title: Polygodial, a sesquiterpene isolated from Drimys brasiliensis (Winteraceae), triggers glucocorticoid-like effects on pancreatic β-cells.
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 anti-inflammatory activity of the natural sesquiterpene polygodial, extracted from the endemic Brazilian plant Drimys brasiliensis Miers (Winteraceae), was investigated. Employing a pancreatic β-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.
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, 09972-270, São Paulo, Brazil.
authors.forename: Kaidu H
authors.initials: KH
authors.lastname: Barrosa
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, 09972-270, São Paulo, Brazil.
authors.forename: Murilo C
authors.initials: MC
authors.lastname: Mecchi
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, 09972-270, São Paulo, Brazil.
authors.forename: Daniela G
authors.initials: DG
authors.lastname: Rando
authors.affiliation: Centro de Estudos Químicos, Centro Universitário da Fundação Instituto de Ensino para Osasco, 06020-190, São Paulo, Brazil.
authors.forename: Ari José S
authors.initials: AJ
authors.lastname: Ferreira
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, 09972-270, São Paulo, Brazil.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sartorelli
authors.affiliation: Institute of Biomedical Sciences, University of São Paulo, 05508-900, São Paulo, Brazil.
authors.forename: Maíra M R
authors.initials: MM
authors.lastname: Valle
authors.affiliation: Institute of Biomedical Sciences, University of São Paulo, 05508-900, São Paulo, Brazil.
authors.forename: Silvana
authors.initials: S
authors.lastname: Bordin
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, 09972-270, São Paulo, Brazil.
authors.forename: Luciana C
authors.initials: LC
authors.lastname: Caperuto
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, 09972-270, São Paulo, Brazil; Center of Natural Sciences and Humanities, Federal University of ABC, 09210-180, São Paulo, Brazil. Electronic address: joao.lago@unifesp.br.
authors.forename: João Henrique G
authors.initials: JH
authors.lastname: Lago
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, 09972-270, São Paulo, Brazil. Electronic address: lellis.unifesp@gmail.com.
authors.forename: Camilo
authors.initials: C
authors.lastname: Lellis-Santos
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D003907:Dexamethasone / Q000737:chemistry / Q000494:pharmacology*; D032424:Drimys / Q000737:chemistry*; D005938:Glucocorticoids / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D062105:Molecular Docking Simulation; D021381:Protein Transport / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D012717:Sesquiterpenes; C034380:polygodial; D003907:Dexamethasone
keywords: Dexamethasone; Glucocorticoid receptor; Molecular docking; Nuclear translocation; Poligodial; β-Cells