A Fluorescent Probe for Investigating the Role of Biothiols in Signaling Pathways Associated with Cerebral Ischemia-Reperfusion Injury

一种研究生物硫醇在脑缺血-再灌注损伤相关信号通路中的作用的荧光探针

主讲人：王泳海

Angew. Chem. Int. Ed. 2023, e202310408

doi.org/10.1002/anie.202310408

Abstract:      

       Cerebral ischemia-reperfusion injury (CIRI) is intimately associated with the redox regulation of biothiol, a crucial antioxidant marker that precludes the onset of ROS. We designed a novel fluorescent probe, DCI-Ac-Py, showing various physicochemical properties, such as high selectivity, exceptional signal-to-noise ratio, near-infrared

     (NIR) optical window, and blood–brain barrier (BBB) penetrability, for detecting biothiols in the brain. The picolinate serves as a specific recognition group that is rapidly activated by biothiol and undergoes nucleophilic substitution with the adjacent acrylic ester to yield the desired NIR probe. Additionally, the probe’s lipid solubility is improved through the inclusion of halogen atoms, which aids in penetrating the BBB. Using DCI-Ac-Py, we investigated changes of biothiols in vivo in the brains of mice during CIRI. We found that biothiol-mediated NF-kB classical (P65-related) and nonclassical (RelB-related) pathways contribute to abundant ROS production induced by CIRI and that biothiols are involved in redox regulation. These findings provide new insights into the study of CIRI and shed light on the physiological and pathological mechanisms of biothiols in the brain.

摘要：

   脑缺血-再灌注损伤（CIRI）与生物硫醇的氧化还原调节密切相关，生物硫醇是阻止ROS发生的重要抗氧化标志物。我们设计了一种新型的荧光探针DCI-Ac-Py，显示了各种物理化学性质，如高选择性、异常的信噪比、近红外（NIR）光学窗口和血脑屏障（BBB）穿透性，用于检测大脑中的生物硫醇。吡啶醇酸盐作为一种特定的识别基团，可被生物硫醇快速激活，并与邻近的丙烯酸酯进行亲核取代，以产生所需的NIR探针。此外，探针通过包含卤素原子提高脂溶度，这有助于穿透血脑屏障。利用DCI-Ac-Py，我们研究了CIRI期间小鼠大脑体内生物硫醇的变化。我们发现生物硫醇介导的NF-kB经典（p65相关）和非经典（relb相关）途径有助于CIRI诱导的大量ROS产生，生物硫醇参与氧化还原调节。这些发现为CIRI的研究提供了新的见解，并阐明了大脑中生物硫醇的生理和病理机制。