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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

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Title: Protective effect of ISO-1 with inhibition of RIPK3 up-regulation and neutrophilic accumulation on acetaminophen-induced liver injury in mice
Authors: Ohkawara, Tatsuya Browse this author →KAKEN DB
Okubo, Naoto Browse this author →KAKEN DB
Maehara, Osamu Browse this author →KAKEN DB
Nishihira, Jun Browse this author
Takeda, Hiroshi Browse this author →KAKEN DB
Keywords: Acetaminophen
Macrophage migration inhibitory factor
Liver injury
Issue Date: 15-Mar-2021
Publisher: Elsevier
Journal Title: Toxicology letters
Volume: 339
Start Page: 51
End Page: 59
Publisher DOI: 10.1016/j.toxlet.2020.12.015
Abstract: 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)-4,5dihydro-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 h (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. (C) 2020 Elsevier B.V. All rights reserved.
Rights: ©2021. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 武田 宏司

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