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Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis
ACS Central Science ( IF 12.7 ) Pub Date : 2018-02-07 00:00:00 , DOI: 10.1021/acscentsci.7b00589
Ron Shah 1 , Mikhail S. Shchepinov 2 , Derek A. Pratt 1
Affiliation  

Lipoxygenases (LOXs) have been implicated as central players in ferroptosis, a recently characterized cell death modality associated with the accumulation of lipid hydroperoxides: the products of LOX catalysis. To provide insight on their role, human embryonic kidney cells were transfected to overexpress each of the human isoforms associated with disease, 5-LOX, p12-LOX, and 15-LOX-1, which yielded stable cell lines that were demonstrably sensitized to ferroptosis. Interestingly, the cells could be rescued by less than half of a diverse collection of known LOX inhibitors. Furthermore, the cytoprotective compounds were similarly potent in each of the cell lines even though some were clearly isoform-selective LOX inhibitors. The cytoprotective compounds were subsequently demonstrated to be effective radical-trapping antioxidants, which protect lipids from autoxidation, the autocatalytic radical chain reaction that produces lipid hydroperoxides. From these data (and others reported herein), a picture emerges wherein LOX activity may contribute to the cellular pool of lipid hydroperoxides that initiate ferroptosis, but lipid autoxidation drives the cell death process.

中文翻译:

解决脂氧合酶在启动和执行肥大症中的作用

脂氧合酶(LOXs)已被认为是促发症的主要参与者,促发症是最近表征的与脂质氢过氧化物积累相关的细胞死亡方式:LOX催化的产物。为了深入了解其作用,人类胚胎肾细胞被转染以过表达与疾病,5-LOX,p12-LOX和15-LOX-1相关的每种人类同工型,产生了稳定的细胞系,该细胞系被证明对肥育症敏感。有趣的是,这些细胞可以被多种多样的已知LOX抑制剂的不到一半拯救。此外,尽管某些细胞显然是同工型选择性LOX抑制剂,但细胞保护化合物在每种细胞系中的作用均相似。细胞保护化合物随后被证明是有效的自由基捕获抗氧化剂,可以保护脂质免受自氧化作用,即产生脂质氢过氧化物的自催化自由基链反应。从这些数据(以及本文中报告的其他数据)中,可以看到一张图片,其中LOX活动可能有助于启动肥大病的脂质氢过氧化物的细胞池,但脂质自氧化作用会驱动细胞死亡过程。
更新日期:2018-02-07
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