Apigenin Prevents Acetaminophen-Induced Liver Injury by Activating the SIRT1 Pathway.

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

doi:10.3389/fphar.2020.00514

Abstract

Acetaminophen (APAP) overdose is the main cause of acute liver failure. Apigenin (API) is a natural dietary flavonol with high antioxidant capacity. Herein, we investigated protection by API against APAP-induced liver injury in mice, and explored the potential mechanism. Cell viability assays and mice were used to evaluate the effects of API against APAP-induced liver injury. Western blotting, immunofluorescence staining, RT-PCR, and Transmission Electron Microscope were carried out to determine the signalling pathways affected by API. Analysis of mouse serum levels of alanine/aspartate aminotransferase (ALT/AST), malondialdehyde (MDA), liver myeloperoxidase (MPO) activity, glutathione (GSH), and reactive oxygen species (ROS) revealed that API (80 mg/kg) owned protective effect on APAP-induced liver injury. Meanwhile, API ameliorated the decreased cell viability in L-02 cells incubated by APAP with a dose dependent. Furthermore, API promoted SIRT1 expression and deacetylated p53. Western blotting showed that API promoted APAP-induced autophagy, activated the NRF2 pathway, and inhibited the transcriptional activation of nuclear p65 in the presence of APAP. Furthermore, SIRT1 inhibitor EX-527 reduced protection by API against APAP-induced hepatotoxicity. Molecular docking results indicate potential interaction between API and SIRT1. API prevents APAP-induced liver injury by regulating the SIRT1-p53 axis, thereby promoting APAP-induced autophagy and ameliorating APAP-induced inflammatory responses and oxidative stress injury.

Highlights

Acetaminophen (APAP, paracetamol) is a widely used antipyretic and analgesic non-prescription drug
APAP significantly increased the levels of alanine/aspartate aminotransferase (ALT/AST) in mouse serum, whereas they were decreased significantly in the presence of API (Figure 1B) at 6 h and mice treated with API alone did not display any obvious differences compared to the vehicle group
EX-527 increased mRNA levels and concentrations of IL-6, TNF-a, and MCP-1 in mouse liver, and concentrations of IL-6, TNFa, and MCP-1 in mouse serum (Figures 7K, L). These results showed that API prevented APAP-induced liver damage by regulating the SIRT1/p53 axis and promoting autophagy, thereby inhibiting inflammatory responses and oxidative stress in vivo

Summary

INTRODUCTION

Acetaminophen (APAP, paracetamol) is a widely used antipyretic and analgesic non-prescription drug It is generally safe and effective, but long-term and/or large doses will lead to severe acute liver injury that can eventually develop into liver failure and even death (Nourjah et al, 2006; Fontana, 2008). We found that flavonoids can protect against various liver diseases, especially acetaminophen-induced liver damage, via anti-oxidation and anti-inflammatory mechanisms (Jing et al, 2018; Shi et al, 2018; Zhao et al, 2019). API can protect against liver injury in an APAP mouse model, but its specific mechanism of action remains unknown (Yang et al, 2013). We investigated apigenin protection mechanisms against APAP-induced liver injury. We investigated the participation of SIRT1 in this process

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT