姜黄素对氧化损伤的小鼠脑神经瘤细胞的保护作用研究
摘要
活性氧诱导的氧化应激已被证实与神经退行性疾病的发病机理密切相关。姜黄素是一种从姜科植物中提取的天然多酚类抗氧化物质。目前国内外关于姜黄素对氧化损伤神经元细胞的保护作用的报道比较少,其作用机理,尤其是细胞水平的机理也不是很清楚。在本研究中,利用H_2O_2诱导氧化损伤的小鼠脑神经瘤细胞Neuro-2A模型探讨姜黄素的神经保护作用及其机理。
将Neuro-2A细胞接种到细胞培养板中,37℃培养过夜,不同浓度姜黄素预孵育1 h,继而30μmol/L H_2O_2作用24 h。细胞存活率的测定采用MTT法,结果显示25μg/ml姜黄素预孵育1 h可使30μmol/L H_2O_2处理24 h后的细胞存活率提高8.5%;细胞凋亡的检测使用核染色法,结果显示姜黄素可显著抑制H_2O_2诱导的Neuro-2A细胞凋亡,姜黄素预孵育1 h可使细胞凋亡率下降15.1%;细胞内总抗氧化能力的测定采用比色法,结果显示25μg/ml姜黄素能够使细胞内总抗氧化能力提高15.9%。应用流式细胞术研究细胞内ROS堆积、线粒体跨膜电位崩塌以及胞外钙离子内流情况,结果显示姜黄素能够抑制细胞内ROS过量生成和胞外钙离子内流,同时可使罗丹明123阴性细胞数比例降低11.81%,即有助于维持正常的线粒体跨膜电位;抗凋亡蛋白表达水平的检测采用Western blot法,结果显示预孵育25μg/ml姜黄素1 h可提高抗凋亡蛋白PARP和Bcl-2的表达量,与H_2O_2处理组相比,这两种蛋白在细胞内的含量分别提高了12.1%和12.0%;Western blot法与胞浆/胞核蛋白分离法结合用来检测细胞内与凋亡及炎症反应相关的NF-κB信号通路的激活情况,发现姜黄素能够抑制H_2O_2引起的IκBα降解,进而阻止NF-κB激活,因此抑制其下游目的基因COX-2的表达,与H_2O_2处理组相比,25μg/ml姜黄素预孵育1 h可使细胞内IκBα含量提高34.3%,抑制NF-κB活化及进入细胞核,进而使得炎症因子COX-2表达量降低31.0%。
总而言之,本研究发现姜黄素对H_2O_2诱导氧化损伤的Neuro-2A细胞具有显著的保护效应。具体的作用机理包括增强细胞内源性总抗氧化能力、抑制ROS堆积、维持正常的线粒体跨膜电位和胞内外钙离子稳态、提高抗凋亡蛋白的表达量,以及阻止NF-κB信号通路的激活。本研究显示姜黄素在与氧化应激有关的神经退行性疾病的预防和治疗中具有潜在的应用前景。
Neurodegenerative disorders are strongly connected with oxidative stress, which is caused by reactive oxygen species (ROS). Curcumin is a natural polyphenol antioxidant extracted from Curcuma longa. Yet until now, there are still few researches focused on the neuroprotective effects of curcumin and its underlying mechanisms have not been fully defined, especially at cellular level. In current study, H_2O_2-induced oxidative stress model in mouse neuroblastoma Neuro-2A cells was employed to research the neuroprotective effects and its potential mechanisms of curcumin.
Neuro-2A cells were seeded into culture plates, cultured overnight at 37℃, and pretreated with curcumin at different concentrations for 1 h before 30μmol/L H_2O_2 exposure for 24 h. Cell viability was measured by MTT assay, and result showed that pretreatment with 25μg/ml curcumin for 1 h enhanced the percentage of viable cells by 8.5%. Cell apoptosis was assessed by nuclear staining, and result showed that the proportion of apoptotic cells was decreased by 15.1%, which indicated that curcumin could inhibit H_2O_2-induced apoptosis in Neuro-2A cells. The level of intracellular total antioxidant capacity, which was determined by colorimetric method, was boosted by 15.9% in 25μg/ml curcumin-pretreated group. Intracellular ROS accumulation, mitochondrial membrane potential loss, and Ca2+ influx were tested by flow cytometry, and results displayed that curcumin could be effect to suppress the augmentation of ROS level and intracellular calcium induced by H_2O_2, furthermore, curcumin also reduced the percentage of the Rhodamine 123 negative cells by 11.81%, which suggested that curcumin is conducive to inhibit the loss of mitochondrial membrane potential. The levels of two antiapoptotic proteins, poly(ADP-ribose) polymerase (PARP) and B cell lymphoma/lewkmia-2 (Bcl-2), which were measured by western blot analysis, were enhanced by 12.1%, and 12.0%, respectively, through pretreating with 25μg/ml curcumin for 1 h. In addition, nuclear and cytoplasmic protein extraction method, combined with western blot analysis, was applied to examine the activation of Nuclear factor-κ-gene binding (NF-κB) signaling pathway which is related to apoptosis and inflammation, and curcumin was found to block H_2O_2-mediate degradation of IκBαwhich was increased by 34.3%, and subsequent activation and relocation of NF-κB, thus inhibit the expression of its target gene Cyclooxygenase-2 (COX-2) which was decreased by 31.0%.
