Abstract
Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. In this study, APAP-treated genetic knockout of Farnesoid X receptor (FXR) and Sirtuin 1 (SIRT1) mice were used for research. The results revealed that IMP could improve the severity of liver injury and inhibit the increase of proinflammatory cytokines, oxidative damage, and apoptosis induced by overdose APAP in an FXR-dependent manner. We also found that IMP enhanced the activation and translocation of FXR by increasing the expression of SIRT1 and the phosphorylation of AMPK. Besides, single administration of IMP at 4 h after APAP injection can also improve necrotic areas and serum transaminase, indicating that IMP have both preventive and therapeutic effects. Taken together, it is the first time to demonstrate that IMP exerts protective effects against APAP overdose-induced hepatotoxicity by stimulating the SIRT1-FXR pathway. These findings suggest that IMP is a potential therapeutic candidate for ALI, offering promise for the treatment of hepatotoxicity associated with APAP overdose.
Highlights
Acetaminophen (APAP), one of the most widely used analgesic and antipyretic drug in the United States, European countries, and Asia, exerts a safe and reliable effect at proper therapeutic doses
The liver protective effects of IMP were initially verified on the liver injury mouse model with inflammatory response and acute oxidative stress, which were established by intraperitoneal injection of LPS or APAP, respectively
Our results suggest that the protective effects of IMP against APAP overdoseinduced liver injury may be dependent on the activation of the Farnesoid X receptor (FXR) signaling pathway
Summary
Acetaminophen (APAP), one of the most widely used analgesic and antipyretic drug in the United States, European countries, and Asia, exerts a safe and reliable effect at proper therapeutic doses. When in excess, it can cause severe acute liver injury (ALI) and even acute liver failure (ALF). APAP is present in large amounts, its metabolite NAPQI depletes GSH in the liver, and the remaining NAPQI will bind to mitochondrial proteins, which causes mitochondrial dysfunction, increases the production of mitochondrial reactive oxygen species (ROS), triggers inflammatory response, and contributes to liver injury [4,5,6]. N-acetylcysteine (NAC) is currently the only drug used for APAP-induced liver injury and is only effective in the early stages of ALI [7]. It is imperative to discover novel and effective therapies against APAP overdose-induced ALI. Reducing the oxidative stress and inflammatory response induced by APAP may be a feasible strategy
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