Abstract：
BACKGROUND: Over-consumption of drugs can result in drug-induced liver damage (DILI), which can worsen liver failure. Numerous studies have shown the significant role ferroptosis plays in the pathophysiology of DILI, which is typified by a marked imbalance between the generation and breakdown of lipid reactive oxygen species (ROS). The content of peroxynitrite (ONOO-) rapidly increased during this process and was thought to be a significant marker of early liver injury. Therefore, the construction of fluorescence probe for the detection and imaging of ONOO- holds immense importance in the early diagnosis and treatment of ferroptosis-mediated DILI.
RESULTS: We designed a probe DILI-ONOO based on the ICT mechanism for the purpose of measuring and visualizing ONOO- in ferroptosis-mediated DILI processes and associated studies. This probe exhibited significant fluorescence changes with good sensitivity, selectivity, and can image exogenous and endogenous ONOO- in cells with low cytotoxicity. Using this probe, we were able to show changes in ONOO- content in ferroptosis-mediated DILI cells and mice models induced by the intervention of acetaminophen (APAP) and isoniazid (INH). By measuring the concentration of ferroptosis-related indicators in mice liver tissue, we were able to validate the role of ferroptosis in DILI. It is worth mentioning that compared to existing alanine transaminase (ALT) and aspartate aminotransferase (AST) detection methods, this probe can achieve early identification of DILI prior to serious liver injury.
CONCLUSIONS: This work has significant reference value in researching the relationship between ferroptosis and DILI and visualizing research. The results indicate a strong correlation between the progression of DILI and ferroptosis. Additionally, the use of DILI-ONOO shows promise in investigating the DILI process and assessing the effectiveness of medications in treating DILI.
RESULTS: We designed a probe DILI-ONOO based on the ICT mechanism for the purpose of measuring and visualizing ONOO- in ferroptosis-mediated DILI processes and associated studies. This probe exhibited significant fluorescence changes with good sensitivity, selectivity, and can image exogenous and endogenous ONOO- in cells with low cytotoxicity. Using this probe, we were able to show changes in ONOO- content in ferroptosis-mediated DILI cells and mice models induced by the intervention of acetaminophen (APAP) and isoniazid (INH). By measuring the concentration of ferroptosis-related indicators in mice liver tissue, we were able to validate the role of ferroptosis in DILI. It is worth mentioning that compared to existing alanine transaminase (ALT) and aspartate aminotransferase (AST) detection methods, this probe can achieve early identification of DILI prior to serious liver injury.
CONCLUSIONS: This work has significant reference value in researching the relationship between ferroptosis and DILI and visualizing research. The results indicate a strong correlation between the progression of DILI and ferroptosis. Additionally, the use of DILI-ONOO shows promise in investigating the DILI process and assessing the effectiveness of medications in treating DILI.
摘要：
背景：药物的过度消耗会导致药物性肝损伤（DILI），会使肝功能衰竭恶化.大量研究表明，铁死亡在DILI的病理生理学中起着重要作用，典型的是脂质活性氧（ROS）的产生和分解之间的显着失衡。过氧亚硝酸盐（ONOO-）的含量在此过程中迅速增加，被认为是早期肝损伤的重要标志。因此,用于ONOO-检测和成像的荧光探针的构建在铁凋亡介导的DILI的早期诊断和治疗中具有重要意义。
结果：我们设计了一种基于ICT机制的探针DILI-ONOO，用于在铁凋亡介导的DILI过程和相关研究中测量和可视化ONOO-。该探针表现出显著的荧光变化，具有良好的灵敏度，选择性,并能在低细胞毒性的细胞中成像外源性和内源性ONOO-。使用这个探测器，我们能够显示铁凋亡介导的DILI细胞和对乙酰氨基酚（APAP）和异烟肼（INH）干预诱导的小鼠模型中ONOO-含量的变化。通过测定小鼠肝组织中铁凋亡相关指标的浓度,我们能够验证铁细胞凋亡在DILI中的作用。值得一提的是，相比于现有的谷丙转氨酶(ALT)和谷草转氨酶(AST)检测方法，该探针可以在严重肝损伤之前实现DILI的早期识别。
结论：这项工作对研究铁中毒与DILI的关系以及可视化研究具有重要的参考价值。结果表明DILI的进展与铁死亡之间存在很强的相关性。此外,使用DILI-ONOO在研究DILI过程和评估药物治疗DILI的有效性方面显示出希望.
结果：我们设计了一种基于ICT机制的探针DILI-ONOO，用于在铁凋亡介导的DILI过程和相关研究中测量和可视化ONOO-。该探针表现出显著的荧光变化，具有良好的灵敏度，选择性,并能在低细胞毒性的细胞中成像外源性和内源性ONOO-。使用这个探测器，我们能够显示铁凋亡介导的DILI细胞和对乙酰氨基酚（APAP）和异烟肼（INH）干预诱导的小鼠模型中ONOO-含量的变化。通过测定小鼠肝组织中铁凋亡相关指标的浓度,我们能够验证铁细胞凋亡在DILI中的作用。值得一提的是，相比于现有的谷丙转氨酶(ALT)和谷草转氨酶(AST)检测方法，该探针可以在严重肝损伤之前实现DILI的早期识别。
结论：这项工作对研究铁中毒与DILI的关系以及可视化研究具有重要的参考价值。结果表明DILI的进展与铁死亡之间存在很强的相关性。此外,使用DILI-ONOO在研究DILI过程和评估药物治疗DILI的有效性方面显示出希望.
