increase in extracellular K+ concentration, leading to isotonic cell swelling, also increased acridine orange fluorescence. Addition of 100 µM glutamate increased acridine orange fluorescence, although it did not appear to affect cell volume. The glutamate-induced alkalinization was blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, and mimicked by NMDA (50 µM). The effect of NMDA was blocked by the removal of extracellular Ca2+. Similarly, NMDA-induced increases in intracellular Ca2+ were blocked under Ca2+-free conditions. Cytosolic pH measurements in the same cells demonstrated an acidification in response to reduced extracellular osmolarity. In contrast, a high K+ solution and 100 µM glutamate both increased cytosolic pH. In conclusion, alkalinization of acidic cellular compartments of retinal ganglion cells is induced not only by NH4CI, chloroquine and maneuvers which induce cell swelling, but also by the neurotransmitter glutamate. The mechanism by which glutamate induces its effect appears to be primarily via increases in intracellular Ca2+. The alkalinization of acidic intracellular compartments, as such, may modify transmitter metabolism and trafficking of cell membrane proteins.
    Keywords: Original Paper ; Retinal Ganglion ; Vesicular Ph ; Swelling ; Biology ; Chemistry
    ISSN: 1015-8987
    E-ISSN: 1421-9778
    Source: Karger (S. Karger AG)
    Source: Karger Journals (S. Karger AG)
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