Dual-Colored Fluorescence Imaging of Mitochondrial HNO and Golgi-HNO in Mice with DILI
Dual-Colored Fluorescence Imaging of Mitochondrial HNO and Golgi-HNO in Mice with DILI
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DOI：
10.1021/acs.analchem.1c00742
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发表时间：
2021-04-13
影响因子：
7.4
通讯作者：
Tang, Bo
中科院分区：
文献类型：
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作者：
Wang, Hui;Liu, Cuifang;Tang, Bo
药物性肝损伤（DILI）是药物上市后停药的最常见原因。对 DILI 机制的了解不足给临床诊断带来了巨大的挑战。先前的证据表明活性氮 (RNS) 与 DILI 之间存在潜在关系。因此，我们开发了两种特异性探针 Golgi-HNO 和 Mito-HNO，分别用于高尔基体和线粒体中硝酰基 (HNO) 的多色同步原位成像。我们发现 DILI 小鼠肝脏中 HNO 水平显着升高，这意味着我们首次揭示了 HNO 水平与 DILI 之间的正相关性。根据HNO水平的变化，我们还成功探索了抗癌剂博莱霉素引起的肝损伤程度。此外，我们还发现过氧化氢酶参与HNO的合成，这是过氧化氢酶前所未有的功能。这些发现表明，HNO是DILI诊断的理想生物标志物，Golgi-HNO和Mito-HNO是研究各种生理生化过程中原位HNO变化的理想荧光探针。
Drug-induced liver injury (DILI) is the most common reason for the post-marketing withdrawal of drugs. Poor understanding of the mechanisms of DILI presents a large challenge in clinical diagnosis. Previous evidences indicate a potential relationship between reactive nitrogen species (RNS) and DILI. Hence, we developed two specific probes, Golgi-HNO and Mito-HNO, for the multicolored and simultaneous in situ imaging of nitroxyl (HNO) in the Golgi apparatus and mitochondria, respectively. We discovered a significant rise in HNO levels in the livers of mice with DILI, which means that for the first time, we revealed a positive correlation between HNO levels and DILI. Based on changes in the HNO level, we also successfully explored the extent of liver damage induced by an anticarcinogen, bleomycin. In addition, we uncovered catalase was involved in HNO synthesis, which is the unprecedented function of catalase. These findings demonstrate that HNO is an ideal biomarker for DILI diagnosis, and Golgi-HNO and Mito-HNO are ideal fluorescent probes to study in situ HNO changes in various physiological and biochemical processes.