In a word, the results of our study suggested that curcumin could significantly protect Neuro-2A cells against oxidative damage induced by H_2O_2. The specific neuroprotective mechanisms of curcumin included reinforcing the endogenous total antioxidant capacity, suppressing intracellular ROS accumulation, maintaining normal mitochondrial membrane potential and calcium homeostasis, improving the expression of antiapoptotic proteins, as well as blocking the activation of NF-κB signaling pathway. Taken together, we speculated that curcumin has great potential for preventing and treating the neurodegenerative diseases associated with oxidative stress.
将Neuro-2A细胞接种到细胞培养板中,37℃培养过夜,不同浓度姜黄素预孵育1 h,继而30μmol/L H_2O_2作用24 h。细胞存活率的测定采用MTT法,结果显示25μg/ml姜黄素预孵育1 h可使30μmol/L H_2O_2处理24 h后的细胞存活率提高8.5%;细胞凋亡的检测使用核染色法,结果显示姜黄素可显著抑制H_2O_2诱导的Neuro-2A细胞凋亡,姜黄素预孵育1 h可使细胞凋亡率下降15.1%;细胞内总抗氧化能力的测定采用比色法,结果显示25μg/ml姜黄素能够使细胞内总抗氧化能力提高15.9%。应用流式细胞术研究细胞内ROS堆积、线粒体跨膜电位崩塌以及胞外钙离子内流情况,结果显示姜黄素能够抑制细胞内ROS过量生成和胞外钙离子内流,同时可使罗丹明123阴性细胞数比例降低11.81%,即有助于维持正常的线粒体跨膜电位;抗凋亡蛋白表达水平的检测采用Western blot法,结果显示预孵育25μg/ml姜黄素1 h可提高抗凋亡蛋白PARP和Bcl-2的表达量,与H_2O_2处理组相比,这两种蛋白在细胞内的含量分别提高了12.1%和12.0%;Western blot法与胞浆/胞核蛋白分离法结合用来检测细胞内与凋亡及炎症反应相关的NF-κB信号通路的激活情况,发现姜黄素能够抑制H_2O_2引起的IκBα降解,进而阻止NF-κB激活,因此抑制其下游目的基因COX-2的表达,与H_2O_2处理组相比,25μg/ml姜黄素预孵育1 h可使细胞内IκBα含量提高34.3%,抑制NF-κB活化及进入细胞核,进而使得炎症因子COX-2表达量降低31.0%。
总而言之,本研究发现姜黄素对H_2O_2诱导氧化损伤的Neuro-2A细胞具有显著的保护效应。具体的作用机理包括增强细胞内源性总抗氧化能力、抑制ROS堆积、维持正常的线粒体跨膜电位和胞内外钙离子稳态、提高抗凋亡蛋白的表达量,以及阻止NF-κB信号通路的激活。本研究显示姜黄素在与氧化应激有关的神经退行性疾病的预防和治疗中具有潜在的应用前景。
Neurodegenerative disorders are strongly connected with oxidative stress, which is caused by reactive oxygen species (ROS). Curcumin is a natural polyphenol antioxidant extracted from Curcuma longa. Yet until now, there are still few researches focused on the neuroprotective effects of curcumin and its underlying mechanisms have not been fully defined, especially at cellular level. In current study, H_2O_2-induced oxidative stress model in mouse neuroblastoma Neuro-2A cells was employed to research the neuroprotective effects and its potential mechanisms of curcumin.
Neuro-2A cells were seeded into culture plates, cultured overnight at 37℃, and pretreated with curcumin at different concentrations for 1 h before 30μmol/L H_2O_2 exposure for 24 h. Cell viability was measured by MTT assay, and result showed that pretreatment with 25μg/ml curcumin for 1 h enhanced the percentage of viable cells by 8.5%. Cell apoptosis was assessed by nuclear staining, and result showed that the proportion of apoptotic cells was decreased by 15.1%, which indicated that curcumin could inhibit H_2O_2-induced apoptosis in Neuro-2A cells. The level of intracellular total antioxidant capacity, which was determined by colorimetric method, was boosted by 15.9% in 25μg/ml curcumin-pretreated group. Intracellular ROS accumulation, mitochondrial membrane potential loss, and Ca2+ influx were tested by flow cytometry, and results displayed that curcumin could be effect to suppress the augmentation of ROS level and intracellular calcium induced by H_2O_2, furthermore, curcumin also reduced the percentage of the Rhodamine 123 negative cells by 11.81%, which suggested that curcumin is conducive to inhibit the loss of mitochondrial membrane potential. The levels of two antiapoptotic proteins, poly(ADP-ribose) polymerase (PARP) and B cell lymphoma/lewkmia-2 (Bcl-2), which were measured by western blot analysis, were enhanced by 12.1%, and 12.0%, respectively, through pretreating with 25μg/ml curcumin for 1 h. In addition, nuclear and cytoplasmic protein extraction method, combined with western blot analysis, was applied to examine the activation of Nuclear factor-κ-gene binding (NF-κB) signaling pathway which is related to apoptosis and inflammation, and curcumin was found to block H_2O_2-mediate degradation of IκBαwhich was increased by 34.3%, and subsequent activation and relocation of NF-κB, thus inhibit the expression of its target gene Cyclooxygenase-2 (COX-2) which was decreased by 31.0%.
In a word, the results of our study suggested that curcumin could significantly protect Neuro-2A cells against oxidative damage induced by H_2O_2. The specific neuroprotective mechanisms of curcumin included reinforcing the endogenous total antioxidant capacity, suppressing intracellular ROS accumulation, maintaining normal mitochondrial membrane potential and calcium homeostasis, improving the expression of antiapoptotic proteins, as well as blocking the activation of NF-κB signaling pathway. Taken together, we speculated that curcumin has great potential for preventing and treating the neurodegenerative diseases associated with oxidative stress.
引文
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