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Nrf1 和 Nrf2 在斑马鱼胚胎发育过程中对谷胱甘肽和氧化还原动态的调节作用。

The role of Nrf1 and Nrf2 in the regulation of glutathione and redox dynamics in the developing zebrafish embryo.

机构信息

Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA.

Division of Pulmonary, Allergy/Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.

出版信息

Redox Biol. 2017 Oct;13:207-218. doi: 10.1016/j.redox.2017.05.023. Epub 2017 May 30.

Abstract

Redox signaling is important for embryogenesis, guiding pathways that govern processes crucial for embryo patterning, including cell polarization, proliferation, and apoptosis. Exposure to pro-oxidants during this period can be deleterious, resulting in altered physiology, teratogenesis, later-life diseases, or lethality. We previously reported that the glutathione antioxidant defense system becomes increasingly robust, including a doubling of total glutathione and dynamic shifts in the glutathione redox potential at specific stages during embryonic development in the zebrafish, Danio rerio. However, the mechanisms underlying these changes are unclear, as is the effectiveness of the glutathione system in ameliorating oxidative insults to the embryo at different stages. Here, we examine how the glutathione system responds to the model pro-oxidants tert-butylhydroperoxide and tert-butylhydroquinone at different developmental stages, and the role of Nuclear factor erythroid 2-related factor (Nrf) proteins in regulating developmental glutathione redox status. Embryos became increasingly sensitive to pro-oxidants after 72h post-fertilization (hpf), after which the duration of the recovery period for the glutathione redox potential was increased. To determine whether the doubling of glutathione or the dynamic changes in glutathione redox potential are mediated by zebrafish paralogs of Nrf transcription factors, morpholino oligonucleotides were used to knock down translation of Nrf1 and Nrf2 (nrf1a, nrf1b, nrf2a, nrf2b). Knockdown of Nrf1a or Nrf1b perturbed glutathione redox state until 72 hpf. Knockdown of Nrf2 paralogs also perturbed glutathione redox state but did not significantly affect the response of glutathione to pro-oxidants. Nrf1b morphants had decreased gene expression of glutathione synthesis enzymes, while hsp70 increased in Nrf2b morphants. This work demonstrates that despite having a more robust glutathione system, embryos become more sensitive to oxidative stress later in development, and that neither Nrf1 nor Nrf2 alone appear to be essential for the response and recovery of glutathione to oxidative insults.

摘要

氧化还原信号对于胚胎发生很重要,指导着决定胚胎模式形成过程的途径,包括细胞极化、增殖和凋亡。在此期间暴露于促氧化剂可能是有害的,导致生理改变、致畸、生命后期疾病或致死。我们之前报道过,谷胱甘肽抗氧化防御系统变得越来越强大,包括总谷胱甘肽增加一倍,以及在斑马鱼 Danio rerio 胚胎发育的特定阶段谷胱甘肽氧化还原电势的动态变化。然而,这些变化的机制尚不清楚,谷胱甘肽系统在不同阶段减轻胚胎氧化应激的有效性也不清楚。在这里,我们研究了谷胱甘肽系统如何在不同发育阶段对模型促氧化剂叔丁基过氧化物和叔丁基对苯二酚作出反应,以及核因子红细胞 2 相关因子(Nrf)蛋白在调节发育谷胱甘肽氧化还原状态中的作用。胚胎在受精后 72 小时(hpf)后对促氧化剂变得越来越敏感,此后谷胱甘肽氧化还原电势的恢复时间延长。为了确定谷胱甘肽的两倍增加还是谷胱甘肽氧化还原电势的动态变化是由斑马鱼 Nrf 转录因子的同源物介导的,使用了 morpholino 寡核苷酸来敲低 Nrf1 和 Nrf2(nrf1a、nrf1b、nrf2a、nrf2b)的翻译。Nrf1a 或 Nrf1b 的敲低扰乱了谷胱甘肽氧化还原状态,直到 72 hpf。Nrf2 同源物的敲低也扰乱了谷胱甘肽氧化还原状态,但对谷胱甘肽对促氧化剂的反应没有显著影响。Nrf1b 突变体的谷胱甘肽合成酶基因表达减少,而 Nrf2b 突变体的 hsp70 增加。这项工作表明,尽管具有更强大的谷胱甘肽系统,胚胎在发育后期对氧化应激变得更加敏感,而且 Nrf1 或 Nrf2 单独似乎都不是谷胱甘肽对氧化应激的反应和恢复所必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8f7/5458767/aa3bf118d5f8/gr1.jpg

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