Abstract
Cardamonin (CD), a naturally occurring chalcone derived from the Alpinia species, has been shown to exert antioxidant and anti-inflammatory activity, but its role in the prevention of acetaminophen- (APAP-) induced hepatotoxicity remains elusive. The objective of this study was to determine the protective effects of CD against APAP-induced acute liver injury (ALI) and the underlying mechanisms. Wild-type or transcription factor nuclear factor erythroid 2-related factor 2- (NFE2L2-) deficient mice were treated with CD (50 or 100 mg/kg, i.p.) or vehicle for 24 h. Subsequently, these mice were challenged with APAP (400 mg/kg, i.p.) for 6 h. Liver and blood samples were collected to evaluate liver injury and protein abundance. Treatment with CD significantly reduced APAP-induced hepatotoxicity. Furthermore, CD effectively reduced APAP-induced inflammation by inhibiting high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and NOD-like receptor protein 3 (NLRP3) signaling. In addition, CD induced activation of sequestosome 1 (p62) and NFE2L2 signaling and facilitated autophagy. By applying autophagy inhibitor 3-methyladenine (3-MA; 20 mg/kg, i.p.), further mechanistic exploration revealed that NFE2L2 deficiency promoted autophagic activity induced by CD treatment, which was conducive to the hepatoprotective effect of CD against APAP-induced hepatoxicity in NFE2L2−/− mice. Overall, data suggest that CD has hepatoprotective effect against APAP-induced ALI, which might contribute to the activation of NFE2L2 and autophagy.
Highlights
Acetaminophen (N-acetyl-p-aminophenol; APAP) is a ubiquitous and widely used nonprescription drug for the relief of pain and fever (Bessems and Vermeulen, 2001)
Histological analysis of liver in the APAP group revealed a noticeable disturbance of liver architecture including hemorrhage, hepatocyte necrosis, and neutrophil infiltration, whereas CD treatment alleviated these alterations (Figures 1D,E)
Compared with the APAP group, CD significantly inhibited the abundance of TLR4 and phosphorylation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase (MAPK) in APAP-stimulated mice (Figures 2F–H)
Summary
Acetaminophen (N-acetyl-p-aminophenol; APAP) is a ubiquitous and widely used nonprescription drug for the relief of pain and fever (Bessems and Vermeulen, 2001). Liver injury disorders caused by excessive administration of APAP are accompanied by sterile inflammation and oxidative stress, which further exacerbates liver injury (Sanz-Garcia et al, 2013; Du et al, 2016). It is well known that APAP poisoning generates excess N-acetyl-p-benzoquinone imine, which evokes depletion of glutathione (GSH) and triggers oxidative stress that results in hepatocellular death (Mitchell et al, 1973; Jaeschke et al, 2012). Extensive cell necrosis caused by APAP-induced hepatotoxicity leads to release of cellular contents and a marked increased blood serum of enzymes related to liver function, which further activates various pattern recognition receptors (PRRs). The damageassociated molecular patterns (DAMPs) released by cells subsequently trigger innate immune systems via TLR4dependent induction of proinflammatory cytokines and transcription of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. During APAP hepatotoxicity, high mobility group box 1 (HMGB1) is identified as a key extracellular coordinator by promoting the inflammation in ALI (Antoine et al, 2010) and its concentration in serum correlates with progression and prognosis of ALI in humans (Antoine et al, 2012)
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