The Late-Stage Protective Effect of Mito-TEMPO against Acetaminophen-Induced Hepatotoxicity in Mouse and Three-Dimensional Cell Culture Models.
The Late-Stage Protective Effect of Mito-TEMPO against Acetaminophen-Induced Hepatotoxicity in Mouse and Three-Dimensional Cell Culture Models.
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DOI：
10.3390/antiox9100965
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发表时间：
2020-10-09
期刊：
影响因子：
--
通讯作者：
Ishitsuka Y
中科院分区：
文献类型：
--
作者：
Abdullah-Al-Shoeb M;Sasaki K;Kikutani S;Namba N;Ueno K;Kondo Y;Maeda H;Maruyama T;Irie T;Ishitsuka Y
对乙酰氨基酚（APAP）是急性肝损伤的最常见原因，过量服用可诱导氧化应激，随后导致线粒体损伤和肝坏死。n -乙酰- l-半胱氨酸（NAC）是唯一公认的抗APAP肝毒性药物，但越晚给药效果越差。本研究评估了线粒体特异性Mito-TEMPO （Mito-T）对apap诱导的C57BL/6J雄性小鼠急性肝损伤的保护作用，并建立了含人肝母细胞瘤细胞系HepG2的三维细胞培养模型。给药Mito-T （20mg /kg, i.p）注射APAP (400 mg/kg, ig) 1 h后，APAP引起的血清转氨酶活性升高和肝坏死明显减轻。然而，Mito-T治疗不影响APAP肝损伤发展的关键因素，包括肝中C -jun n末端激酶（JNK）的激活和转录因子C/EBP同源蛋白（CHOP）的表达。然而，Mito-T显著降低了apap诱导的肝脏氧化应激标志物、硝基酪氨酸和DNA断裂的增加。在HepG2 3d细胞培养模型中，Mito-T显著减弱APAP诱导的细胞毒性。此外，APAP肝毒性后的肝再生不受Mito-T的影响，增殖细胞核抗原形成没有变化。因此，在APAP过量小鼠的晚期，Mito-T具有肝保护作用。
An overdose of acetaminophen (APAP), the most common cause of acute liver injury, induces oxidative stress that subsequently causes mitochondrial impairment and hepatic necroptosis. N-acetyl-L-cysteine (NAC), the only recognized drug against APAP hepatotoxicity, is less effective the later it is administered. This study evaluated the protective effect of mitochondria-specific Mito-TEMPO (Mito-T) on APAP-induced acute liver injury in C57BL/6J male mice, and a three dimensional (3D)-cell culture model containing the human hepatoblastoma cell line HepG2. The administration of Mito-T (20 mg/kg, i.p.) 1 h after APAP (400 mg/kg, i.p.) injection markedly attenuated the APAP-induced elevated serum transaminase activity and hepatic necrosis. However, Mito-T treatment did not affect key factors in the development of APAP liver injury including the activation of c-jun N-terminal kinases (JNK), and expression of the transcription factor C/EBP homologous protein (CHOP) in the liver. However, Mito-T significantly reduced the APAP-induced increase in the hepatic oxidative stress marker, nitrotyrosine, and DNA fragmentation. Mito-T markedly attenuated cytotoxicity induced by APAP in the HepG2 3D-cell culture model. Moreover, liver regeneration after APAP hepatotoxicity was not affected by Mito-T, demonstrated by no changes in proliferating cell nuclear antigen formation. Therefore, Mito-T was hepatoprotective at the late-stage of APAP overdose in mice.
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影响因子：
--
作者：
Liu FC;Lee HC;Liao CC;Li AH;Yu HP
通讯作者：
Yu HP
影响因子：
5.9
作者：
Jaeschke H;McGill MR;Ramachandran A
通讯作者：
Ramachandran A
影响因子：
4.1
作者：
Hinson, JA;Pike, SL;Mayeux, PR
通讯作者：
Mayeux, PR
影响因子：
3.8
作者：
Gujral, JS;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
DOI：
10.1016/j.bbadis.2019.165583
发表时间：
2020-01-01
影响因子：
6.2
作者：
Chen, Qian;Yan, Dehong;Wan, Xiaochun
通讯作者：
Wan, Xiaochun