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

Matheus de Freitas Silva,Letizia Pruccoli,Fabiana Morroni,Claudio Viegas,Francesca Seghetti,Andrea Tarozzi,Giulia Sita

doi:10.3390/molecules23071803

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.

Highlights

Chalcone or 1,3-diaryl-2-propen-1-one is a common chemical scaffold found in several natural and synthetic chalcone derivates, that exists as either a trans (E) or cis (Z) isomer (Figure 1a), of which the trans isomer is thermodynamically more stable [1]
This study showed that nuclear factor- κB (NF-κB) and Nuclear factor erythroid 2-related factor 2 (Nrf2) could be therapeutic targets of chalcones to control the pathogenesis of DCM
The present review indicates that chalcones mainly exert antioxidant, anti-inflammatory, antidiabetic, cardioprotective, neuroprotective and cytoprotective activities through Kelch-like ECH-associated protein 1 (Keap1)/Nrf2–antioxidant response element (ARE)

Summary

Introduction

Chalcone or 1,3-diaryl-2-propen-1-one is a common chemical scaffold found in several natural and synthetic chalcone derivates, that exists as either a trans (E) or cis (Z) isomer (Figure 1a), of which the trans isomer is thermodynamically more stable [1]. 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway (Figure 2) through covalent bonds with the cysteines of Keap, which contains at least 27 cysteine residues with different levels of reactivity and acts as a redox sensor and negative regulator of Nrf2 [6,7,8]. The Keap1/Nrf pathway can exert anti-inflammatory effects through indirect mechanisms by reducing reactive oxygen species (ROS) levels and NF-κB activity, and through direct mechanisms by modulating the transcription of anti- and pro-inflammatory genes, and inhibiting IKK activity through the interaction with Keap1 [13] In this regard, the chalcones demonstrate the ability to control inflammation through the inhibition of IKK activity and the DNA binding of NF-κB via a Michael acceptor-related mechanism [15,16,17,18]. The authors evaluated a surrogate marker of Keap1-Nrf2-ARE pathway activation; b oral administration

Targeting the Nrf2 Pathway by Natural Chalcones

Targeting the Nrf2 Pathway by Synthetic Chalcones

Conclusions