IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation.

Autor: Converti A; Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Bianchi MS; Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Martinez MD; CONICET-Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina.; Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina., Montaner AD; Instituto de Ciencia y Tecnología (ICT-Milstein), Buenos Aires, Argentina., Lux-Lantos V; Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Bonaventura MM; Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.; Universidad Nacional de San Martin (UNSAM), ECyT, Buenos Aires, Argentina.
Jazyk: angličtina
Zdroj: Physiological reports [Physiol Rep] 2023 Aug; Vol. 11 (15), pp. e15790.
DOI: 10.14814/phy2.15790
Abstrakt: We have demonstrated that oligodeoxynucleotide IMT504 promotes significant improvement in the diabetic condition in diverse animal models. Based on these results, here we evaluated whether these effects observed in vivo could be due to direct effects on β-cells. We demonstrate by immunofluorescence that IMT504 enters the cell and locates in cytoplasm where it induces GSK-3β phosphorylation that inactivates this kinase. As GSK-3β tags Pdx1 for proteasomal degradation, by inactivating GSK-3β, IMT504 induces an increase in Pdx1 protein levels, demonstrated by Western blotting. Concomitantly, an increase in Ins2 and Pdx1 gene transcription was observed, with no significant increase in insulin content or secretion. Enhanced Pdx1 is promising since it is a key transcription factor for insulin synthesis and is also described as an essential factor for the maintenance β-cell phenotype and function. Dose-dependent inhibition of H 2 O 2 -induced apoptosis determined by ELISA as well as decreased expression of Bax was also observed. These results were confirmed in another β-cell line, beta-TC-6 cells, in which a cytokine mix induced apoptosis that was reversed by IMT504. In addition, an inhibitor of IMT504 entrance into cells abrogated the effect IMT504. Based on these results we conclude that the β-cell recovery observed in vivo may include direct effects of IMT504 on β-cells, by maintaining their identity/phenotype and protecting them from oxidative stress and cytokine-induced apoptosis. Thus, this work positions IMT504 as a promising option in the framework of the search of new therapies for type I diabetes treatment.
(© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
Databáze: MEDLINE
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