Fisetin Prevents Acetaminophen-Induced Liver Injury by Promoting Autophagy.

Jiaqi Zhang,Tao Wang,Hao Hu,Yuanye Jiang,Mingming Jin,Licong Zhao,Cheng Hu,Guang Ji,Juan Lu,Qin Cao,Long Chen,Chenqu Wu

doi:10.3389/fphar.2020.00162

Abstract

Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in clinical and hospital settings. Fisetin (FST) is a phenolic compound derived from natural products such as fruit and vegetables. Our research investigated the protective mechanisms of FST in APAP-induced hepatic injury in vitro and vivo. Assessment of mouse serum levels of alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) demonstrated the protective effects of FST toward APAP-induced liver injury. FST also reversed an APAP-induced decrease in mouse L-02 cell line viability. Our results also showed that FST significantly promoted APAP-induced autophagy and inhibited inflammasome activation both in vivo and in vitro. We also found that silencing ATG5, using si-ATG5, reduced the protective effects of FST against APAP-induced hepatotoxicity and reversed the effects on autophagy. Finally, we used the autophagy inhibitor, 3-methyladenine (3-MA) to validate the involvement of autophagy in FST against APAP-induced hepatotoxicity in vitro. We demonstrated that FST prevented APAP-induced hepatotoxicity by increasing ATG5 expression, thereby promoting autophagy and inhibiting inflammasome activation.

Highlights

Acetaminophen is an antipyretic analgesics ingredient, which is safe to use when correctly adhering to prescribed therapeutic dosages
Fisetin Protects Against AcetaminophenInduced Liver Damage in Mice
Hematoxylin & eosin staining (Figure 1C) showed that APAP led to serious hepatic damage, induced by hepatocyte necrosis, intrahepatic hemorrhage, lymphocyte infiltration, and liver structure destruction, whereas they were ameliorated by FST

Summary

Introduction

Acetaminophen is an antipyretic analgesics ingredient, which is safe to use when correctly adhering to prescribed therapeutic dosages. Acetaminophen (APAP) overdosing can cause serious hepatic injury in animals and humans (Larson et al, 2005; Blieden et al, 2014; Jaeschke et al, 2014). APAP has become one of the most widely reason of acute liver injury in the United States and other western countries (Bernal, 2003; Fontana, 2008; Canbay et al, 2009; Blieden et al, 2014). APAP forms a highly reactive metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which induces hepatotoxicity (Alonso et al, 2015). Cellular reduced glutathione (GSH) has been shown to detoxify this metabolite, it becomes depleted once APAP is overdosed and forms excessive NAPQI. Superabundant NAPQI binds with free thiol groups in proteins, leading to reactive oxygen species (ROS) accumulation and subsequent disturbances in cellular redox homeostasis (Cohen et al, 1997; Gunawan and Kaplowitz, 2007; Jaeschke et al, 2012)

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Results

Conclusion