当前位置: X-MOL 学术Toxicol. Lett. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Induction of apoptosis in Ogg1-null mouse embryonic fibroblasts by GSH depletion is independent of DNA damage
Toxicology Letters ( IF 2.9 ) Pub Date : 2020-10-01 , DOI: 10.1016/j.toxlet.2020.06.019
Ellen B Higgs 1 , Roger Godschalk 2 , Nicholas J Coltman 3 , Grant S Stewart 4 , Frederik-Jan van Schooten 2 , Nikolas J Hodges 3
Affiliation  

Reactive oxygen species (ROS) within the cell are rapidly detoxified by antioxidants such as glutathione. Depletion of glutathione will therefore increase levels of intracellular ROS, which can lead to oxidative DNA damage and the induction of apoptosis. The working hypothesis was that Ogg1 null mouse embryonic fibroblasts (mOgg1-/- MEFs) would be more sensitive in response to GSH depletion due to their deficiency in the removal of the oxidative DNA modification, 8-oxo-7,8-dihydroguanine (8-oxoG). Following GSH depletion, an increase in intracellular ROS and a subsequent induction of apoptosis was measured in mOgg1-/- MEFs; as expected. Unexpectedly, an elevated basal level of ROS was identified in mOgg1-/- MEFs compared to wild type MEFs; which we suggest is partly due to the differential expression of key anti-oxidant genes. The elevated basal ROS levels in mOgg1-/- MEFs were not accompanied by a deficiency in ATP production or a large increase in 8-oxoG levels. Although 8-oxoG levels did increase following GSH depletion in mOgg1-/- MEFs; this increase was significantly lower than observed following treatment with a non-toxic dose of hydrogen peroxide. Reconstitution of Ogg1 into mOgg1-/- MEFs resulted in an increased viability following glutathione depletion, however this rescue did not differ between a repair-proficient and a repair-impaired variant of Ogg1. The data indicates that induction of apoptosis in response to oxidative stress in mOgg1-/- MEFs is independent of DNA damage and OGG1-initiated DNA repair.

中文翻译:

通过 GSH 耗竭诱导 Ogg1-null 小鼠胚胎成纤维细胞凋亡与 DNA 损伤无关

细胞内的活性氧 (ROS) 会被谷胱甘肽等抗氧化剂迅速解毒。因此,谷胱甘肽的消耗会增加细胞内 ROS 的水平,这会导致氧化性 DNA 损伤和诱导细胞凋亡。工作假设是 Ogg1 无效小鼠胚胎成纤维细胞 (mOgg1-/- MEF) 对 GSH 耗竭更敏感,因为它们缺乏去除氧化性 DNA 修饰,8-oxo-7,8-dihydroguanine (8 -oxoG)。在 GSH 耗尽后,在 mOgg1-/- MEF 中测量到细胞内 ROS 的增加和随后的细胞凋亡诱导;正如预期的那样。出乎意料的是,与野生型 MEF 相比,mOgg1-/- MEF 中 ROS 的基础水平升高;我们认为这部分是由于关键抗氧化基因的差异表达。mOgg1-/- MEF 中升高的基础 ROS 水平并未伴随着 ATP 产生不足或 8-oxoG 水平的大幅增加。尽管在 mOgg1-/- MEF 中 GSH 耗尽后 8-oxoG 水平确实增加了;这种增加明显低于用无毒剂量的过氧化氢治疗后观察到的。将 Ogg1 重组为 mOgg1-/- MEF 导致谷胱甘肽耗尽后的生存能力增加,但是这种拯救在 Ogg1 的修复熟练和修复受损变体之间没有差异。数据表明,在 mOgg1-/- MEFs 中响应氧化应激诱导细胞凋亡与 DNA 损伤和 OGG1 启动的 DNA 修复无关。尽管在 mOgg1-/- MEF 中 GSH 耗尽后 8-oxoG 水平确实增加了;这种增加明显低于用无毒剂量的过氧化氢治疗后观察到的。将 Ogg1 重组为 mOgg1-/- MEF 导致谷胱甘肽耗尽后的生存能力增加,但是这种拯救在 Ogg1 的修复熟练和修复受损变体之间没有差异。数据表明,在 mOgg1-/- MEFs 中响应氧化应激诱导细胞凋亡与 DNA 损伤和 OGG1 启动的 DNA 修复无关。尽管在 mOgg1-/- MEF 中 GSH 耗尽后 8-oxoG 水平确实增加了;这种增加明显低于用无毒剂量的过氧化氢治疗后观察到的。将 Ogg1 重组为 mOgg1-/- MEF 导致谷胱甘肽耗尽后的生存能力增加,但是这种拯救在 Ogg1 的修复熟练和修复受损变体之间没有差异。数据表明,在 mOgg1-/- MEFs 中响应氧化应激诱导细胞凋亡与 DNA 损伤和 OGG1 启动的 DNA 修复无关。然而,这种拯救在 Ogg1 的修复熟练和修复受损变体之间没有区别。数据表明,在 mOgg1-/- MEFs 中响应氧化应激诱导细胞凋亡与 DNA 损伤和 OGG1 启动的 DNA 修复无关。然而,这种拯救在 Ogg1 的修复熟练和修复受损变体之间没有区别。数据表明,在 mOgg1-/- MEFs 中响应氧化应激诱导细胞凋亡与 DNA 损伤和 OGG1 启动的 DNA 修复无关。
更新日期:2020-10-01
down
wechat
bug