mangostin and Chemical-and-Drug-Induced-Liver-Injury

The purpose of this study was to evaluate the protective effects of α-mangostin against acetaminophen (APAP)-induced acute liver injury and discover its potential mechanisms in mice. Mice were continuously treated with α-mangostin (12.5 and 25 mg/kg) by intragastric administration once daily for 6 days, and injected intraperitoneally with APAP (300 mg/kg) after 1 h of α-mangostin administration on the last day. After APAP exposure for 24 h, the liver and serum were gathered to evaluate the hepatotoxicity. The results showed that α-mangostin effectively decreased the serum levels of alanine aminotransferase, aspartate transaminase, tumor necrosis factor (TNF-α), interleukin-1β and 6 (IL-1β, IL-6), and hepatic malondialdehyde level; and recovered hepatic glutathione (GSH), superoxide dismutase and catalase activities. Liver histopathological observation provided further evidence that α-mangostin pretreatment significantly inhibited APAP-induced hepatocellular necrosis, infiltration of inflammatory cell and hyperemia. According to the analysis of western-blot and RT-PCR detection, α-mangostin pretreatment validly inhibited the phosphorylation of ERK, JNK and p38 MAPK induced by APAP, which was consistent with the changes of TNF-α, IL-6 and IL-1β levels; the phosphorylation of IκBα and the translocation of NF-κBp65 were also attenuated by α-mangostin. These results provided a new mechanism for the protective effects of α-mangostin against APAP-induced acute liver injury. α-Mangostin significantly restrainted the oxidative stress induced by APAP. Moreover, the anti-inflammatory property of α-mangostin, which is mediated by the NF-κB and MAPK signaling pathways, also contributed to its hepatoprotective effect. Taken together, we believed that α-mangostin might be a potential material for drug development against drug-related hepatotoxicity.

Topics: Acetaminophen; Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cytoprotection; Gene Expression Regulation, Enzymologic; Male; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Phosphorylation; RNA, Messenger; Xanthones

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.

Topics: Acetaminophen; Animals; Apoptosis; Autophagy; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Garcinia mangostana; Humans; Liver; Male; Mice; Mice, Inbred ICR; Microtubule-Associated Proteins; Oxidative Stress; TOR Serine-Threonine Kinases; Xanthones

The purpose of this study was to investigate the hepatoprotective effect of α-mangostin (α-MG) on lipopolysaccharide/d-galactosamine (LPS/D-GalN)-induced acute liver failure and discover its potential mechanisms in mice. The results showed that α-MG could attenuate LPS/D-GalN-induced liver pathological injury, and decrease the hepatic malondialdehyde (MDA) level, serum alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor (TNF-α), interleukin-1β and 6 (IL-1β, IL-6) levels and recovery hepatic glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) activities. The results also indicated that α-MG inhibited LPS/D-GalN-induced toll-like receptor 4 (TLR4) expression and NF-κB activation. In addition, α-MG up-regulated the expressions of Nrf2 and heme oxygenase-1 (HO-1). In conclusion, the results indicated that α-MG could protect against LPS/D-GalN-induced liver failure by activating Nrf2 to induce antioxidant defense and inhibiting TLR4 signaling pathway to induce anti-inflammatory effect.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Chemical and Drug Induced Liver Injury; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Galactosamine; Heme Oxygenase-1; Lipopolysaccharides; Liver; Liver Failure, Acute; Male; Membrane Proteins; Mice, Inbred ICR; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Toll-Like Receptor 4; Xanthones

alpha-Mangostin derived from mangosteen was identified as a mosquito sterol carrier protein-2 inhibitor via high throughput insecticide screening, alpha-Mangostin was tested for its larvicidal activity against third instar larvae of six mosquito species, and the median lethal concentration values range from 0.84 to 2.90 ppm. The residual larvicidal activity of alpha-mangostin was examined under semifield conditions. The results indicated that alpha-mangostin was photolytic with a half-life of 53 min in water under full sunlight exposure. The effect of alpha-mangostin on activities of major detoxification enzymes such as P450, glutathione S-transferase, and esterase was investigated. The results showed that alpha-mangostin significantly elevated activities of P450 and glutathione S-transferase in larvae, whereas it suppressed esterase activity. Toxicity of alpha-mangostin against young rats was studied, and there was no detectable adverse effect at dosages as high as 80 mg/kg. This is the first multifaceted study of the biological activity of alpha-mangostin in mosquitoes. The results suggest that alpha-mangostin may be a lead compound for the development of a new organically based mosquito larvicide.

Topics: Alanine Transaminase; Animals; Carrier Proteins; Chemical and Drug Induced Liver Injury; Culicidae; Insecticides; Larva; Male; Rats; Xanthones