Inhibition of Oxidative Stress and ALOX12 and NF-κB Pathways Contribute to the Protective Effect of Baicalein on Carbon Tetrachloride-Induced Acute Liver Injury.

Chongshan Dai,Jianzhong Shen,Yang Wang,Tony Velkov,Hui Li,Shusheng Tang

doi:10.3390/antiox10060976

Abstract

This study investigates the protective effect of baicalein on carbon tetrachloride (CCl4)-induced acute liver injury and the underlying molecular mechanisms. Mice were orally administrated baicalein at 25 and 100 mg/kg/day for 7 consecutive days or ferrostatin-1 (Fer-1) at 10 mg/kg was i.p. injected in mice at 2 and 24 h prior to CCl4 injection or the vehicle. Our results showed that baicalein or Fer-1 supplementation significantly attenuated CCl4 exposure-induced elevations of serum alanine aminotransferase and aspartate aminotransferase, and malondialdehyde levels in the liver tissues and unregulated glutathione levels. Baicalein treatment inhibited the nuclear factor kappa-B (NF-κB) pathway, activated the erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway in liver tissues, and markedly improved CCl4-induced apoptosis, inflammation and ferroptosis in liver tissues exposed with CCl4. In vitro, baicalein treatment improved CCl4 -induced decreases of cell viabilities and knockdown of Nrf2 and arachidonate 12-lipoxygenase (ALOX12) genes partly abolished the protective effect of baicalein on CCl4 -induced cytotoxicity in HepG2 cells. In conclusion, our results reveal that baicalein supplementation ameliorates CCl4-induced acute liver injury in mice by upregulating the antioxidant defense pathways and downregulating oxidative stress, apoptosis, inflammation and ferroptosis, which involved the activation of Nrf2 pathway and the inhibition of ALOX12 and NF-κB pathways.

Highlights

Over the past several decades, liver disease has been consistently on the rise, so much so that it has become one of the leading causes of mortality and morbidity worldwide [1].Currently, approved drugs for treating liver injury usually have many side-effects and limited efficacy [2], such that to date, safer, effective hepatoprotective drugs remain an unmet medical need.Drugs, chemicals or alcohol-caused acute liver injury are common in most countries and serious liver injury often leads to liver failure, and even death [3]
Our results suggested that baicalein protects against CCl4 induced acute liver injury via activation of the Nrf2/heme oxygenase 1 (HO-1) anti-oxidant pathway
Baicalein supplementation inhibited ferroptosis in HepG2 cells following erastin treatment. These findings suggest that baicalein supplementation can inhibit CCl4 -induced ferroptosis that partly contributes to its protective effect on CCl4 -induced acute liver injury in mice

Summary

Introduction

Over the past several decades, liver disease has been consistently on the rise, so much so that it has become one of the leading causes of mortality and morbidity worldwide [1].Currently, approved drugs for treating liver injury usually have many side-effects and limited efficacy [2], such that to date, safer, effective hepatoprotective drugs remain an unmet medical need.Drugs, chemicals or alcohol-caused acute liver injury are common in most countries and serious liver injury often leads to liver failure, and even death [3]. Over the past several decades, liver disease has been consistently on the rise, so much so that it has become one of the leading causes of mortality and morbidity worldwide [1]. The pathology of acute liver injury involves necrosis, infiltration of inflammatory cells and apoptosis [4,5,6,7]. Carbon tetrachloride (CCl4 ) is commonly used as the inducing agent in animal models of acute injury liver (e.g., mice, rats or rabbits), which are commonly employed to identify or screen for hepatoprotective agents [4,5,6,7]. It is well known that CCl4 is metabolized by the liver cytochrome P4502E1, which leads to the production of highly reactive trichloromethyl free radicals and excessive reactive oxygen species (ROS) [8].

Methods

Discussion

Conclusion