Amlexanox, a clinically approved small-molecule therapeutic presently used to treat allergic rhinitis, ulcer, and asthma, is an inhibitor of the noncanonical IkB kinase-ε (IKKε) and TANK-binding kinase 1 (TBK1). This study was to investigate the protective mechanism of amlexanox in acetaminophen (APAP)-induced acute liver injury (ALI). Mice were intraperitoneally injected with APAP (300 mg/kg, 12 h) to induce ALI and were orally administrated with amlexanox (25, 50 and 100 mg/kg) one hour after APAP treatment. Inhibition of IKKε and TBK1 by treatment of amlexanox attenuated APAP-induced ALI as confirmed by decreased serum levels of aspartate aminotransferase and alanine aminotransferase. Furthermore, amlexanox significantly decreased hepatocellular apoptosis in injured livers of mice as evidenced by histopathologic observation. Consistently, reduced oxidative stress by amlexanox was observed by increased hepatic glutathione concomitant with decreased levels of malondialdehyde. Amlexanox also enhanced expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes including heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase in injured livers of mice. Mechanistic insights into the mode of action of amlexanox against APAP-induced hepatotoxicity were involved in increasing phosphorylation of AMP-activated protein kinase (AMPK) and nuclear translocation of Nrf2, both in vivo and in vitro. Furthermore, the protective effects of amlexanox on APAP-induced hepatotoxicity were abolished by compound C, an AMPK inhibitor. Taken together, our findings suggest that amlexanox exerts antioxidative activities against APAP-mediated hepatotoxicity via AMPK/Nrf2 pathway.

中文翻译：

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Amlexanox通过减少小鼠的氧化应激来改善对乙酰氨基酚引起的急性肝损伤。

Amlexanox是一种临床认可的小分子疗法，目前用于治疗变应性鼻炎，溃疡和哮喘，是非规范性IkB激酶-ε（IKKε）和TANK结合激酶1（TBK1）的抑制剂。本研究旨在探讨氨来那克斯在对乙酰氨基酚（APAP）诱导的急性肝损伤（ALI）中的保护机制。小鼠腹膜内注射APAP（300 mg / kg，12 h）以诱导ALI，并在APAP治疗后一小时口服氨苯ano酸（25、50和100 mg / kg）。天冬氨酸转氨酶和丙氨酸转氨酶的血清水平降低证实，氨苯of酸可抑制APAP诱导的ALI对IKKε和TBK1的抑制作用。此外，如组织病理学观察所证明，氨lexanox显着降低了小鼠受伤肝脏中的肝细胞凋亡。始终如一 肝谷胱甘肽水平升高同时丙二醛水平降低，从而观察到氨甲磺酸减少了氧化应激。Amlexanox还增强了小鼠肝损伤中包括血红素加氧酶1，NAD（P）H：醌氧化还原酶1和谷氨酸-半胱氨酸连接酶在内的核因子类红细胞2相关因子2（Nrf2）靶基因的表达水平。对氨lexanox对抗APAP诱导的肝毒性的作用方式的机械学见解参与了体内和体外AMP激活蛋白激酶（AMPK）磷酸化的增加和Nrf2的核易位。此外，氨甲ano呤对AMPAP抑制剂化合物C消除了对APAP诱导的肝毒性的保护作用。在一起