Molecular Optimization of a Near-Infrared Fluorogenic Probe for Hydrogen Polysulfide Imaging in Acute Liver Injury

• Zheng Wen Wei Peng Yongzhi Qi Wenjia Zhang * Ruirui Zhai Xuejun Zhou Heng Liu*

• Fabiao Yu*

研究要点

多硫化氢（H₂Sₙ）作为关键活性硫物种，在细胞信号传导、抗氧化应激及死亡调控中发挥核心作用。揭示体内H₂Sₙ水平的动态变化对其生理功能解析至关重要，但其固有不稳定性导致实时检测面临挑战。本研究筛选出一种近红外荧光探针DCICl-H₂Sₙ，用于细胞和小鼠模型中H₂Sₙ的检测。该探针采用邻位硝基取代苯磺酸酯修饰的二氰基异佛尔酮骨架，赋予其优异的光物理特性及对H₂Sₙ的高特异性。当与H₂Sₙ反应时，DCICl-H₂Sₙ在675 nm波长处产生荧光"开启"信号。凭借其卓越的光学性能，该探针实现了活细胞外源性与内源性H₂Sₙ水平变化的动态监测。基于DCICl-H₂Sₙ，我们探究了对乙酰氨基酚（APAP）或四氯化碳（CCl₄）诱导的急性肝损伤（ALI）小鼠模型中H₂Sₙ的作用。结果表明H₂Sₙ水平与肝损伤严重程度呈负相关，提示其可作为评估ALI严重程度的潜在生物标志物。此外，口服水飞蓟宾（SLB）显著减轻肝损伤并上调H₂Sₙ水平。本研究所开发的DCICl-H₂Sₙ探针被证实为研究H₂Sₙ动态变化的有效工具，有助于揭示肝损伤的分子机制。

Abstract

Hydrogen polysulfides (H2Sn), a key reactive sulfur species, play pivotal roles in cellular signaling, antioxidative stress, and cell death regulation. Revealing the dynamic changes of H2Sn levels in vivo is crucial for elucidating its physiological functions. However, real-time detection of H2Sn in vivo faces significant challenges due to its inherent instability. In this study, we screened a near-infrared fluorogenic (NIRF) probe DCICl-H2Sn for the detection of H2Sn in cells and mice models. This probe employed a dicyanoisophorone scaffold functionalized with ortho-NO2 substituted phenyl sulfonate groups, which endowed it with exceptional photophysical properties and high specificity toward H2Sn. Upon reaction with H2Sn, DCICl-H2Sn emitted a fluorescent “turn-on” signal at 675 nm. Benefiting from its excellent optical properties, DCICl-H2Sn enabled monitoring of both exogenous and endogenous H2Sn level changes in live cells. Leveraging DCICl-H2Sn, we explored the role of H2Sn in APAP or CCl4-induced acute liver injury (ALI) mice models. The results revealed a negative correlation between H2Sn levels and the severity of liver injury, suggesting that H2Sn could be used as a potential biomarker for assessing the severity of ALI. Moreover, oral administration of silybin (SLB) significantly reduced liver injury and up-regulated H2Sn levels. The present probe DCICl-H2Sn proved to be an effective tool for investigating the dynamic changes of H2Sn, which could help to uncover the molecular mechanisms of liver injury.

原文链接：https://pubs.acs.org/doi/10.1021/acs.analchem.5c00931

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