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Protective effect of ISO-1 with inhibition of RIPK3 up-regulation and neutrophilic accumulation on acetaminophen-induced liver injury in mice
Toxicology Letters ( IF 2.9 ) Pub Date : 2021-03-01 , DOI: 10.1016/j.toxlet.2020.12.015
Tatsuya Ohkawara , Naoto Okubo , Osamu Maehara , Jun Nishihira , Hiroshi Takeda

Overdose use of acetaminophen (APAP) often occurs a severe liver injury, and its liver injury is lethal in some cases. Macrophage migration inhibitory factor (MIF) is expressed in a variety of cells and has multifunctional roles. However, the role of MIF in APAP-induced liver injury has not been fully investigated. In this study, we investigated whether treatment with (S,R)-3-(4-hydroxyphenil)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), a MIF inhibitor, protected mice from acute APAP-induced liver injury. Acute liver injury was induced by injection of APAP (300 mg/kg body weight). Mice were treated with a single injection of ISO-1(15 mg/kg body weight) 1 hour (h) before APAP administration. Histological, biochemical and molecular analyses were performed in liver of mice 12 h after APAP administration. ISO-1 remarkably improved the histological findings of APAP-induced liver injury in mice. The increases in serum levels of alanine aminotransferase (ALT), and macrophage inflammatory protein-2 (MIP-2) by APAP were inhibited by ISO-1. In addition, ISO-1 reduced the increased number of the myeloperoxidase-staining cells and that of TUNEL-positive staining cells in the liver of mice with APAP-induced liver injury. Up-regulation of hepatic receptor interacting protein kinase (RIPK)3 and heat shock protein70 by APAP was suppressed in the liver of mice given ISO-1. These results provide the additional evidence that inhibition of MIF activity may be clinically effective for treatment of acute APAP-induced liver injury.

中文翻译:

ISO-1 抑制 RIPK3 上调和中性粒细胞积累对对乙酰氨基酚所致小鼠肝损伤的保护作用

对乙酰氨基酚(APAP)的过量使用往往会发生严重的肝损伤,在某些情况下其肝损伤是致命的。巨噬细胞迁移抑制因子 (MIF) 在多种细胞中表达并具有多功能作用。然而,MIF 在 APAP 诱导的肝损伤中的作用尚未得到充分研究。在这项研究中,我们研究了用 (S,R)-3-(4-hydroxyphenil)-4,5-dihydro-5-isoxazole 醋酸甲酯 (ISO-1)(一种 MIF 抑制剂)治疗是否能保护小鼠免受急性APAP 引起的肝损伤。通过注射APAP(300mg/kg体重)诱导急性肝损伤。在APAP给药前1小时(h)用单次注射ISO-1(15mg/kg体重)处理小鼠。在 APAP 给药后 12 小时,在小鼠肝脏中进行组织学、生化和分子分析。ISO-1 显着改善了 APAP 诱导的小鼠肝损伤的组织学结果。血清丙氨酸氨基转移酶 (ALT) 和巨噬细胞炎症蛋白 2 (MIP-2) 的升高被 APAP 抑制了 ISO-1。此外,ISO-1 减少了 APAP 诱导的肝损伤小鼠肝脏中髓过氧化物酶染色细胞和 TUNEL 阳性染色细胞数量的增加。在给予 ISO-1 的小鼠肝脏中,APAP 对肝受体相互作用蛋白激酶 (RIPK)3 和热休克蛋白 70 的上调受到抑制。这些结果提供了额外的证据,即抑制 MIF 活性可能在临床上有效治疗急性 APAP 诱导的肝损伤。和巨噬细胞炎症蛋白-2 (MIP-2) 的 APAP 被 ISO-1 抑制。此外,ISO-1 减少了 APAP 诱导的肝损伤小鼠肝脏中髓过氧化物酶染色细胞和 TUNEL 阳性染色细胞数量的增加。在给予 ISO-1 的小鼠肝脏中,APAP 对肝受体相互作用蛋白激酶 (RIPK)3 和热休克蛋白 70 的上调受到抑制。这些结果提供了额外的证据,即抑制 MIF 活性可能在临床上有效治疗急性 APAP 诱导的肝损伤。和巨噬细胞炎症蛋白-2 (MIP-2) 的 APAP 被 ISO-1 抑制。此外,ISO-1 减少了 APAP 诱导的肝损伤小鼠肝脏中髓过氧化物酶染色细胞和 TUNEL 阳性染色细胞数量的增加。在给予 ISO-1 的小鼠肝脏中,APAP 对肝受体相互作用蛋白激酶 (RIPK)3 和热休克蛋白 70 的上调受到抑制。这些结果提供了额外的证据,即抑制 MIF 活性可能在临床上有效治疗急性 APAP 诱导的肝损伤。在给予 ISO-1 的小鼠肝脏中,APAP 对肝受体相互作用蛋白激酶 (RIPK)3 和热休克蛋白 70 的上调受到抑制。这些结果提供了额外的证据,即抑制 MIF 活性可能在临床上有效治疗急性 APAP 诱导的肝损伤。在给予 ISO-1 的小鼠肝脏中,APAP 对肝受体相互作用蛋白激酶 (RIPK)3 和热休克蛋白 70 的上调受到抑制。这些结果提供了额外的证据,即抑制 MIF 活性可能在临床上有效治疗急性 APAP 诱导的肝损伤。
更新日期:2021-03-01
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