硫氧還蛋白抵抗糖皮質(zhì)激素神經(jīng)毒性的分子機制研究
發(fā)布時間：2018-11-10 07:32
【摘要】：抑郁癥是一種常見的精神障礙疾病,給患者家屬和社會帶來巨大精神和經(jīng)濟負擔,到2020年抑郁癥將成為除癌癥外導致人類死亡的最主要原因。暴露于應激條件下是大多數(shù)抑郁癥發(fā)展的一個重要的環(huán)境因素。在正常生理條件下,應激激活下丘腦-垂體-腎上腺(hypothalamus-pituitary-adrenal, HP A)軸,導致腎上腺皮質(zhì)釋放糖皮質(zhì)激素(glucocorticoid, GC)。而過度應激,使得糖皮質(zhì)激素過度釋放,導致神經(jīng)元損傷,最終產(chǎn)生情感低落,失眠,健忘,性功能紊亂等抑郁癥狀。 內(nèi)質(zhì)網(wǎng)(Endoplasmic reticulum, ER)是細胞內(nèi)鈣儲存以及蛋白合成及折疊的主要場所,在調(diào)節(jié)細胞內(nèi)鈣信號以及糖基化中起重要作用,對環(huán)境中穩(wěn)態(tài)的改變高度敏感。未折疊蛋白和錯誤折疊蛋白異常堆積引起自我保護的信號通路稱為未折疊蛋白響應(unfolded protein response, UPR),可導致內(nèi)質(zhì)網(wǎng)的內(nèi)質(zhì)網(wǎng)應激,最終會通過激活C/EBP同源蛋白(C/EBP homologous protein, CHOP)和Procaspase12等誘導的細胞凋亡。小鼠抑郁模型中以及抑郁自殺患者額葉皮質(zhì),發(fā)現(xiàn)葡萄糖調(diào)節(jié)蛋白78(glucose-regulated protein, GRP78)、葡萄糖調(diào)節(jié)蛋白94(glucose-regulated protein, GRP94)和鈣網(wǎng)蛋白表達異常等表達增加異常；說明了內(nèi)質(zhì)網(wǎng)應激與抑郁癥密切相關。 硫氧還蛋白(Thioredoxin, Trx)是一個12kDa的小分子量蛋白,其活性位點為,-Cys-Gly-Pro-Cys-。X射線和紫外線照射,過氧化氫,病毒感染以及缺血再灌注都可以誘導其表達。具有調(diào)節(jié)細胞內(nèi)氧化還原狀態(tài)平衡的作用,此外,還具有促進細胞生長,保護神經(jīng),調(diào)節(jié)炎癥,抗凋亡作用。 抑郁與氧化應激損傷及內(nèi)質(zhì)網(wǎng)應激有關,而Trx-1可以抵抗氧化應激,抵抗內(nèi)質(zhì)網(wǎng)應激,但Trx-1與抑郁癥之間的關系還未見報道。本課題使用地塞米松模擬抑郁的細胞損傷模型,研究內(nèi)質(zhì)網(wǎng)應激和Trx-1表達改變。同時檢測抗抑郁藥物氟西汀對地塞米松誘導的神經(jīng)細胞的影響。此外,進一步檢測Trx-1誘導劑替普瑞酮(geranylgeranylacetone, GGA)對地塞米松處理的神經(jīng)細胞的影響。 本文主要結果如下： (1)地塞米松誘導內(nèi)質(zhì)網(wǎng)應激及神經(jīng)損傷。地塞米松刺激PC12細胞后,PC12細胞活力呈劑量依賴下降,地塞米松誘導了Procaspase3及內(nèi)質(zhì)網(wǎng)凋亡標志Procaspase12的激活,但對線粒體凋亡標志Procaspase9沒有影響。這些結果說明：地塞米松是通過誘導內(nèi)質(zhì)網(wǎng)應激通路導致細胞凋亡的,從而產(chǎn)生神經(jīng)損傷。 (2)地塞米松降低Trx-1的表達。Trx-1具有抵抗氧化應激,抑制氧化應激引起的細胞損傷作用。地塞米松刺激PC12細胞24小時后,細胞中Trx-1的表達明顯被抑制,單胺氧化酶的表達增加。這些結果說明：地塞米松誘導神經(jīng)元細胞凋亡可能與Trx-1的表達下降有關。 (3)抗抑郁藥氟西汀(Fluoxetine)抵抗地塞米松引起的內(nèi)質(zhì)網(wǎng)應激及細胞凋亡。Fluoxetine是臨床上常用的抗抑郁藥物,Fluoxetine刺激細胞后,促進了PC12細胞中Trx-1的表達。Fluoxetine預刺激可以抵抗地塞米松引起的神經(jīng)損傷,并回復地塞米松所致的Trx-1表達水平的下降,抑制單胺氧化酶的上升。此外,Fluoxetine還可以抑制GRP78表達及Procaspase12的激活。這些結果表明：Fluoxetine可以誘導Trx-1的產(chǎn)生,并抑制地塞米松引起內(nèi)質(zhì)網(wǎng)應激和細胞損傷。 (4)Trx-1誘導物GGA抵抗地塞米松引起的內(nèi)質(zhì)網(wǎng)應激。GGA預刺激可以抵抗地塞米松引起的神經(jīng)元損傷,回復地塞米松所致的Trx-1表達水平的下降,抑制單胺氧化酶的上升。此外,GGA還可以抵抗地塞米松引起的內(nèi)質(zhì)網(wǎng)應激,抑制GRP78表達及Procaspase12的激活。這些結果表明：Trx-1誘導物GGA抑制地塞米松引起的內(nèi)質(zhì)網(wǎng)應激和細胞損傷。 總結,地塞米松降低Trx-1的表達并且誘導內(nèi)質(zhì)網(wǎng)應激以及細胞凋亡；抗抑郁藥物Fluoxetine可以誘導Trx-1的表達,并抑制地塞米松引起的內(nèi)質(zhì)網(wǎng)應激；Trx-1的誘導物GGA,可以通過誘導Trx的表達,抑制內(nèi)質(zhì)網(wǎng)應激以及神經(jīng)細胞損傷。
[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
【學位授予單位】：昆明理工大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R749.4
本文編號：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
【學位授予單位】：昆明理工大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R749.4
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相關期刊論文 前2條
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，本文編號：2321808
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