Polygodial, a sesquiterpene isolated from Drimys brasiliensis (Winteraceae), triggers glucocorticoid-like effects on pancreatic beta-cells

Polygodial, a sesquiterpene isolated from Drimys brasiliensis (Winteraceae), triggers glucocorticoid-like effects on pancreatic beta-cells

Author Barrosa, Kaidu Hanashiro Autor UNIFESP Google Scholar
Mecchi, Murilo C. Autor UNIFESP Google Scholar
Rando, Daniela Goncales Autor UNIFESP Google Scholar
Ferreira, Ari Jose S. Google Scholar
Sartorelli, Patricia Autor UNIFESP Google Scholar
Valle, Maira M. R. Google Scholar
Bordin, Silvana Google Scholar
Caperuto, Luciana Chagas Autor UNIFESP Google Scholar
Lago, Joao Henrique Ghilardi Autor UNIFESP Google Scholar
Lellis-Santos, Camilo Autor UNIFESP Google Scholar
Abstract Despite its common use, the synthetic glucocorticoid dexamethasone can cause several adverse effects, such as diabetes and insulin-related metabolic impairment. Thus, research on molecules that could provide the same anti-inflammatory response with milder side effects is constant. In this work the antiinflammatory activity of the natural sesquiterpene polygodial, extracted from the endemic Brazilian plant Drimys brasiliensis Miers (Winteraceae), was investigated. Employing a pancreatic beta-cell model (INS 1E), the effect of polygodial on signaling pathways is similar to that caused by dexamethasone - both increased MKP1 and decreased ERK1/2 expression in a dose-response and time-dependent manner. Relating to such finding, nuclear translocation of the glucocorticoid receptor was also discovered to be induced by the sesquiterpene. Molecular modeling results indicated that polygodial was capable of docking to the glucocorticoid receptor, but presented preference for the Arg611 binding site rather than Thr739 when set to bind freely inside the pocket. At last, fragmentation of DNA was verified as consequence of sesquiterpene-induced cell death. Altogether, our results suggest that, like dexamethasone, polygodial interacts the glucocorticoid receptor ligand binding domain but create fewer ligand-protein interactions at the site, yielding a weaker effector response. Such property provides an advantage when regarding the adverse effects resulting from stronger affinity ligands of the glucocorticoid receptor, such as in the case of the current standard dexamethasone-based treatment. This aspect, also, turns polygodial an interesting hit compound to the development of new drugs based on its backbone structure providing less harmful anti-inflammatory treatments. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords Poligodial
Dexamethasone
beta-Cells
Glucocorticoid receptor
Nuclear translocation
Molecular docking
xmlui.dri2xhtml.METS-1.0.item-coverage Clare
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 2015/11936-2
FAPESP: 2010/10778-0
Date 2016
Published in Chemico-Biological Interactions. Clare, v. 258, p. 245-256, 2016.
ISSN 0009-2797 (Sherpa/Romeo, impact factor)
Publisher Elsevier Ireland Ltd
Extent 245-256
Origin http://dx.doi.org/10.1016/j.cbi.2016.09.013
Access rights Closed access
Type Article
Web of Science ID WOS:000385368700026
URI https://repositorio.unifesp.br/handle/11600/56885

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