Fisetin Prevents Acetaminophen-Induced Liver Injury by Promoting Autophagy

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 APAPinduced 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.

Neuroprotective Effect of Fisetin Through Suppression of IL-1R/TLR Axis and Apoptosis in Pentylenetetrazole-Induced Kindling in Mice

“…Interestingly, upon oral administration, fisetin and its active metabolite, geraldol, get rapidly circulated to the blood vessels of the brain accompanied by slower dispersion into the brain parenchyma of mice and gets localized in the nucleoli of neuronal cells (28). Several biological benefits of fisetin include anti-inflammatory, cardioprotective, hepatoprotective, anti-cancer, and anti-diabetic effects (29)(30)(31)(32)(33). Preclinical studies have shown that fisetin protects against traumatic brain injury (TBI), aluminum chloride-induced neurotoxicity, and methylmercury-induced neurotoxicity owing to its anti-inflammatory property (34)(35)(36).…”

Silencing of miR-150-5p Ameliorates Diabetic Nephropathy by Targeting SIRT1/p53/AMPK Pathway

“…Autophagy is considered to play an important role in the pathogenesis of various diseases (Doherty and Baehrecke, 2018 ). Increasing evidence shows that autophagy can regulate many key functions of the kidney in the normal and diseased state (Su et al, 2019 ; Zhang et al, 2020 ). STZ-induced autophagy is inhibited in the proximal and early tubules of DM rats, which is associated with renal tubular hypertrophy.…”

The paeonol target gene autophagy-related 5 has a potential therapeutic value in psoriasis treatment

“…Also, autophagy inhibition results in exacerbating skin inflammation and increased disease severity (Wu & Adamopoulos, 2017). Zhang et al (2020) revealed that acetaminophen-induced inflammation, apoptosis, and proliferation inhibition in the hepatocyte L-02 cell line could be enhanced by inhibiting autophagy and rescued by activating autophagy, respectively. They showed that the inhibition of autophagy in hepatocytes increased inflammation cytokines including IL-18 and IL-1β.…”

“…ATG5-mediated autophagy is crucial for a wide range of biological processes, including DNA damage, cell proliferation, apoptosis, inflammation, differentiation, and drug resistance ( Han et al, 2020 ; Kim et al, 2020b ; Peng et al, 2019 ; Yue et al, 2019 ). The inhibition of autophagy might induce an increase in cell apoptosis and inflammation and a reduction in cell proliferation in hepatocytes ( Wu & Adamopoulos, 2017 ; Zhang et al, 2020 ). Also, autophagy inhibition results in exacerbating skin inflammation and increased disease severity ( Wu & Adamopoulos, 2017 ).…”