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Marburg an der Lahn, Germany

Dolga A.M.,University of Marburg | Netter M.F.,Institute For Physiologie Und Pathophysiologie | Perocchi F.,Harvard University | Perocchi F.,Ludwig Maximilians University of Munich | And 11 more authors.
Journal of Biological Chemistry | Year: 2013

Small conductance calcium-activated potassium (SK2/KCa2.2) channels are known to be located in the neuronal plasma membrane where they provide feedback control of NMDA receptor activity. Here, we provide evidence that SK2 channels are also located in the inner mitochondrial membrane of neuronal mitochondria. Patch clamp recordings in isolated mitoplasts suggest insertion into the inner mitochondrial membrane with the C andNtermini facing the intermembrane space. Activation of SK channels increased mitochondrial K+ currents, whereas channel inhibition attenuated these currents. In a model of glutamate toxicity, activation of SK2 channels attenuated the loss of the mitochondrial transmembrane potential, blocked mitochondrial fission, prevented the release of proapoptotic mitochondrial proteins, and reduced cell death. Neuroprotection was blocked by specific SK2 inhibitory peptides and siRNA targeting SK2 channels. Activation of mitochondrial SK2 channels may therefore represent promising targets for neuroprotective strategies in conditions of mitochondrial dysfunction ©2013 by The American Society for Biochemistry and Molecular Biology, Inc.


D'Attilio L.,National University of Rosario | Bozza V.V.,National University of Rosario | Santucci N.,National University of Rosario | Bongiovanni B.,National University of Rosario | And 6 more authors.
Annals of the New York Academy of Sciences | Year: 2012

Supernatants (SN) from cultures of peripheral blood mononuclear cells (PBMC) of tuberculosis (TB) patients inhibit dehydroepiandrosterone (DHEA) secretion by the adrenal cell line NCI-H295R. To analyze whether TGF-β is involved in this effect, SN of PBMC from healthy controls or patients with severe TB infections, stimulated or not with Mycobacterium tuberculosis (Mtb SN), were added to adrenal cells under basal conditions or following stimulation with forskolin. Cortisol and DHEA concentrations were evaluated in supernatants of the adrenal cells cultured with or without the addition of anti-TGF-β. Treatment with Mtb SN from TB inhibited DHEA production, and this effect was reversed when SN were treated with anti-TGF-β. The increase in cortisol production induced by SN from TB patients was not affected by TGF-β neutralization. Mediators released during the anti-TB immune response differentially modulate steroid production by adrenal cells, and TGF-β is a cytokine implicated in the inhibition of DHEA production observed in TB. © 2012 New York Academy of Sciences.


Bongiovanni B.,National University of Rosario | Diaz A.,National University of Rosario | D'Attilio L.,National University of Rosario | Santucci N.,National University of Rosario | And 9 more authors.
Annals of the New York Academy of Sciences | Year: 2012

We evaluated immune and endocrine status following antituberculosis treatment in HIV-negative patients with newly diagnosed tuberculosis (TB). Treatment led to a decrease in IL-6, IL-1β, and C-reactive protein levels. Cortisol levels decreased throughout the anti-TB treatment, particularly after 4 months, but changes were less pronounced than those seen in proinflammatory mediators. Specific therapy resulted in increased dehydroepiandrosterone (DHEA) levels, which peaked after 4 months and started to decline after 6 months of treatment, reaching levels below those detected at inclusion. In contrast, in most patients, dehydroepiandrosterone sulfate (DHEAS) levels remained unchanged, although a trend toward increased concentrations was observed in a few cases 3 months after the treatment was finished. Specific therapy also resulted in more balanced cortisol/DHEA and cortisol/DHEAS ratios. Etiologic treatment involves favorable immune and endocrine changes, which may account for its beneficial effects. © 2012 New York Academy of Sciences.


Bottasso O.,National University of Rosario | Bay M.L.,Institute For Physiologie Und Pathophysiologie | Besedovsky H.,Institute For Physiologie Und Pathophysiologie | del Rey A.,Institute For Physiologie Und Pathophysiologie
Current Immunology Reviews | Year: 2010

Tuberculosis (TB) accounts for an increasing morbidity and mortality across the world. Approximately 8.8 million new TB cases emerge and 1.6 million people die of this disease every year. Host defense against microbial pathogens involves an inflammatory reaction in which innate and adaptive immune mechanisms play an active role in its development. When the pathogen cannot be contained by the initial response, as usually occurs in TB, a systemic response characterized by multiple metabolic and neuroendocrine changes develops. Essential functions like defensive responses and metabolism are regulated by a series of molecules with pleiotropic effects, like pro-inflammatory cytokines, adrenal steroids, and adipocytokines; which affect both the regulation and/or redirectioning of energy sources and immune activity. Patients with TB, frequently displaying a consumption state, and their highly exposed close-household contacts (HHC) constitute "natural models" for analyzing this type of immune-endocrine-metabolic relation. We have shown the existence of an immune-endocrine imbalance in TB patients characterized by increased circulating levels of IFN-γ, IL-6, prolactin, thyroid hormones, cortisol, and growth hormone, accompanied by decreased concentrations of leptin and DHEA, and without significant differences in insulin-like growth factor-1. In contrast HHC coursing a latent subclinical infection, showed a modest decrease of DHEA in presence of increased amounts of leptin. In vitro studies showed that culture supernatants from M. tuberculosis-stimulated PBMC of TB patients inhibited DHEA secretion by a human adrenal cell line. It was also found that the unbalanced immune-endocrine relation of TB patients was associated to the weight loss they presented, which in turn accounted for the impairment on their specific in vitro cellular immune responses. The host response during TB results in an altered immune-endocrine communication, affecting essential biological functions, like the development of protective responses, control of tissue damage and metabolism, implied in a poorer disease course. © 2010 Bentham Science Publishers Ltd.


Bottasso O.,National University of Rosario | Bay M.L.,National University of Rosario | Besedovsky H.,Institute For Physiologie Und Pathophysiologie | del Rey A.,Institute For Physiologie Und Pathophysiologie
Molecular and Cellular Neuroscience | Year: 2013

The nervous, endocrine and immune systems play a crucial role in maintaining homeostasis and interact with each other for a successful defensive strategy against injurious agents. However, the situation is different in long-term diseases with marked inflammation, in which defensive mechanisms become altered. In the case of tuberculosis (TB), this is highlighted by several facts: an imbalance of plasma immune and endocrine mediators, that results in an adverse environment for mounting an adequate response against mycobacteria and controlling inflammation; the demonstration that dehidroepiandrosterone (DHEA) secretion by a human adrenal cell line can be inhibited by culture supernatants from Mycobacterium tuberculosis-stimulated peripheral blood mononuclear cells - PBMC - of TB patients, with this effect being partly reverted when neutralizing transforming growth factor-β in such supernantants; the in vitro effects of adrenal steroids on the specific immune response of PBMC from TB patients, that is a cortisol inhibition of mycobacterial antigen-driven lymphoproliferation and interferon-γ production as well as a suppression of TGF-β production in DHEA-treated PBMC; and lastly the demonstration that immune and endocrine compounds participating in the regulation of energy sources and immune activity correlated with the consumption state of TB patients. Collectively, immune-endocrine disturbances of TB patients are involved in critical components of disease pathology with implications in the impaired clinical status and unfavorable disease outcome. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'. © 2012 Elsevier Inc.

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