Targeting SIRT1/AMPK/Nrf2/NF-кB by sitagliptin protects against oxidative stress-mediated ER stress and inflammation during ANIT-induced cholestatic liver injury.
Toxicology
; 507: 153889, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-39029735
ABSTRACT
Intrahepatic cholestasis is a common clinical form of hepatobiliary injury characterized by the intrahepatic accumulation of toxic bile acids. Besides its antidiabetic activity, the dipeptidyl peptidase IV inhibitor sitagliptin (SG) has been recently assigned diverse pharmacological activities and therapeutic potential against different disorders owing to its emerging antioxidant and anti-inflammatory properties. The current study explored the potential hepatoprotective effect of SG on α-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury (CLI) in mice and investigate its possible targeted signaling pathways. Mice received SG (10 and 20â¯mg/kg) for four consecutive days, two days before and after a single oral administration of ANIT (75â¯mg/kg). Our results revealed that SG administration remarkably prevented ANIT-induced histopathological lesions in the liver and maintained hepatic functions and oxidative/antioxidant balance. Ultimately, SG counteracted the inflammatory response in the liver, as indicated by the marked suppression of hepatic expression of NF-κB, TNF-α, and IL-6. Moreover, it inhibited the endoplasmic reticulum (ER) stress response in the liver. These beneï¬cial effects of SG were accompanied by upregulation of SIRT1, p-AMPK, and Nrf2 expressions while downregulating keap1 expression in the liver. In conclusion, this study is the first to demonstrate the ability of SG to protect against ANIT-induced CLI through modulating multiple signaling cascades, including SIRT1/AMPK, Nrf2/keap1, and NF-кB, which resulted in enhanced antioxidant capacity and repressed inflammatory and ER stress responses in the liver.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
FN-kappa B
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Estrés Oxidativo
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Factor 2 Relacionado con NF-E2
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Proteínas Quinasas Activadas por AMP
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Sirtuina 1
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Estrés del Retículo Endoplásmico
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Fosfato de Sitagliptina
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1-Naftilisotiocianato
Límite:
Animals
Idioma:
En
Revista:
Toxicology
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Irlanda