| Full text | |
| Author(s): |
Barrosa, Kaidu H.
;
Mecchi, Murilo C.
;
Rando, Daniela G.
;
Ferreira, Ari Jose S.
;
Sartorelli, Patricia
;
Valle, Maira M. R.
;
Bordin, Silvana
;
Caperuto, Luciana C.
;
Lago, Joao Henrique G.
;
Lellis-Santos, Camilo
Total Authors: 10
|
| Document type: | Journal article |
| Source: | Chemico-Biological Interactions; v. 258, p. 245-256, OCT 25 2016. |
| Web of Science Citations: | 2 |
| 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. (AU) | |
| FAPESP's process: | 10/10778-0 - Modulation of inflammation- and diabetes-related intracellular signalling pathways by phenolic compounds extracted from brazilian native fruits extracts |
| Grantee: | Camilo de Lellis Santos |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 15/11936-2 - Use of chemodiversity of plant species in remaining areas of Atlantic Forest from São Paulo State in the selection of biologically active prototypes |
| Grantee: | João Henrique Ghilardi Lago |
| Support Opportunities: | Regular Research Grants |