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Molecules 2018, 23(7), 1803; https://doi.org/10.3390/molecules23071803

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

1
PeQuiM-Laboratory of Research in Medicinal Chemistry, Federal University of Alfenas, Jovino Fernandes Sales Avenue, 2600 Alfenas, MG 37130-840, Brazil
2
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy
3
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
4
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
5
INBB, National Institute for Biostructures and Biosystems, 00136 Rome, Italy
*
Author to whom correspondence should be addressed.
Academic Editors: Angela Rampa and Alessandra Bisi
Received: 26 June 2018 / Revised: 18 July 2018 / Accepted: 18 July 2018 / Published: 20 July 2018
(This article belongs to the Special Issue Chalcone: A Privileged Structure in Medicinal Chemistry)
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Abstract

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. View Full-Text
Keywords: chalcones; Nrf2; Keap1; NF-κB; antioxidant activity; anti-inflammatory activity; multi-target activity chalcones; Nrf2; Keap1; NF-κB; antioxidant activity; anti-inflammatory activity; multi-target activity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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de Freitas Silva, M.; Pruccoli, L.; Morroni, F.; Sita, G.; Seghetti, F.; Viegas Jr, C.; Tarozzi, A. The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones. Molecules 2018, 23, 1803.

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