Mangiferin ameliorates acetaminophen-induced hepatotoxicity through APAP-Cys and JNK modulation
Mangiferin ameliorates acetaminophen-induced hepatotoxicity through APAP-Cys and JNK modulation
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芒果苷通过 APAP-Cys 和 JNK 调节改善对乙酰氨基酚诱导的肝毒性
DOI：
10.1016/j.biopha.2019.109097
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发表时间：
2019-09-01
影响因子：
7.5
通讯作者：
Sun, Ying
中科院分区：
文献类型：
--
作者：
Chowdhury, Apu;Lu, Jihong;Sun, Ying
过量使用最常用的止痛药对乙酰氨基酚（APAP）是急性肝功能衰竭的主要原因之一。已确定谷胱甘肽被APAP反应性中间体N-乙酰基-对苯醌-亚胺（NAPQI）耗尽。这导致磷酸化c-Jun N-末端激酶（p-JNK）升高，其进一步激活活性氧（ROS），引发炎症反应，并最终导致严重的肝损伤。本研究旨在探讨芒果苷（MAN），一种天然存在的氧杂蒽酮和抗氧化剂，对APAP诱导的肝毒性的保护作用。在APAP攻击前1小时，用或不用MAN预处理C57 BL/6小鼠。MAN以12.5-50 mg/kg沿着施用，APAP以400 mg/kg的剂量施用。根据ALT/AST比值，25 mg/kg MAN是进一步实验的最有效剂量。在APAP + MAN（25 mg/kg）处理的小鼠中，在6、12和24 h时观察到血清ALT和AST耗竭。早期（APAP治疗后1小时）GSH耗尽APAP过量恢复MAN治疗，减少APAP-Cys加合物的形成，促进保护。在MAN处理的小鼠中观察到p-JNK下调和AMPK活化，这可以机械地减少氧化应激和炎症。MAN可上调肝脏GSH和SOD活性，降低脂质过氧化反应。HO-1蛋白和p47 phox mRNA表达表明MAN在调节氧化应激的同时沿着JNK失活。炎症反应基因TNF-α、IL-6、MCP-1、CXCL-1和CXCL-2的表达在MAN治疗后达到基础水平。IL-1 β的mRNA、蛋白质和血清水平降低，NF-κ B表达与MAN处理的APAP小鼠相似。MAN处理后（APAP处理后1小时）也保护小鼠免受肝毒性。总之，MAN通过改善对乙酰氨基酚的代谢和APAP-Cys加合物的形成，随后是JNK介导的氧化应激和炎症，在APAP诱导的肝毒性中具有保护和治疗作用。
An overdose of the most popular analgesic, acetaminophen (APAP), is one of the leading causes of acute liver failure. It is well established that glutathione is exhausted by APAP-reactive intermediate N-acetyl-p-benzoquinone-imine (NAPQI). This leads to elevated phosphorylated-c-Jun N-terminal kinase (p-JNK), which further activates reactive oxygen species (ROS), initiates an inflammatory response, and finally leads to severe hepatic injury. The present study was conducted to investigate the protective role of mangiferin (MAN), a naturally occurring xanthone and anti-oxidant, on APAP-induced hepatotoxicity. C57BL/6 mice were pretreated with or without MAN at 1 h prior to APAP challenge. MAN was administered at a dose of 12.5-50 mg/kg along with APAP at a dose of 400 mg/kg. According to the ALT/AST ratio, 25 mg/kg MAN was the most potent dose for further experiments. Serum ALT and AST depletion were observed in APAP + MAN (25 mg/kg)-treated mice at 6, 12, and 24 h. Early (1 h after APAP treatment) GSH depletion by APAP overdose was restored by MAN treatment, which reduced APAP-Cys adduct formation and promoted protection. p-JNK downregulation and AMPK activation were observed in MAN-treated mice, which could mechanistically reduce oxidative stress and inflammation. MAN up-regulated liver GSH and SOD and reduced lipid peroxidation. HO-1 protein and p47 phox mRNA expression indicated that MAN regulated oxidative stress along with JNK deactivation. The expression of inflammatory response genes TNF-alpha, IL-6, MCP-1, CXCL-1, and CXCL-2 reached the basal levels after MAN treatment. mRNA, protein, and serum levels of IL-1 beta were reduced, and NF-kappa B expression was similar to that of the MAN-treated APAP mice. MAN post-treatment (1 h after APAP treatment) also protected the mice from hepatotoxicity. In conclusion, MAN had a protective and therapeutic role in APAP-induced hepatotoxicity by improving the metabolism of acetaminophen and APAP-Cys adduct formation followed by JNK-mediated oxidative stress and inflammation.