Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, Tikhoretskii pr. 4, 194064 St. Petersburg, Russia.
Higher Engineering Physics School of the Institute of Physics, Nanotechnology and Telecommunications, Peter the Great St. Petersburg Polytechnic University, Polytechnicheskaya St. 29, 195251 St. Petersburg, Russia.
Int J Mol Sci. 2021 Oct 31;22(21):11851. doi: 10.3390/ijms222111851.
In our previous study, we found that high doses of several substances with antioxidant capacities (Tempol, resveratrol, diphenyleneiodonium) can cause genotoxic stress and induce premature senescence in the human mesenchymal stem cells (MSCs). Here, using whole-transcriptome analysis, we revealed the signs of endoplasmic reticulum stress and unfolded protein response (UPR) in MSCs stressed with Tempol and resveratrol. In addition, we found the upregulation of genes, coding the UPR downstream target APC/C, and E3 ubiquitin ligase that regulate the stability of cell cycle proteins. We performed the molecular analysis, which further confirmed the untimely degradation of APC/C targets (cyclin A, geminin, and Emi1) in MSCs treated with antioxidants. Human fibroblasts responded to antioxidant applications similarly. We conclude that endoplasmic reticulum stress and impaired DNA synthesis regulation can be considered as potential triggers of cell damage and premature senescence stimulated by high-dose antioxidant treatments.
在我们之前的研究中，我们发现高剂量的几种具有抗氧化能力的物质（Tempol、白藜芦醇、二苯乙烯碘）会导致人骨髓间充质干细胞（MSCs）产生遗传毒性应激并诱导其过早衰老。在这里，我们通过全转录组分析，揭示了 Tempol 和白藜芦醇处理的 MSCs 中内质网应激和未折叠蛋白反应（UPR）的迹象。此外，我们发现了 UPR 下游靶标 APC/C 和 E3 泛素连接酶的基因上调，这些基因调节细胞周期蛋白的稳定性。我们进行了分子分析，进一步证实了抗氧化剂处理的 MSC 中 APC/C 靶标（细胞周期蛋白 A、geminin 和 Emi1）的非适时降解。人成纤维细胞对抗氧化剂的应用也有类似的反应。我们的结论是，内质网应激和受损的 DNA 合成调节可以被认为是由高剂量抗氧化剂治疗刺激的细胞损伤和过早衰老的潜在触发因素。
