Khái niệm cốt lõi
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.
Tóm tắt
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.
Thống kê
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.
Trích dẫn
"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."