Ellagic acid protects Lipopolysaccharide/d-galactosamine-induced acute hepatic injury in mice

https://doi.org/10.1016/j.intimp.2014.07.005Get rights and content

Highlights

  • Ellagic acid has a protective effect on LPS/GalN-induced liver injury.

  • Ellagic acid inhibits LPS/GalN-induced NF-κB activation.

  • Ellagic acid induces the expression of Nrf2 and heme oxygenase-1.

Abstract

Ellagic acid, a natural polyphenol found in certain fruits, nuts and vegetables, has been reported to have anti-inflammatory, anti-tumor, and antioxidant activities. However, the effects of ellagic acid on acute hepatic injury have not been reported. In the present study, we investigated the effects of ellagic acid on Lipopolysaccharide/d-galactosamine-induced acute hepatic injury in mice. The results showed that LPS/GalN increased hepatic malondialdehyde (MDA) content, TNF-α level, serum ALT and AST levels and TNF-α level. However, these changes were attenuated by ellagic acid. Western blot analysis showed that ellagic acid inhibited LPS/GalN-induced NF-κB activation. Furthermore, ellagic acid induced the expression of Nrf2 and heme oxygenase-1. In conclusion, our results showed that ellagic acid protected against LPS/GalN-induced liver injury by enhancing the antioxidative defense system and reducing inflammatory response.

Introduction

Endotoxemia occurs frequently in patients leading to fulminant hepatic failure [1]. Fulminant hepatic failure is a life-threatening syndrome which is associated with high mortality [2]. LPS and GalN-induced acute hepatic injury is a well-known model for liver failure [3], [4]. It closely relates to human liver failure and has been widely used to investigate the mechanisms and potential therapeutic drugs for clinical fulminant hepatic failure [5]. GalN is a hepatotoxic agent that could inhibit macromolecule synthesis [6]. LPS stimulates liver macrophages and induces NF-κB activation and inflammatory mediator production [7], [8], [9], [10]. Among the inflammatory mediators, TNF-α has been reported to play a vital role in the pathogenesis of hepatic failure [11]. It causes inflammatory and oxidative damage to liver tissues.

Ellagic acid (EA), a naturally occurring plant phenol found in certain fruits, nuts and vegetables, has been reported to have anti-inflammatory, anti-tumor, and antioxidant activities [12], [13], [14], [15]. Ellagic acid has been reported to inhibit LPS-induced prostaglandin E2 production in human monocytes [16]. Previous reports showed that ellagic acid had a protective effect on murine model of Crohn's disease [17]. Furthermore, ellagic acid inhibited oxidized LDL-mediated ROS production and LOX-1 expression [18]. However, the effect of ellagic acid on LPS/GalN-induced acute hepatic injury remains unclear. In this study, we sought to assess the effects of ellagic acid on LPS/GalN-induced acute hepatic injury in mice.

Section snippets

Materials

Ellagic acid was purchased from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). A mouse TNF-α ELISA kit was purchased from Biolegend (CA, USA). LPS (Escherichia coli, O55:B5) and d-galactosamine were purchased from Sigma (St. Louis, MO, USA). The myeloperoxidase (MPO) determination kit, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) detection kits were provided by the Jiancheng Bioengineering Institute of Nanjing

Effect of ellagic acid on serum ALT and AST levels induced by LPS/GalN

Liver injury was assessed by measuring serum ALT and AST activities. The results showed that increased ALT and AST activities were observed in LPS/GalN treated mice. Pretreatment with ellagic acid significantly inhibited serum ALT and AST levels induced by LPS/GalN (Fig. 1).

Effects of ellagic acid on LPS/GalN-induced liver histopathologic changes

The histological features of the control group showed normal lobular architecture and cellular structure. However, livers at 8 h after LPS/GalN treatment showed significant pathologic changes, including extensive areas of

Discussion

Ellagic acid, a natural polyphenol found in certain fruits, nuts and vegetables, has been reported to have anti-inflammatory and antioxidant activities [13], [19]. The present study was conducted to examine the protective effect of ellagic acid on LPS/GalN-induced acute hepatic injury in mice. Previous studies showed that ellagic acid had a protective effect on acute lung injury induced by acid in mice at the doses of 10 mg/kg. Meanwhile, ellagic acid had been reported to have a protective

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