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Arachidonic acid promotes glutamate-induced cell death associated with necrosis by 12-lipoxygenase activation in glioma cells

机译:花生四烯酸通过神经胶质瘤细胞中的12-脂氧合酶激活促进谷氨酸诱导的与坏死相关的细胞死亡

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摘要

Glutamate induced glutathione (GSH) depletion in C6 rat glioma cells, which resulted in cell death. This cell death seemed to be apoptosis through accumulation of reactive oxygen species (ROS) or hydroperoxides representing cytochrome c release from mitochondria and internucleosomal DNA fragmentation. A significant increase of 12-lipoxygenase enzyme activity was observed in the presence of arachidonic acid (AA) under GSH depletion induced by glutamate. AA promoted the glutamate-induced cell death, which reduced caspase-3 activity and diminished internucleosomal DNA fragmentation. Furthermore, AA reduced intracellular NAD, ATP and membrane potentials, which indicated dysfunction of the mitochondrial membrane. Protease inhibitors such as N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and 3, 4-dichloroisocumarin (DCI) but no Ac-DEVD, a caspase inhibitor, suppressed the glutamate-induced cell death. AA reduced the inhibitory effect of TPCK and DCI on the glutamate-induced cell death. These results suggest that AA promotes cell death by inducing necrosis from caspase-3-independent apoptosis. This might occur through lipid peroxidation initiated by ROS or lipid hydroperoxides generated during GSH depletion in C6 cells. (C) 2007 Published by Elsevier Inc.
机译:谷氨酸诱导C6大鼠神经胶质瘤细胞中的谷胱甘肽(GSH)耗竭,导致细胞死亡。这种细胞死亡似乎是由于活性氧(ROS)或氢过氧化物的积累引起的细胞凋亡,代表细胞色素c从线粒体释放和核小体间DNA片段化。在谷氨酸诱导的谷胱甘肽耗竭下,花生四烯酸(AA)存在下,观察到12-脂氧合酶活性显着增加。 AA促进了谷氨酸诱导的细胞死亡,从而降低了caspase-3活性并减少了核糖体间DNA片段化。此外,AA降低了细胞内NAD,ATP和膜电位,这表明线粒体膜功能异常。蛋白酶抑制剂,例如N-α-甲苯磺酰基-L-苯丙氨酸氯甲基酮(TPCK)和3,4-二氯异cumarin(DCI),但没有胱天蛋白酶抑制剂Ac-DEVD抑制谷氨酸诱导的细胞死亡。 AA降低了TPCK和DCI对谷氨酸诱导的细胞死亡的抑制作用。这些结果表明,AA通过诱导caspase-3非依赖性细胞凋亡的坏死来促进细胞死亡。这可能是由R​​OS引发的脂质过氧化或C6细胞中GSH耗竭期间产生的脂质氢过氧化物引起的。 (C)2007由Elsevier Inc.出版

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