Cynarin alleviates acetaminophen-induced acute liver injury through the activation of Keap1/Nrf2-mediated lipid peroxidation defense via the AMPK/SIRT3 signaling pathway.
Food Funct
; 15(9): 4954-4969, 2024 May 07.
Article
em En
| MEDLINE
| ID: mdl-38602356
ABSTRACT
Overdose of Acetaminophen (APAP) is a major contributor to acute liver injury (ALI), a complex pathological process with limited effective treatments. Emerging evidence links lipid peroxidation to APAP-induced ALI. Cynarin (Cyn), a hydroxycinnamic acid derivative, exhibits liver protective effects, but whether it mitigates APAP-induced ALI is unclear. Our aim was to verify the protective impact of Cyn on APAP-induced ALI and elucidate the molecular mechanisms governing this process. Herein, the regulation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) interaction was determined to be a novel mechanism underlying this protective impact of Cyn against APAP-induced ALI. Nrf2 deficiency increased the severity of APAP-induced ALI and lipid peroxidation and counteracted the protective effect of Cyn against this pathology. Additionally, Cyn promoted the dissociation of Nrf2 from Keap1, enhancing the nuclear translocation of Nrf2 and the transcription of downstream antioxidant proteins, thereby inhibiting lipid peroxidation. Molecular docking demonstrated that Cyn bound competitively to Keap1, and overexpression of Keap1 reversed Nrf2-activated anti-lipid peroxidation. Additionally, Cyn activated the adenosine monophosphate-activated protein kinase (AMPK)/sirtuin (SIRT)3 signaling pathway, which exhibits a protective effect on APAP-induced ALI. These findings propose that Cyn alleviates APAP-induced ALI by enhancing the Keap1/Nrf2-mediated lipid peroxidation defense via activation of the AMPK/SIRT3 signaling pathway.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peroxidação de Lipídeos
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Transdução de Sinais
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Fator 2 Relacionado a NF-E2
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Proteínas Quinases Ativadas por AMP
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Doença Hepática Induzida por Substâncias e Drogas
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Proteína 1 Associada a ECH Semelhante a Kelch
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Acetaminofen
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Food Funct
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Reino Unido