硫氧还蛋白抵抗糖皮质激素神经毒性的分子机制研究
发布时间：2018-11-10 07:32
【摘要】：抑郁症是一种常见的精神障碍疾病,给患者家属和社会带来巨大精神和经济负担,到2020年抑郁症将成为除癌症外导致人类死亡的最主要原因。暴露于应激条件下是大多数抑郁症发展的一个重要的环境因素。在正常生理条件下,应激激活下丘脑-垂体-肾上腺(hypothalamus-pituitary-adrenal, HP A)轴,导致肾上腺皮质释放糖皮质激素(glucocorticoid, GC)。而过度应激,使得糖皮质激素过度释放,导致神经元损伤,最终产生情感低落,失眠,健忘,性功能紊乱等抑郁症状。 内质网(Endoplasmic reticulum, ER)是细胞内钙储存以及蛋白合成及折叠的主要场所,在调节细胞内钙信号以及糖基化中起重要作用,对环境中稳态的改变高度敏感。未折叠蛋白和错误折叠蛋白异常堆积引起自我保护的信号通路称为未折叠蛋白响应(unfolded protein response, UPR),可导致内质网的内质网应激,最终会通过激活C/EBP同源蛋白(C/EBP homologous protein, CHOP)和Procaspase12等诱导的细胞凋亡。小鼠抑郁模型中以及抑郁自杀患者额叶皮质,发现葡萄糖调节蛋白78(glucose-regulated protein, GRP78)、葡萄糖调节蛋白94(glucose-regulated protein, GRP94)和钙网蛋白表达异常等表达增加异常；说明了内质网应激与抑郁症密切相关。 硫氧还蛋白(Thioredoxin, Trx)是一个12kDa的小分子量蛋白,其活性位点为,-Cys-Gly-Pro-Cys-。X射线和紫外线照射,过氧化氢,病毒感染以及缺血再灌注都可以诱导其表达。具有调节细胞内氧化还原状态平衡的作用,此外,还具有促进细胞生长,保护神经,调节炎症,抗凋亡作用。 抑郁与氧化应激损伤及内质网应激有关,而Trx-1可以抵抗氧化应激,抵抗内质网应激,但Trx-1与抑郁症之间的关系还未见报道。本课题使用地塞米松模拟抑郁的细胞损伤模型,研究内质网应激和Trx-1表达改变。同时检测抗抑郁药物氟西汀对地塞米松诱导的神经细胞的影响。此外,进一步检测Trx-1诱导剂替普瑞酮(geranylgeranylacetone, GGA)对地塞米松处理的神经细胞的影响。 本文主要结果如下： (1)地塞米松诱导内质网应激及神经损伤。地塞米松刺激PC12细胞后,PC12细胞活力呈剂量依赖下降,地塞米松诱导了Procaspase3及内质网凋亡标志Procaspase12的激活,但对线粒体凋亡标志Procaspase9没有影响。这些结果说明：地塞米松是通过诱导内质网应激通路导致细胞凋亡的,从而产生神经损伤。 (2)地塞米松降低Trx-1的表达。Trx-1具有抵抗氧化应激,抑制氧化应激引起的细胞损伤作用。地塞米松刺激PC12细胞24小时后,细胞中Trx-1的表达明显被抑制,单胺氧化酶的表达增加。这些结果说明：地塞米松诱导神经元细胞凋亡可能与Trx-1的表达下降有关。 (3)抗抑郁药氟西汀(Fluoxetine)抵抗地塞米松引起的内质网应激及细胞凋亡。Fluoxetine是临床上常用的抗抑郁药物,Fluoxetine刺激细胞后,促进了PC12细胞中Trx-1的表达。Fluoxetine预刺激可以抵抗地塞米松引起的神经损伤,并回复地塞米松所致的Trx-1表达水平的下降,抑制单胺氧化酶的上升。此外,Fluoxetine还可以抑制GRP78表达及Procaspase12的激活。这些结果表明：Fluoxetine可以诱导Trx-1的产生,并抑制地塞米松引起内质网应激和细胞损伤。 (4)Trx-1诱导物GGA抵抗地塞米松引起的内质网应激。GGA预刺激可以抵抗地塞米松引起的神经元损伤,回复地塞米松所致的Trx-1表达水平的下降,抑制单胺氧化酶的上升。此外,GGA还可以抵抗地塞米松引起的内质网应激,抑制GRP78表达及Procaspase12的激活。这些结果表明：Trx-1诱导物GGA抑制地塞米松引起的内质网应激和细胞损伤。 总结,地塞米松降低Trx-1的表达并且诱导内质网应激以及细胞凋亡；抗抑郁药物Fluoxetine可以诱导Trx-1的表达,并抑制地塞米松引起的内质网应激；Trx-1的诱导物GGA,可以通过诱导Trx的表达,抑制内质网应激以及神经细胞损伤。
[Abstract]:Depression is a common mental disorder that brings great mental and financial burden to the family and society of the patient, and depression will become the main cause of human death in the event of cancer by 2020. Exposure to stress is an important environmental factor for the development of most depression. Under normal physiological conditions, the hypothalamic-pituitary-adrenal (HP A) axis is activated by stress, leading to the release of the glucocorticoid (GC) in the adrenal cortex. Excessive stress can lead to excessive release of the glucocorticoid, resulting in neuronal damage, resulting in depression such as depression, insomnia, amnesia, sexual disorder, and the like. Endoplasmic reticulatum (ER) is the main place for intracellular calcium storage and protein synthesis and folding, and plays an important role in regulating intracellular calcium signal and glycosylation, and changes the steady state in the environment. The signal pathway of self-protection is called unfolded protein response (UPR), which can lead to the endoplasmic reticulum stress of the endoplasmic reticulum, which can eventually be induced by the activation of C/ EBP homologous protein (CHOP) and procaspase 12. The expression of glucose-regulated protein (GRP78), glucose-regulated protein (GRP94) and calcium-net protein was found to be abnormal in the model of depression and the frontal cortex of the patients with depression and suicide, and the relationship between endoplasmic reticulum stress and depression was described. Related. The thioredoxin (Trx) is a small molecular weight protein of 12kDa, the active site of which is,-Cys-Gly-Pro-Cys-. Xray and UV irradiation, hydrogen peroxide, viral infection, and ischemia-reperfusion may has the effects of regulating the balance of the redox state in the cell, and has the effects of promoting cell growth, protecting nerves, regulating inflammation, Anti-apoptotic effects. Depression is associated with oxidative stress injury