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The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones

Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,β-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activat...

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Autores principales: de Freitas Silva, Matheus, Pruccoli, Letizia, Morroni, Fabiana, Sita, Giulia, Seghetti, Francesca, Viegas Jr, Claudio, Tarozzi, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100069/
https://www.ncbi.nlm.nih.gov/pubmed/30037040
http://dx.doi.org/10.3390/molecules23071803
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author de Freitas Silva, Matheus
Pruccoli, Letizia
Morroni, Fabiana
Sita, Giulia
Seghetti, Francesca
Viegas Jr, Claudio
Tarozzi, Andrea
author_facet de Freitas Silva, Matheus
Pruccoli, Letizia
Morroni, Fabiana
Sita, Giulia
Seghetti, Francesca
Viegas Jr, Claudio
Tarozzi, Andrea
author_sort de Freitas Silva, Matheus
collection PubMed
description Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,β-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activate the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway through a Michael addition reaction with the cysteines of Keap1, which acts as a redox sensor and negative regulator of Nrf2. This modification allows the dissociation of Nrf2 from the cytoplasmic complex with Keap1 and its nuclear translocation. At this level, Nrf2 binds to the antioxidant response element (ARE) and activates the expression of several detoxification, antioxidant and anti-inflammatory genes as well as genes involved in the clearance of damaged proteins. In this regard, the Keap1/Nrf2–ARE pathway is a new potential pharmacological target for the treatment of many chronic diseases. In this review we summarize the current progress in the study of Keap1/Nrf2–ARE pathway activation by natural and synthetic chalcones and their potential pharmacological applications. Among the pharmacological activities highlighted, anti-inflammatory activity was more evident than others, suggesting a multi-target Michael acceptor mechanism for the chalcones involving key regulators of the Nrf2 and nuclear factor- κB (NF-κB) pathways.
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spelling pubmed-61000692018-11-13 The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones de Freitas Silva, Matheus Pruccoli, Letizia Morroni, Fabiana Sita, Giulia Seghetti, Francesca Viegas Jr, Claudio Tarozzi, Andrea Molecules Review Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,β-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activate the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway through a Michael addition reaction with the cysteines of Keap1, which acts as a redox sensor and negative regulator of Nrf2. This modification allows the dissociation of Nrf2 from the cytoplasmic complex with Keap1 and its nuclear translocation. At this level, Nrf2 binds to the antioxidant response element (ARE) and activates the expression of several detoxification, antioxidant and anti-inflammatory genes as well as genes involved in the clearance of damaged proteins. In this regard, the Keap1/Nrf2–ARE pathway is a new potential pharmacological target for the treatment of many chronic diseases. In this review we summarize the current progress in the study of Keap1/Nrf2–ARE pathway activation by natural and synthetic chalcones and their potential pharmacological applications. Among the pharmacological activities highlighted, anti-inflammatory activity was more evident than others, suggesting a multi-target Michael acceptor mechanism for the chalcones involving key regulators of the Nrf2 and nuclear factor- κB (NF-κB) pathways. MDPI 2018-07-20 /pmc/articles/PMC6100069/ /pubmed/30037040 http://dx.doi.org/10.3390/molecules23071803 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
de Freitas Silva, Matheus
Pruccoli, Letizia
Morroni, Fabiana
Sita, Giulia
Seghetti, Francesca
Viegas Jr, Claudio
Tarozzi, Andrea
The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones
title The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones
title_full The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones
title_fullStr The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones
title_full_unstemmed The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones
title_short The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones
title_sort keap1/nrf2-are pathway as a pharmacological target for chalcones
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100069/
https://www.ncbi.nlm.nih.gov/pubmed/30037040
http://dx.doi.org/10.3390/molecules23071803
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