Dietary α-Mangostin Provides Protective Effects against Acetaminophen-Induced Hepatotoxicity in Mice via Akt/mTOR-Mediated Inhibition of Autophagy and Apoptosis

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.

Potent effects of dioscin against hepatocellular carcinoma through regulating TP53‐induced glycolysis and apoptosis regulator (TIGAR)‐mediated apoptosis, autophagy, and DNA damage

“…The results revealed that dioscin induced autophagy against HCC in vivo and in vitro. The signal of Akt/mTOR is important in regulating intracellular homeostasis, and it is reported that activation of Akt/mTOR signal is essential in autophagy (Yan et al, ). Interestingly, recent studies have highlighted that TIGAR knockdown can enhance epriubicin‐induced autophagy by inhibiting mTOR pathway, suggesting the protective effect of autophagy on the survival of cancer cells when TIGAR is knocked down (Kumar, Iqbal, Singh, & Bamezai, ).…”

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

“…It is well known that excessive ROS induced by APAP results in phosphorylation of JNK, which further amplifies mitochondria oxidative stress [23]. Moreover, the pro-apoptotic protein Bax, which belongs to the Bcl-2 family of proteins, is highly expressed exposed to an APAP overdose [24,25,26]. The pathophysiological importance of Bax in APAP hepatotoxicity has been shown by the temporary inhibition of nuclear DNA fragmentation and delayed cell death in Bax-deficient mice [27].…”

“…Bax is a pro-apoptotic Bcl-2 family member located predominantly in the cytosol. Exposed to an APAP overdose, it is highly expressed [24,25,26]. It has been reported that APAP-induced mitochondrial Bax expression was attenuated by the inhibition of JNK activation [11].…”

α-Mangostin, a Dietary Xanthone, Exerts Protective Effects on Cisplatin-Induced Renal Injury via PI3K/Akt and JNK Signaling Pathways in HEK293 Cells

“…The desiccative mangosteen pericarp powder (20 g) was extracted with 200 mL of 85% ethanol for 5 min twice by the smashing tissue extraction (STE) method. 4 The purity of α-MG is more than 98%.…”