and endoplasmic reticulum stress, while Trx-1 can resist oxidative stress, resist endoplasmic reticulum stress, but Trx-1 and depression The relationship between the endoplasmic reticulum stress and T was studied by using dexamethasone to simulate the cell damage model of depression. change of rx-1 expression. The effect of Trx-1 inducer for dexamethasone treatment was further tested. The effect of nerve cells. The main results of this paper are as follows: (1) the ground plug In order to induce the endoplasmic reticulum stress and nerve injury, the activity of PC12 cells decreased in the dose-dependent manner after stimulation of PC12 cells. There is no effect on rocaspas9. These results indicate that dexamethasone is caused by the induction of the endoplasmic reticulum stress pathway Apoptosis of the cells, resulting in nerve damage. (2) Dexamethasone reduces the expression of Trx-1. Trx-1 has resistance to oxidation. Effect of excitation and inhibition of cell damage induced by oxidative stress. After 24 hours of stimulation of PC12 cells by dexamethasone, the table of Trx-1 in the cells As a result, the expression of single-amine oxidase was increased. These results indicated that dexamethasone-induced neuronal cells Apoptosis may be associated with a decrease in the expression of Trx-1. (3) Antidepressant Fluoxine) Endoplasmic reticulum stress and apoptosis induced by dexamethasone. Fluoxetine is a commonly used anti-depressant drug, Fluoxetine stimulates the cells. After that, the expression of Trx-1 in PC12 cells is promoted. Fluoxetine pre-stimulation can resist the nerve damage caused by dexamethasone and respond to the Trx-induced Trx-1. In addition, Fluoxetine can inhibit the GRP. The results showed that Fluoxetine can induce Trx-1 production. and inhibits the endoplasmic reticulum stress and cell damage caused by dexamethasone. (4) Tr The x-1 inducer GGA is resistant to the endoplasmic reticulum stress induced by dexamethasone. The GGA pre-stimulation can resist the neuronal damage caused by dexamethasone and respond to dexamethasone. In addition, GGA can resist the endoplasmic reticulum stress induced by dexamethasone, and inhibit the increase of the expression level of Trx-1. The expression of GRP78 and activation of procaspase 12. These results indicated that Trx-1 induction GGA inhibits the endoplasmic reticulum stress and cell damage induced by dexamethasone. The expression of Trx-1 is reduced and endoplasmic reticulum stress and cell apoptosis are induced by dexamethasone. Fluoxetine, an antidepressant, can induce Trx-1 expression and inhibit the endoplasmic reticulum stress induced by dexamethasone.; Trx-1 inducer GGA may
【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.4
本文编号：2321808
[Abstract]:Depression is a common mental disorder that brings great mental and financial burden to the family and society of the patient, and depression will become the main cause of human death in the event of cancer by 2020. Exposure to stress is an important environmental factor for the development of most depression. Under normal physiological conditions, the hypothalamic-pituitary-adrenal (HP A) axis is activated by stress, leading to the release of the glucocorticoid (GC) in the adrenal cortex. Excessive stress can lead to excessive release of the glucocorticoid, resulting in neuronal damage, resulting in depression such as depression, insomnia, amnesia, sexual disorder, and the like. Endoplasmic reticulatum (ER) is the main place for intracellular calcium storage and protein synthesis and folding, and plays an important role in regulating intracellular calcium signal and glycosylation, and changes the steady state in the environment. The signal pathway of self-protection is called unfolded protein response (UPR), which can lead to the endoplasmic reticulum stress of the endoplasmic