Core Concepts
Capsaicin, a natural compound derived from chili peppers, can effectively mitigate oxidative stress by directly disrupting the KEAP1-NRF2 interaction and activating the NRF2-ARE signaling pathway.
Abstract
The study investigated the protective effects of capsaicin (CAP) against ethanol-induced oxidative damage in gastric mucosal cells and tissues. Key findings:
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CAP pretreatment significantly enhanced cell viability, reduced ROS levels, and modulated redox balance in gastric epithelial cells exposed to ethanol.
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CAP promoted the nuclear translocation of NRF2 and upregulated the expression of downstream antioxidant genes like HO-1, Trx, and NQO1.
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CAP directly bound to the Kelch domain of KEAP1 and disrupted the KEAP1-NRF2 interaction, leading to NRF2 stabilization and activation.
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In a rat model of ethanol-induced acute gastric mucosal injury, CAP and CAP-loaded nanoparticles (IR-HSA@CAP) effectively alleviated oxidative damage, inflammation, and histopathological changes.
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Mechanistically, IR-HSA@CAP nanoparticles activated the NRF2/ARE signaling pathway and suppressed the production of pro-inflammatory cytokines in the gastric tissues.
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The study provides evidence that CAP is a safe and novel NRF2 agonist that acts by allosterically regulating KEAP1, offering a promising therapeutic approach for oxidative stress-related diseases.
Stats
Exposure to 5% ethanol for 1.5 hours decreased cell viability to approximately 50% in GES-1 cells.
Pretreatment with 8 μM CAP significantly enhanced cell viability to 93.84% in GES-1 cells exposed to ethanol.
CAP pretreatment reduced the percentage of apoptotic GES-1 cells from 28.85% to 13.95% in the ethanol-exposed group.
CAP pretreatment decreased intracellular ROS levels in GES-1 cells from 83.1% to 48.9%.
CAP treatment increased SOD activity and decreased MDA levels in GES-1 cells exposed to ethanol.
The ulcer injury (UI) index in the ethanol-exposed rat group was 36.0, which was significantly reduced to 7.0 and 5.3 in the CAP and IR-HSA@CAP pretreatment groups, respectively.
IR-HSA@CAP pretreatment reduced the pathological damage index in the rat gastric tissues from 6.3 in the ethanol group to 1.7.
IR-HSA@CAP pretreatment decreased ROS levels by 36.99% and lipid peroxidation (MDA) by 72.82% in the rat gastric tissues compared to the ethanol group.
Quotes
"CAP ameliorated mitochondrial damage, facilitated the nuclear translocation of NRF2, thereby promoting the expression of downstream antioxidant response elements, HO-1, Trx, GSS and NQO1 in GES1 cells."
"CAP non-covalently bound to Kelch domain and allosterically regulated three regions of KEAP1: L342-L355, D394-G423 and N482-N495."
"Our work provided new insights that CAP is a safe and novel NRF2 agonist by allosterically regulating KEAP1, which may contribute to the development of lead drugs for oxidative stress-related illness, e.g. aging, cancer, neurodegenerative and cardiovascular diseases."