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首页> 外文期刊>Medical Gas Research >ACS6, a Hydrogen sulfide-donating derivative of sildenafil, inhibits homocysteine-induced apoptosis by preservation of mitochondrial function
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ACS6, a Hydrogen sulfide-donating derivative of sildenafil, inhibits homocysteine-induced apoptosis by preservation of mitochondrial function

机译：西地那非的硫化氢供体衍生物ACS6通过保持线粒体功能抑制同型半胱氨酸诱导的细胞凋亡

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Background The hydrogen sulfide-releasing sildenafil, ACS6, has been demonstrated to inhibit superoxide formation through donating hydrogen sulfide (H2S). We have found that H2S antagonizes homocysteine-induced oxidative stress and neurotoxicity. The aim of the present study is to explore the protection of ACS6 against homocysteine-triggered cytotoxicity and apoptosis and the molecular mechanisms underlying in PC12 cells. Methods Cell viability was determined by Cell Counting Kit-8 assay. Cell apoptosis was observed using the chromatin dye Hoechst 33258 and analyzed by Flow Cytometry after propidium iodide staining. Mitochondrial membrane potential was monitored using the fluorescent dye Rh123. Intracellular reactive oxygen species were determined by oxidative conversion of cell permeable 2',7'-dichlorfluorescein-diacetate to fluorescent 2',7'-dichlorfluorescein. The expression of cleaved caspase-3 and bcl-2 and the accumulation of cytosolic cytochrome c were analyzed by Western blot. Results We show that ACS6 protects PC12 cells against cytotoxicity and apoptosis induced by homocysteine and blocks homocysteine-triggered cytochrome c release and caspase-3 activation. ACS6 treatment results in not only prevention of homocysteine-caused mitochondrial membrane potential (Δψ) loss and reactive oxygen species (ROS) overproduction but also reversal of Bcl-2 down-expression. Conclusions These results indicate that ACS6 protects PC12 cells against homocysteine-induced cytotoxicity and apoptosis by preservation of mitochondrial function though inhibiting both loss of Δψ and accumulation of ROS as well as modulating the expression of Bcl-2. Our study provides evidence both for a neuroprotective effect of ACS6 and for further evaluation of ACS6 as novel neuroprotectants for Alzheimer's disease associated with homocysteine.
机译：背景技术已经证明，释放硫化氢的西地那非ACS6可通过捐赠硫化氢（H 2 S）抑制超氧化物的形成。我们发现H 2 S拮抗高半胱氨酸诱导的氧化应激和神经毒性。本研究的目的是探讨ACS6对高半胱氨酸触发的细胞毒性和凋亡的保护作用以及PC12细胞中潜在的分子机制。方法用Cell Counting Kit-8法测定细胞活力。使用染色质染料Hoechst 33258观察细胞凋亡，并在碘化丙锭染色后通过流式细胞术进行分析。使用荧光染料Rh123监测线粒体膜电位。通过将细胞可渗透的2'，7'-二氯荧光素-二乙酸酯氧化转化为荧光2'，7'-二氯荧光素来确定细胞内活性氧种类。通过Western印迹分析裂解的caspase-3和bcl-2的表达以及胞浆细胞色素c的积累。结果我们表明，ACS6保护PC12细胞免受高半胱氨酸诱导的细胞毒性和凋亡，并阻止高半胱氨酸触发的细胞色素c释放和caspase-3活化。 ACS6处理不仅可以预防高半胱氨酸引起的线粒体膜电位（Δψ）损失和活性氧（ROS）过量产生，而且还可以逆转Bcl-2下表达。结论这些结果表明，ACS6通过保持线粒体功能，同时抑制Δψ的丢失和ROS的积累以及调节Bcl-2的表达，保护PC12细胞免受高半胱氨酸诱导的细胞毒性和细胞凋亡。我们的研究为ACS6的神经保护作用以及对ACS6作为与高半胱氨酸相关的阿尔茨海默氏病的新型神经保护剂的进一步评估提供了证据。

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