Activation of the Kelch-like ECH-Associated Protein 1 (Keap1)/NF-E2-Related Factor 2 (Nrf2) Pathway through Covalent Modification of the 2-Alkenal Group of Aliphatic Electrophiles in Coriandrum sativum L.

Abstract

Phytochemicals able to activate the transcription factor NF-E2-related factor 2 (Nrf2) were isolated from an extract of Coriandrum sativum L. (C. sativum) leaves by preparative octadecyl silica column chromatography. Ultraperformance liquid chromatography and liquid chromatography-tandem mass spectrometry analysis of the isolated components after derivatization with 2-diphenylacetyl-1,3-inandione-1-hydrazone and experiments with HepG2 cells revealed that (E)-2-alkenals with different carbon numbers play a role in Nrf2 activation in these cells. Such Nrf2 activation appears to be attributable to S-alkylation of Kelch-like ECH-associated protein 1 (Keap1), the negative regulator for Nrf2, as determined by a biotin-PEAC5-maleimide assay. Interestingly, (E)-2-butenal caused Keap1 modification and Nrf2 activation, whereas butanal did not. These results suggest that (E)-2-alkenals with an α,β-unsaturated aldehyde moiety, which is a common substituent in phytochemicals isolated from C. sativum leaves, activate the Keap1/Nrf2 pathway associated with cellular protection.

Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery

“…Under normal conditions, the oxidative sensor protein Keap1 retains Nrf2 in the cytosol and acts as an adaptor for an E3 ligase to degrade Nrf2 through an ubiquitin-proteasome system (52). Oxidative stresses (such as reactive oxygen species (ROS)) and other electrophiles (including aldehydes) modify the cysteine residues in Keap1, causing Nrf2 activation, which in turn promotes the transcriptions of its target genes involved in oxidative stress resistance and cell survival (37,53). Disruption of Keap1 and overexpression of Nrf2 in mice independently induce hyperproliferation in keratinocytes and skin barrier defect phenotypes such as increased TEWL and hyperkeratosis (54,55).…”

Environmental Electrophiles: Protein Adducts, Modulation of Redox Signaling, and Interaction with Persulfides/Polysulfides

“…Given that the p K a of a Cys thiol is decreased when it is proximal to basic amino acids such as lysine, histidine, or arginine, it is possible that a variety of quinones can covalently bind to AhR through the Cys residues, leading to the induction of CYP1A1 because little appreciable modification of HSP90 was detected under the conditions. As mentioned above, our group has demonstrated that the activation of effector molecules is coupled to the covalent attachment of environmental electrophiles to sensor proteins. ,,,,,,, AhR activation by 1,2-NQ is the first example of activation of a redox signal transduction through direct arylation of the transcription factor by environmental quinones.…”

“…As mentioned above, our group has demonstrated that the activation of effector molecules is coupled to the covalent attachment of environmental electrophiles to sensor proteins. 19,37,84,85,88,96,164,175 AhR activation by 1,2-NQ is the first example of activation of a redox signal transduction through direct arylation of the transcription factor by environmental quinones.…”

“…In this manner, one of the Keap1/Nrf2 pathways functions as an adaptive response against oxidative and electrophilic stresses. Environmental electrophiles such as 1,2-NQ, 1,4-NQ, TBQ, ( E )-2-alkenals, Cd, and MeHg are able to modify Keap1 protein through reactive thiols (thiolate ions), thereby activating Nrf2 (Table ). We also found that knockout of Nrf2 enhances cellular toxicities during exposure to environmental electrophiles, supporting the notion of Nrf2 as a cytoprotective regulator of environmental electrophiles as shown in Figure . , …”

Isorhapontigenin ameliorates cerebral ischemia/reperfusion injury via modulating Kinase Cε/Nrf2/HO‐1 signaling pathway

“…In many oxidative stress animal models, PKCε is closely associated with lung injury, either by drug blockade or by gene knockout (Liu, et al., 2017 ; Yadav et al., 2018 ). The cytoplasm‐localized transcription factor Nrf2 is closely related to oxidative stress (Je & Lee, 2015 ; Zhu et al., 2017 ) and induces transcription of many ARE‐dependent target genes (Abiko et al., 2014 ; Zhong & Kowluru, 2012 ), including HO‐1. HO‐1 expression is increased under oxidative stress and plays an antioxidant role in the pathological development of various diseases (Dias‐Teixeira et al., 2017 ).…”