A ROS-responsive, self-immolative and self-reporting hydrogen sulfide donor with multiple biological activities for the treatment of myocardial infarction.
A ROS-responsive, self-immolative and self-reporting hydrogen sulfide donor with multiple biological activities for the treatment of myocardial infarction.
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DOI：
10.1016/j.bioactmat.2021.07.011
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发表时间：
2022-03
影响因子：
18.9
通讯作者：
Zhang N
中科院分区：
文献类型：
--
作者：
Yao M;Lu Y;Shi L;Huang Y;Zhang Q;Tan J;Hu P;Zhang J;Luo G;Zhang N
心肌梗死（MI）是全球死亡的主要原因之一，迫切需要有效的治疗。近年来，硫化氢（H2S）被认为是一种有前途的心肌梗死治疗药物，但其时空控制递送仍然是限制临床转化的主要问题。为了解决这一限制，我们设计并合成了一种新的H2S供体（HSD-R），它可以产生H2S并响应于在病变部位高度表达的活性氧（ROS）而发射荧光。HSD-R可以特异性靶向线粒体，并提供红色荧光，以可视化和定量体外和体内H2S释放。在治疗上，HSD-R显著促进大鼠MI模型的心脏结构和功能的重建。从机制上讲，心肌保护是通过减少心肌细胞凋亡、减轻局部炎症和促进血管生成来实现的。此外，抑制典型的促凋亡基因（Bid、Apaf-1和p53）在HSD-R抗凋亡作用中发挥重要作用，从而实现心肌保护，这些基因被确定为H2S抗心肌缺血损伤的新治疗靶点。这种ROS响应性、自分解性和荧光H2S供体可以作为MI和其他缺血性疾病的新的治疗诊断剂。开发了一种活性氧响应和自报告H2S供体（HSD-R）用于受控H2S递送。HSD-R显示出理想的荧光，用于在由活性氧物质触发时对H2S释放进行成像。HSD-R在大鼠中显示出显著的心脏保护作用。HSD-R具有多种生物活性，包括抗凋亡、抗炎和促血管生成作用。HSD-R的抗凋亡活性是由于抑制几种促凋亡因子的表达。
Myocardial infarction (MI), as one of the leading causes of global death, urgently needs effective therapies. Recently, hydrogen sulfide (H2S) has been regarded as a promising therapeutic agent for MI, while its spatiotemporally controlled delivery remains a major issue limiting clinical translation. To address this limitation, we designed and synthesized a novel H2S donor (HSD-R) that can produce H2S and emit fluorescence in response to reactive oxygen species (ROS) highly expressed at diseased sites. HSD-R can specifically target mitochondria and provide red fluorescence to visualize and quantify H2S release in vitro and in vivo. Therapeutically, HSD-R significantly promoted the reconstruction of cardiac structure and function in a rat MI model. Mechanistically, myocardial protection is achieved by reducing cardiomyocyte apoptosis, attenuating local inflammation, and promoting angiogenesis. Furthermore, inhibition of typical pro-apoptotic genes (Bid, Apaf-1, and p53) played an important role in the anti-apoptotic effect of HSD-R to achieve cardioprotection, which were identified as new therapeutic targets of H2S against myocardial ischemia injury. This ROS-responsive, self-immolative, and fluorescent H2S donor can serve as a new theranostic agent for MI and other ischemic diseases. A reactive oxygen species-responsive and self-reporting H2S donor (HSD-R) is developed for controlled H2S delivery. HSD-R shows desirable fluorescence for imaging H2S release upon triggering by reactive oxygen species. HSD-R displays significant cardioprotective effects in rats. HSD-R exhibits multiple biological activities including anti-apoptotic, anti-inflammatory, and pro-angiogenic effects. Anti-apoptotic activity of HSD-R is due to inhibiting the expression of several pro-apoptotic factors.
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影响因子：
37.8
作者：
Calvert JW;Elston M;Nicholson CK;Gundewar S;Jha S;Elrod JW;Ramachandran A;Lefer DJ
通讯作者：
Lefer DJ
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
通过近红外荧光探针对药物性肝损伤和肝癌中亮氨酸氨肽酶活性进行体内成像
影响因子：
8.4
作者：
He X;Li L;Fang Y;Shi W;Li X;Ma H
通讯作者：
Ma H
影响因子：
28.1
作者：
Hu S;Li Z;Shen D;Zhu D;Huang K;Su T;Dinh PU;Cores J;Cheng K
通讯作者：
Cheng K
DOI：
10.1073/pnas.0705891104
发表时间：
2007-09-25
影响因子：
11.1
作者：
Elrod, John W.;Calvert, John W.;Lefer, David J.
通讯作者：
Lefer, David J.