reticulum, which can eventually be induced by the activation of C/ EBP homologous protein (CHOP) and procaspase 12. The expression of glucose-regulated protein (GRP78), glucose-regulated protein (GRP94) and calcium-net protein was found to be abnormal in the model of depression and the frontal cortex of the patients with depression and suicide, and the relationship between endoplasmic reticulum stress and depression was described. Related. The thioredoxin (Trx) is a small molecular weight protein of 12kDa, the active site of which is,-Cys-Gly-Pro-Cys-. Xray and UV irradiation, hydrogen peroxide, viral infection, and ischemia-reperfusion may has the effects of regulating the balance of the redox state in the cell, and has the effects of promoting cell growth, protecting nerves, regulating inflammation, Anti-apoptotic effects. Depression is associated with oxidative stress injury and endoplasmic reticulum stress, while Trx-1 can resist oxidative stress, resist endoplasmic reticulum stress, but Trx-1 and depression The relationship between the endoplasmic reticulum stress and T was studied by using dexamethasone to simulate the cell damage model of depression. change of rx-1 expression. The effect of Trx-1 inducer for dexamethasone treatment was further tested. The effect of nerve cells. The main results of this paper are as follows: (1) the ground plug In order to induce the endoplasmic reticulum stress and nerve injury, the activity of PC12 cells decreased in the dose-dependent manner after stimulation of PC12 cells. There is no effect on rocaspas9. These results indicate that dexamethasone is caused by the induction of the endoplasmic reticulum stress pathway Apoptosis of the cells, resulting in nerve damage. (2) Dexamethasone reduces the expression of Trx-1. Trx-1 has resistance to oxidation. Effect of excitation and inhibition of cell damage induced by oxidative stress. After 24 hours of stimulation of PC12 cells by dexamethasone, the table of Trx-1 in the cells As a result, the expression of single-amine oxidase was increased. These results indicated that dexamethasone-induced neuronal cells Apoptosis may be associated with a decrease in the expression of Trx-1. (3) Antidepressant Fluoxine) Endoplasmic reticulum stress and apoptosis induced by dexamethasone. Fluoxetine is a commonly used anti-depressant drug, Fluoxetine stimulates the cells. After that, the expression of Trx-1 in PC12 cells is promoted. Fluoxetine pre-stimulation can resist the nerve damage caused by dexamethasone and respond to the Trx-induced Trx-1. In addition, Fluoxetine can inhibit the GRP. The results showed that Fluoxetine can induce Trx-1 production. and inhibits the endoplasmic reticulum stress and cell damage caused by dexamethasone. (4) Tr The x-1 inducer GGA is resistant to the endoplasmic reticulum stress induced by dexamethasone. The GGA pre-stimulation can resist the neuronal damage caused by dexamethasone and respond to dexamethasone. In addition, GGA can resist the endoplasmic reticulum stress induced by dexamethasone, and inhibit the increase of the expression level of Trx-1. The expression of GRP78 and activation of procaspase 12. These results indicated that Trx-1 induction GGA inhibits the endoplasmic reticulum stress and cell damage induced by dexamethasone. The expression of Trx-1 is reduced and endoplasmic reticulum stress and cell apoptosis are induced by dexamethasone. Fluoxetine, an antidepressant, can induce Trx-1 expression and inhibit the endoplasmic reticulum stress induced by dexamethasone.; Trx-1 inducer GGA may
【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.4
【参考文献】
相关期刊论文 前2条
1 周芙玲;张王刚;苏智祥;蒙昕;田纬;;急性白血病患者氧化应激状态与抑郁情绪之间的关系[J];中国实验血液学杂志;2006年05期
2 何莉;李丹;侯科佐;刘云鹏;;p38丝裂原活化蛋白激酶调节急性淋巴细胞性白血病CEM细胞株糖皮质激素受体功能的分子机制研究[J];中华儿科杂志;2007年09期
，本文编号：2321808
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