Abstract
Acetaminophen overdose-induced hepatotoxicity is the most common cause of acute liver failure in many countries. Previously, alpha-mangostin (α-MG) has been confirmed to exert protective effects on a variety of liver injuries, but the protective effect on acetaminophen-induced acute liver injury (ALI) remains largely unknown. This work investigated the regulatory effect and underlying cellular mechanisms of α-MG action to attenuate acetaminophen-induced hepatotoxicity in mice. The increased serum aminotransferase levels and glutathione (GSH) content and reduced malondialdehyde (MDA) demonstrated the protective effect of α-MG against acetaminophen-induced hepatotoxicity. In addition, α-MG pretreatment inhibited increases in tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) caused by exposure of mice to acetaminophen. In liver tissues, α-MG inhibited the protein expression of autophagy-related microtubule-associated protein light chain 3 (LC3) and BCL2/adenovirus E1B protein-interacting protein 3 (BNIP3). Western blotting analysis of liver tissues also proved evidence that α-MG partially inhibited the activation of apoptotic signaling pathways via increasing the expression of Bcl-2 and decreasing Bax and cleaved caspase 3 proteins. In addition, α-MG could in part downregulate the increase in p62 level and upregulate the decrease in p-mTOR, p-AKT and LC3 II /LC3 I ratio in autophagy signaling pathways in the mouse liver. Taken together, our findings proved novel perspectives that detoxification effect of α-MG on acetaminophen-induced ALI might be due to the alterations in Akt/mTOR pathway in the liver.
Highlights
Drug-induced liver injury (DILI) is a major problem resulting in acute liver failure (ALF) in drug development and clinical application all over the world [1], in particular, acetaminophen (APAP) severely threatens human health [2]
APAP is the most frequent causative agent when misused at a single overdose in animals and human [27]
It has been established that the overdose of APAP is bio-transformed to NAPQI, which binds covalently to tissue macromolecules and oxidizes lipids, leading to hepatotoxicity [28]
Summary
Drug-induced liver injury (DILI) is a major problem resulting in acute liver failure (ALF) in drug development and clinical application all over the world [1], in particular, acetaminophen (APAP) severely threatens human health [2]. Autophagy was triggered to cause drug-induced liver injury, as demonstrated in overdose APAP treatment [11]. As the most important secondary metabolite in the plant, α-MG demonstrates a wide variety of pharmacological effects including anti-inflammation [14,15], anti-oxidant [16], anti-apoptosis, antibacterial [17], and anti-Alzheimer’s disease [18]. Based on accumulating evidence on liver cirrhosis in vivo, it is possible that APAP-induced hepatic injury may cause further liver fibrosis. The working hypothesis here is that α-MG may have the capacity to prevent APAP-induced hepatotoxicity due to its protective effect against liver fibrosis and anti-apoptosis effect. Considering that APAP-induced hepatotoxicity can lead to inflammation, oxidative stress, autophagy, and cellular necrosis, a study of the protective effects of α-MG and relevant molecular mechanisms were undertaken
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