Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity

Abstract

Acetaminophen (APAP) overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2) is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A) upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our findings indicated that Lico A effectively decreased tert-butyl hydroperoxide (t-BHP)- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase and aspartate aminotransferase levels, malondialdehyde formation, myeloperoxidase level and superoxide dismutase depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor and cytochrome c release. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis, and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2-/- mice. These investigations firstly implicated that Lico A has protective potential against APAP-induced hepatotoxicity which may be strongly associated with the Nrf2-mediated defense mechanisms.

Activation of Nrf2/HO-1 Pathway by Nardochinoid C Inhibits Inflammation and Oxidative Stress in Lipopolysaccharide-Stimulated Macrophages

“…Keap1 is a negative regulator of the transcription factor Nrf2, which mediated the inactivation of Nrf2 and thus enhanced Nrf2 translocation into the nucleus ( Satoh et al, 2006 ; Lv et al, 2018 ). It has been reported that protein p62, which is on the upstream of Nrf2 pathway, can inactivate Keap1 and activate Nrf2 ( Komatsu et al, 2010 ).…”

Isoorientin Ameliorates APAP-Induced Hepatotoxicity via Activation Nrf2 Antioxidative Pathway: The Involvement of AMPK/Akt/GSK3β

“…Natural products have made enormous contributions to drug discovery, as they have many advantages over conventional chemical compound-based medications, such as fewer side effects, less long-term toxicity, and variable bioavailability and biological activity ( Kim, 2018 ). In recent years, intensive studies have demonstrated the protective effects of natural products against APAP-induced hepatotoxicity due to their multiple mechanisms of action in inflammation, oxidant/antioxidant balance and damage responses ( Ko et al, 2017 ; Lv et al, 2018 ). Iso (or homoorientin) is a chemical flavonoid-like compound that has been shown to exert anti-inflammatory effects and exhibit antioxidant potential ( Ye et al, 2016 ).…”

“…Oxidative stress causes injury in cells by generating reactive oxygen species (ROS), and excessive ROS in the liver can cause extensive liver injury ( Chan et al, 2006 ). Based on the significant pathophysiological role of antioxidation/detoxification system dysfunction in the development of liver diseases, antioxidant agents can be an effective strategy for fighting oxidative stress that causes liver damage and diseases ( Lv et al, 2018 ). Therefore, the ability of Iso to act as an antioxidant with anti-inflammatory activity renders this compound a prime candidate to be a hepatoprotective agent.…”

Fucoidan Alleviates Acetaminophen-Induced Hepatotoxicity via Oxidative Stress Inhibition and Nrf2 Translocation

“…At therapeutic doses, APAP is mainly metabolized to nontoxic water-soluble metabolites by glucuronidation and sulfation in the liver, and only a small fraction of APAP is metabolized by various cytochrome P450s (CYPs) such as CYP2E1, CYP3A4, CYP1A2, and CYP1A1 to a toxic active product, N -acetyl-p-benzoquinoneimine (NAPQI) [4,5]. NAPQI forms APAP-glutathione, APAP-cysteine, and APAP- N -acetylcysteine by conjugating with glutathione (GSH) [6]. However, an APAP overdose exhausts glucuronidation and sulfation pathways and produces excess NAPQI, subsequently consuming GSH excessively.…”