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首页> 外文期刊>Journal of Neuroscience Research >Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF-kappaB, and MAP kinases.
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Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF-kappaB, and MAP kinases.

机译：吡咯烷二硫代氨基甲酸酯对神经元细胞活力的新型双相效应是由细胞内锌和铜离子水平，NF-κB和MAP激酶的差异调节介导的。

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摘要

Nuclear factor kappaB (NF-kappaB) is a transcription factor involved in the expression of a wide range of genes, most of which code for proteins that play a role in immunity and inflammation. Pyrrolidine dithiocarbamate (PDTC) is a well-known inhibitor of NF-kappaB. Although its mechanism of action is conferred by its antioxidant property, other mechanisms by which PDTC can act as a prooxidant, metal chelator, and free thiol group modulator have recently been suggested. Here we report that PDTC caused a dual effect on cell viability in neuronal rat pheochromocytoma (PC12) cells, depending on its concentration. Increase of intracellular zinc and copper ion levels selectively potentiated the cytotoxic PDTC effect in a dose-dependent manner, and thiol reagents, such as glutathione and N-acetylcysteine, as well as divalent metal-chelating reagents, such as EDTA and bathocuproline disulfonic acid, blocked its cell death effect. The differential effect of PDTC on cell viability correlates well with the inhibition of NF-kappaB activities. In addition, PDTC differentially activated microtubule-associated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), but not p38, depending on its dose, and the coaddition of glutathione (GSH), other antioxidants, and metal ions also modulated their activities. Furthermore, stable Bcl-2 expression blocked the PDTC-induced cell death. These results suggest that the thiol groups and free zinc and copper ion levels are important for the novel biphasic PDTC effect on cell viability, which is associated with the differential activation of NF-kappaB and MAP kinases.
机译：核因子κB（NF-kappaB）是一种转录因子，涉及多种基因的表达，其中大多数编码在免疫和炎症中起作用的蛋白质。吡咯烷二硫代氨基甲酸酯（PDTC）是一种众所周知的NF-κB抑制剂。尽管其作用机理是由其抗氧化性能赋予的，但最近有人提出了PDTC可以用作抗氧化剂，金属螯合剂和游离硫醇基调节剂的其他机理。在这里我们报告PDTC取决于其浓度对神经元大鼠嗜铬细胞瘤（PC12）细胞中的细胞活力造成双重影响。细胞内锌和铜离子水平的升高以剂量依赖的方式选择性增强了细胞毒性PDTC的作用，硫醇试剂（如谷胱甘肽和N-乙酰半胱氨酸）以及二价金属螯合剂（如EDTA和浴丁二氢二磺酸）阻止了其细胞死亡效应。 PDTC对细胞生存力的差异作用与抑制NF-κB活性密切相关。此外，PDTC差异激活微管相关蛋白（MAP）激酶，例如细胞外信号调节激酶（ERK），c-Jun N端激酶（JNK），但不依赖p38，具体取决于其剂量和谷胱甘肽（GSH），其他抗氧化剂和金属离子也调节了它们的活性。此外，稳定的Bcl-2表达阻止了PDTC诱导的细胞死亡。这些结果表明，巯基和游离的锌和铜离子水平对于新的双相PDTC对细胞生存力的影响很重要，这与NF-κB和MAP激酶的差异激活有关。

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