Ratiometric Fluorescent Sensors Illuminate Cellular Magnesium Imbalance in a Model of Acetaminophen-Induced Liver Injury.
Ratiometric Fluorescent Sensors Illuminate Cellular Magnesium Imbalance in a Model of Acetaminophen-Induced Liver Injury.
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DOI：
10.1021/jacs.3c05704
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发表时间：
2023-10-11
影响因子：
15
通讯作者：
Buccella, Daniela
中科院分区：
文献类型：
--
作者：
Brady, Michael;Shchepetkina, Veronika I.;Gonzalez-Recio, Irene;Martinez-Chantar, Maria L.;Buccella, Daniela
镁(II)在生物体中起着催化、结构、调节和信号传递的作用。这种金属的异常水平与许多病理疾病有关，包括心血管疾病、糖尿病、代谢综合征、免疫缺陷、癌症，以及最近影响人类的肝脏病理。然而，镁在肝病病理生理学中的作用已被干扰二价阳离子(如钙离子)浓度的伴随变化所遮挡，这使得用现有的分子镁指示剂进行实验的解释复杂化。在这里，我们介绍了一种新的基于喹啉的荧光传感器MagZet1，它的激发和发射波长发生了变化，可以通过荧光显微镜和流式细胞仪对细胞内的镁离子进行比率检测。这种新型传感器将目标金属与亚毫米级的离解常数结合在一起，非常适合于检测细胞内游离镁离子的变化，并对钙离子显示出10倍的选择性。此外，荧光比率对生理范围内的pH变化不敏感，提供了优于现有指示剂的总体性能。我们提供了基于计算模型的新传感器的金属选择性分布的见解，并将其应用于阐明在对乙酰氨基酚过量引起的药物诱导肝损伤的细胞模型中细胞内游离镁离子的减少和金属转运体表达的变化。
Magnesium(II) plays catalytic, structural, regulatory, and signaling roles in living organisms. Abnormal levels of this metal have been associated with numerous pathologies, including cardiovascular disease, diabetes, metabolic syndrome, immunodeficiency, cancer, and, most recently, liver pathologies affecting humans. The role of Mg2+ in the pathophysiology of liver disease, however, has been occluded by concomitant changes in concentration of interfering divalent cations, such as Ca2+, which complicates the interpretation of experiments conducted with existing molecular Mg2+ indicators. Herein, we introduce a new quinoline-based fluorescent sensor, MagZet1, that displays a shift in its excitation and emission wavelengths, affording ratiometric detection of cellular Mg2+ by both fluorescence microscopy and flow cytometry. The new sensor binds the target metal with a submillimolar dissociation constant—well suited for detection of changes in free Mg2+ in cells—and displays a 10-fold selectivity against Ca2+. Furthermore, the fluorescence ratio is insensitive to changes in pH in the physiological range, providing an overall superior performance over existing indicators. We provide insights into the metal selectivity profile of the new sensor based on computational modeling, and we apply it to shed light on a decrease in cytosolic free Mg2+ and altered expression of metal transporters in cellular models of drug-induced liver injury caused by acetaminophen overdose.
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影响因子：
3.8
作者：
Li, Mingjiang;Jiang, Jianmin;Yue, Lixia
通讯作者：
Yue, Lixia
影响因子：
5.9
作者：
Fiorentini D;Cappadone C;Farruggia G;Prata C
通讯作者：
Prata C
影响因子：
3.8
作者：
Bajt, ML;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
DOI：
10.1107/s0567740881005037
发表时间：
1981-01-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE
影响因子：
--
作者：
EINSPAHR, H;BUGG, CE
通讯作者：
BUGG, CE
影响因子：
15
作者：
Komatsu, H;Iwasawa, N;Suzuki, K
通讯作者：
Suzuki, K