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Dmitriev P.,University Paris - Sud | Dmitriev P.,French Institute of Health and Medical Research | Stankevicins L.,University Paris - Sud | Ansseau E.,University of Mons | And 12 more authors.
Journal of Biological Chemistry | Year: 2013

Background: FSHD is characterized by the overexpression of double homeobox genes DUX4 and DUX4c. Results: We found 29 miRNAs differentially expressed between FSHD and normal myoblasts. Twelve of these miRNAs were up-regulated in myoblasts ectopically expressing DUX4c. Conclusion: DUX4c is linked to the abnormal miRNA expression profile observed in FSHD. Significance: We observe a defective gene regulation by miRNAs in FSHD. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source


Behensky A.A.,University of South Florida | Yasny I.E.,IBC Generium | Shuster A.M.,IBC Generium | Seredenin S.B.,Russian Academy of Medical Sciences | Cuevas J.,University of South Florida
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the leading cause of senile dementia in the United States. Accumulation of amyloid-β (Aβ) and the effects of this peptide on microglial cells contribute greatly to the etiology of AD. Experiments were carried out to determine whether the pan-selective σ-receptor agonist afobazole can modulate microglial response to the cytotoxic Aβ fragment, Aβ25-35. Treatment with afobazole decreased microglial activation in response to Aβ, as indicated by reduced membrane ruffling and cell migration. The effects of afobazole on Aβ25-35-evoked migration were concentration dependent and consistent with σ-receptor activation. When afobazole was coapplied with either BD-1047 [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide] or rimcazole, which are σ-1- and σ-2-selective antagonists, respectively, the inhibition of Aβ25-35-induced migration by afobazole was reduced. Prolonged exposure of microglia to Aβ25-35 resulted in glial cell death that was associated with increased expression of the proapoptotic protein Bax and the death protease caspase-3. Coapplication of afobazole with Aβ25-35 decreased the number of cells expressing both Bax and caspase-3 and resulted in a concomitant enhancement in cell survival. Although afobazole inhibited activation of microglia cells by Aβ25-35, it preserved normal functional responses in these cells after exposure to the amyloid peptide. Intracellular calcium increases induced by ATP were depressed in microglia after 24-hour exposure to Aβ25-35. However, coincubation in afobazole returned these responses to near control levels. Therefore, stimulation of σ-1 and σ-2 receptors by afobazole prevents Aβ25-35 activation of microglia and inhibits Aβ25-35-associated cytotoxicity, suggesting that afobazole may be useful for AD therapeutics. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics. Source


Behensky A.A.,University of South Florida | Yasny I.E.,IBC Generium | Shuster A.M.,IBC Generium | Seredenin S.B.,Russian Academy of Medical Sciences | And 2 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a continual decline of cognitive function. No therapy has been identified that can effectively halt or reverse its progression. One hallmark of AD is accumulation of the amyloid-β peptide (Aβ), which alone induces neuronal injury via various mechanisms. Data presented here demonstrate that prolonged exposure (1-24 hours) of rat cortical neurons to Aβ 25-35 results in an increase in basal intracellular Ca2+ concentration ([Ca2+]i), and that coincubation with the compound afobazole inhibits these [Ca2+]i increases. The effect of afobazole on [Ca2+]i is due to activation of σ-1 receptors but could not be mimicked by a second pan-selective σ receptor agonist, 1,3-di-o-tolylguanidine (DTG). Afobazole was also found to lessen nitric oxide (NO) production in response to Aβ25-35 application but did not affect elevations in reactive oxygen species elicited by the Aβ fragment. The reductions in [Ca2+]i and NO perturbation produced by afobazole were associated with a decrease in neuronal cell death, whereas DTG failed to enhance cell survival. Examining the molecular mechanisms involved in the increased neuronal survival demonstrates that afobazole incubation results in lower expression of the proapoptotic protein Bax and the death protease caspase-3, while at the same time increasing expression of the antiapoptotic protein, Bcl-2. Given the importance of Aβ neurotoxicity in AD etiology, the findings reported here suggest that afobazole may be an effective AD therapeutic agent. Furthermore, σ-1 receptors may represent a useful target for AD treatment, although not all σ ligands appear to be equally beneficial. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics. Source

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