δ-tocotrienol protects mouse and human hematopoietic progenitors from γ-irradiation through extracellular signal-regulated kinase/mammalian target of rapamycin signaling
δ-tocotrienol protects mouse and human hematopoietic progenitors from γ-irradiation through extracellular signal-regulated kinase/mammalian target of rapamycin signaling
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DOI：
10.3324/haematol.2010.026492
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发表时间：
2010-12-01
期刊：
影响因子：
--
通讯作者：
Xiao, Mang
中科院分区：
文献类型：
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作者：
Li, Xiang Hong;Fu, Dadin;Xiao, Mang
研究背景γ射线照射可引起造血细胞快速凋亡和骨髓抑制。然而，对于急性辐射综合征，没有批准的辐射对策。在这项研究中，我们证明，天然δ-生育三烯酚，维生素E的异构体之一，显着提高全身致死照射小鼠的生存。我们探讨了delta-tocotrienol对造血祖细胞存活的影响和机制后，γ射线照射在体内和体外experiments.Design和MethodsCD 2F 1小鼠和人造血祖细胞CD 34（+）细胞与delta-tocotrienol或车辆控制前24小时或6小时后γ射线照射。通过克隆形成研究、流式细胞术和骨髓组织化学染色评价δ-生育三烯酚对造血祖细胞存活和再生的影响。用免疫荧光染色、免疫印迹和短干扰RNA分析法检测δ-生育三烯酚和γ-辐射诱导的信号调节活性。单次注射δ-生育三烯酚保护100%的CD 2F 1小鼠免于全身辐射诱导的死亡，如通过辐射后30天存活率所测量的。δ-生育三烯酚增加了受辐射小鼠骨髓中造血微灶和谱系（-）/Sca-1（+）/ckit（+）干细胞和祖细胞的存活和再生，并保护人CD 34（+）细胞免受辐射诱导的损伤。δ-生育三烯酚激活细胞外信号相关激酶1/2磷酸化，并显著抑制DNA损伤标记物γ-H2 AX灶的形成。此外，δ-生育三烯酚上调雷帕霉素的哺乳动物靶标及其下游效应子4 EBP-1的磷酸化。这些改变与mRNA翻译调节因子eIF 4 E和核糖体蛋白S6的激活有关，后者负责细胞的存活和生长。通过短干扰RNA抑制细胞外信号相关激酶1/2表达消除了δ-生育三烯酚诱导的哺乳动物雷帕霉素磷酸化靶点和克隆形成，结论我们的数据表明，δ-生育三烯酚通过细胞外信号相关激酶激活保护小鼠骨髓和人CD 34+细胞免受辐射诱导的损伤。相关的哺乳动物雷帕霉素靶生存途径。
BackgroundExposure to gamma-radiation causes rapid hematopoietic cell apoptosis and bone marrow suppression. However, there are no approved radiation countermeasures for the acute radiation syndrome. In this study, we demonstrated that natural delta-tocotrienol, one of the isomers of vitamin E, significantly enhanced survival in total body lethally irradiated mice. We explored the effects and mechanisms of delta-tocotrienol on hematopoietic progenitor cell survival after gamma -irradiation in both in vivo and in vitro experiments.Design and MethodsCD2F1 mice and human hematopoietic progenitor CD34(+) cells were treated with delta-tocotrienol or vehicle control 24 h before or 6 h after gamma-irradiation. Effects of delta-tocotrienol on hematopoietic progenitor cell survival and regeneration were evaluated by clonogenicity studies, flow cytometry, and bone marrow histochemical staining. delta-tocotrienol and gamma-irradiation-induced signal regulatory activities were assessed by immunofluorescence staining, immunoblotting and short-interfering RNA assay.Resultsdelta-tocotrienol displayed significant radioprotective effects. A single injection of delta-tocotrienol protected 100% of CD2F1 mice from total body irradiation-induced death as measured by 30-day post-irradiation survival. delta-tocotrienol increased cell survival, and regeneration of hematopoietic microfoci and lineage(-)/Sca-1(+)/ckit(+) stem and progenitor cells in irradiated mouse bone marrow, and protected human CD34(+) cells from radiation-induced damage. delta-tocotrienol activated extracellular signal-related kinase 1/2 phosphorylation and significantly inhibited formation of DNA-damage marker gamma-H2AX foci. In addition, delta-tocotrienol up-regulated mammalian target of rapamycin and phosphorylation of its downstream effector 4EBP-1. These alterations were associated with activation of mRNA translation regulator eIF4E and ribosomal protein S6, which is responsible for cell survival and growth. Inhibition of extracellular signal-related kinase 1/2 expression by short interfering RNA abrogated delta-tocotrienol-induced mammalian target of rapamycin phosphorylation and clonogenicity, and increased gamma-H2AX foci formation in irradiated CD34(+) cells.ConclusionsOur data indicate that delta-tocotrienol protects mouse bone marrow and human CD34+ cells from radiation-induced damage through extracellular signal-related kinase activation-associated mammalian target of rapamycin survival pathways.