The multiple mechanisms and modes of cell death after acetaminophen overdose.

Exploration of digestive diseases Pub Date : 2025-01-01 Epub Date: 2025-04-07 DOI:10.37349/edd.2025.100569
Hartmut Jaeschke, Anup Ramachandran
{"title":"The multiple mechanisms and modes of cell death after acetaminophen overdose.","authors":"Hartmut Jaeschke, Anup Ramachandran","doi":"10.37349/edd.2025.100569","DOIUrl":null,"url":null,"abstract":"<p><p>Acetaminophen (APAP)-induced liver injury and acute liver failure is a significant clinical problem worldwide; in addition, APAP overdoses in animals or in cell culture are used as popular models to study drug-induced liver injury mechanisms and test therapeutic interventions. Early assumptions that APAP toxicity is caused by a single mechanism resulting in a defined mode of cell death in hepatocytes had to be questioned when over the years many different mechanisms and modes of cell death were reported. Although many of the contradictory results and conclusions reported over the years can be attributed to lack of understanding of established mechanisms, methodological problems, and misinterpretation of data, it is increasingly recognized that some of the reported differences in signaling mechanisms and even a switch in the mode of cell death can be caused by variations in the experimental conditions. In this review, examples will be discussed how experimental conditions (dose, solvent, etc.), the experimental system (species, strain, and substrain in vivo, cell type, and in vitro conditions), and also adaptive responses and off-target effects of genetic manipulations and chemical interventions, can impact the mechanisms of cell death. Given that the conditions will determine the results, it is therefore of critical importance to keep in mind the translational aspect of the experiments, i.e., the conditions relevant to the human pathophysiology. Only the full appreciation of these issues will lead to reproducible and clinically relevant results that advance our understanding of all facets of the human pathophysiology and identify clinically relevant therapeutic targets.</p>","PeriodicalId":520511,"journal":{"name":"Exploration of digestive diseases","volume":"4 ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12074662/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Exploration of digestive diseases","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.37349/edd.2025.100569","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/7 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Acetaminophen (APAP)-induced liver injury and acute liver failure is a significant clinical problem worldwide; in addition, APAP overdoses in animals or in cell culture are used as popular models to study drug-induced liver injury mechanisms and test therapeutic interventions. Early assumptions that APAP toxicity is caused by a single mechanism resulting in a defined mode of cell death in hepatocytes had to be questioned when over the years many different mechanisms and modes of cell death were reported. Although many of the contradictory results and conclusions reported over the years can be attributed to lack of understanding of established mechanisms, methodological problems, and misinterpretation of data, it is increasingly recognized that some of the reported differences in signaling mechanisms and even a switch in the mode of cell death can be caused by variations in the experimental conditions. In this review, examples will be discussed how experimental conditions (dose, solvent, etc.), the experimental system (species, strain, and substrain in vivo, cell type, and in vitro conditions), and also adaptive responses and off-target effects of genetic manipulations and chemical interventions, can impact the mechanisms of cell death. Given that the conditions will determine the results, it is therefore of critical importance to keep in mind the translational aspect of the experiments, i.e., the conditions relevant to the human pathophysiology. Only the full appreciation of these issues will lead to reproducible and clinically relevant results that advance our understanding of all facets of the human pathophysiology and identify clinically relevant therapeutic targets.

对乙酰氨基酚过量后细胞死亡的多种机制和模式。
对乙酰氨基酚(APAP)引起的肝损伤和急性肝衰竭是世界范围内重要的临床问题;此外,动物或细胞培养中APAP过量被用作研究药物性肝损伤机制和测试治疗干预措施的流行模型。早期的假设是APAP毒性是由单一机制引起的,导致肝细胞的一种确定的细胞死亡模式,但随着多年来许多不同的细胞死亡机制和模式的报道,这一假设受到了质疑。尽管多年来报道的许多相互矛盾的结果和结论可归因于缺乏对既定机制的理解、方法问题和对数据的误解,但人们越来越认识到,一些报道的信号传导机制差异,甚至细胞死亡模式的转换,可能是由实验条件的变化引起的。在这篇综述中,将讨论实验条件(剂量,溶剂等),实验系统(物种,菌株和亚菌株在体内,细胞类型和体外条件),以及遗传操作和化学干预的适应性反应和脱靶效应如何影响细胞死亡机制。鉴于条件将决定结果,因此牢记实验的转化方面至关重要,即与人类病理生理学相关的条件。只有充分认识到这些问题,才能得到可重复的和临床相关的结果,从而促进我们对人类病理生理学各个方面的理解,并确定临床相关的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信