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首页> 外文期刊>Neurotoxicity research >Non-hypoxic stabilization of hypoxia-inducible factor alpha (HIF-alpha): relevance in neural progenitor/stem cells.
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Non-hypoxic stabilization of hypoxia-inducible factor alpha (HIF-alpha): relevance in neural progenitor/stem cells.

机译:低氧诱导因子α(HIF-alpha)的非缺氧稳定:在神经祖细胞/干细胞中的相关性。

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Hypoxia-inducible factor-1 (HIF-1) plays an important role in neural progenitor cell (NPC) propagation and dopaminergic differentiation. In the presence of oxygen and iron, hypoxia-inducible factor 1 alpha (HIF-1alpha) is rapidly degraded via the prolyl hydroxylase (PHD)/VHL pathway. In addition to hypoxia, various non-hypoxic stimuli can stabilize HIF-1alpha in NPCs and influence the transcription of HIF-regulated genes. Here, we investigate various hypoxia mimetics: deferoxamine (DFO), ciclopirox olamine (CPX), dimethyloxallyl glycine (DMOG), a novel HIF-PHD inhibitor (FG-4497) and cobalt chloride (CoCl(2)) with respect to their ability to enhance in vitro proliferation, neurogenesis and dopaminergic differentiation of human fetal mesencephalic NPCs (hmNPCs) in ambient oxygen (21%). Although able to stabilize HIF-1alpha, iron chelators (DFO and CPX) and DMOG were toxic to hmNPCs. CoCl(2) was beneficial only towards neuronal and dopaminergic differentiation, while FG-4497 enhanced proliferation, neurogenesis and dopaminergic differentiation of hmNPCs. Both CoCl(2) and FG-4497 were protective to human dopaminergic neurons. Finally, exposure to hyperbaric oxygen (HBO) also stabilized HIF-1alpha in hmNPCs and induced neurogenesis in vitro. These findings suggest that several HIF stabilizing agents or conditions can rescue impaired neurons and promote neurogenesis in vitro.
机译:缺氧诱导因子-1(HIF-1)在神经祖细胞(NPC)繁殖和多巴胺能分化中起重要作用。在氧气和铁的存在下,缺氧诱导因子1α(HIF-1alpha)通过脯氨酰羟化酶(PHD)/ VHL途径迅速降解。除了缺氧外,各种非缺氧刺激还可以稳定NPC中的HIF-1alpha,并影响HIF调控基因的转录。在这里,我们研究了各种低氧模拟物:去铁胺(DFO),环吡氧胺(CPX),二甲基草烯丙基甘氨酸(DMOG),新型HIF-PHD抑制剂(FG-4497)和氯化钴(CoCl(2))以增强人类胎儿中脑NPC(hmNPC)在环境氧气(21%)中的体外增殖,神经发生和多巴胺能分化。尽管能够稳定HIF-1α,但铁螯合剂(DFO和CPX)和DMOG对hmNPC有毒。 CoCl(2)仅对神经元和多巴胺能分化有益,而FG-4497增强了hmNPC的增殖,神经发生和多巴胺能分化。 CoCl(2)和FG-4497都对人类多巴胺能神经元具有保护作用。最后,暴露于高压氧(HBO)也使hmNPC中的HIF-1alpha稳定并在体外诱导神经发生。这些发现表明,几种HIF稳定剂或条件可以挽救受损的神经元并促进体外神经发生。

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