發(fā)布時間：2018-06-21 19:41

  本文選題：馬度米星銨 + 毒性��； 參考：《南京農業(yè)大學》2015年博士論文

【摘要】：為探討馬度米星銨對心肌和骨骼肌細胞的毒性作用機制,本研究采用H9c2和C2C12細胞作為模型,考察馬度米星銨的毒性,檢測其對細胞周期分布、細胞凋亡和細胞自噬的影響,探討細胞內相關信號通路在馬度米星銨所致細胞毒性中的作用。具體分為以下幾個部分:1.馬度米星銨在心肌細胞和骨骼肌細胞中的毒性作用分別以H9c2細胞和C2C12細胞作為心肌細胞和骨骼肌細胞模型,不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理5天,顯微鏡下觀察細胞形態(tài)的變化并拍照,胰酶消化后計數;不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理24、48或72h,One solution法檢測細胞活性,臺盼藍染色法檢測細胞存活率。結果顯示,馬度米星銨處理5天后,細胞生長被抑制,形態(tài)變圓,部分細胞脫落漂浮于培養(yǎng)液中,貼壁細胞中出現空泡,處理組細胞數量明顯少于未處理組,呈濃度依賴性;馬度米星銨處理24、48或72 h后,細胞活性顯著降低,細胞存活率顯著下降,呈濃度和時間依賴性。結果表明,馬度米星銨抑制H9c2細胞和C2C12細胞生長,降低細胞活性,增加細胞死亡率,馬度米星銨對心肌細胞和骨骼肌細胞具有毒性作用。2.馬度米星銨對心肌細胞和骨骼肌細胞細胞周期分布的影響及其機制不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理24h或0.5μg/mL馬度米星銨處理不同時間(H9c2細胞:0、36、48和72h,C2C12細胞:0、24、48和72 h),PI染色后經流式細胞儀檢測細胞周期的分布;不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理24 h,Western blot檢測周期相關蛋白的表達水平。結果顯示,不同濃度馬度米星銨處理24 h后,H9c2細胞G_0/G_1期比例先升高后降低,S期比例先降低后升高,G_2/M期比例逐漸降低;C2C12細胞G_0/G_1期比例逐漸升高,S期比例逐漸降低,G_2/M期比例逐漸降低;0.5μg/mL馬度米星銨處理不同時間后,H9c2細胞和C2C12細胞G_0/G_1期比例逐漸升高,S期比例逐漸降低,G_2/M期比例逐漸降低;不同濃度馬度米星銨處理24 h后,H9c2細胞周期素、CDK6、CDC25B表達增加;C2C12細胞Cyclin D1、CDK4、CDK6和CDC25A表達量減少,p21Cip1和p27Kip1表達增加,Rb條帶出現位移、磷酸化水平降低。結果表明,馬度米星銨對H9c2細胞和C2C12細胞有明顯的細胞周期阻滯作用,抑制細胞增殖。3.馬度米星銨對心肌細胞和骨骼肌細胞細胞凋亡的影響及其機制不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理72h,Annexin V-PI雙染經流式細胞儀檢測細胞凋亡率的變化;不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理24h,Western blot檢測凋亡相關蛋白的表達量;z-VAD-fmk預處理1h后馬度米星銨(0.5μg/mL和1μg/mL)處理24或48 h,Western blot檢測Cleaved caspase 3和Cleaved PARP的表達情況,臺盼藍染色檢測細胞死亡率的變化情況;不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理24h,Western blot檢測AIF蛋白的表達量,免疫熒光法定位細胞內AIF蛋白。結果顯示,馬度米星銨處理72 h后,細胞凋亡率顯著升高,呈濃度依賴性;馬度米星銨處理24h后,H9c2細胞中TRAIL、DR4、Cleaved caspase 8、Cleaved caspase 3和Cleaved PARP的表達水平升高,C2C12細胞中BAK、BAD、TRAIL、DR4、TRADD、Cleaved caspase 9、Cleaved caspase 8、Cleaved caspase 3和Cleaved PARP蛋白表達水平升高;z-VAD-fmk預處理可削弱馬度米星銨導致的Caspase 3和PARP蛋白裂解及細胞死亡;馬度米星銨處理24 h后,H9c2細胞中AIF表達增加且更多地轉位到細胞核中,C2C12細胞中AIF表達量不變但轉位到細胞核中的AIF增多。結果表明,馬度米星銨能誘導H9c2細胞和C2C12細胞凋亡,從而導致其對心肌細胞和骨骼肌細胞的毒性作用。4.馬度米星按對心肌細胞和骨骼肌細胞細胞自噬的影響不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理24 h,Western blot檢測自噬相關蛋白的表達量;腺病毒干擾24 h表達GFP標記的LC3蛋白,不同濃度馬度米星按(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理24 h,熒光顯微鏡下觀察定位細胞內LC3蛋白。結果顯示,馬度米星銨處理24 h后,細胞中LC3Ⅱ和p62蛋白水平升高;腺病毒干擾表達GFP標記的LC3蛋白,馬度米星銨處理24h后,熒光顯微鏡下觀察,藥物處理組與對照組相比,細胞內有大量綠色熒光點,表明LC3蛋白聚集。結果表明,馬度米星銨能誘導H9c2細胞和C2C12細胞自噬并阻斷自噬流。5.馬度米星銨對心肌細胞和骨骼肌細胞MAPK通路蛋白和蛋白磷酸酶的影響不同濃度馬度米星按(0～1μg/mL)處理H9c2細胞和C2C12細胞24 h,Western blot檢測MAPK通路相關蛋白和蛋白磷酸酶的表達量;腺病毒干擾表達MKK1-R4F和顯性失活PP2A,0.5μg/mL和1μg/mL馬度米星銨處理H9c2細胞24 h或48 h,Western blot檢測p-ERK蛋白的表達量,顯微鏡下觀察細胞形態(tài)的變化并拍照,One solution法檢測細胞活性;PP2A抑制劑Okadaic acid預處理1 h,0.5μg/mL和1μg/mL馬度米星銨處理H9c2細胞48 h,顯微鏡下觀察細胞形態(tài)的變化并拍照,One solution法檢測細胞活性;腺病毒干擾表達顯性失活c-Jun,0.5μg/mL和1μg/mL馬度米星銨處理C2C12細胞24h或48h,Western blot檢測c-Jun蛋白的表達量,顯微鏡下觀察細胞形態(tài)的變化并拍照,One solution法檢測細胞活性;腺病毒干擾過表達PP5,0.5μg/mL和1μg/mL馬度米星銨處理C2C12細胞24 h或48 h,Western blot檢測p-JNK和p-c-Jun蛋白的表達量,顯微鏡下觀察細胞形態(tài)的變化并拍照,One solution法檢測細胞活性;JNK抑制劑SP600125預處理1 h,0.5μg/mL和1μg/mL馬度米星銨處理C2C12細胞48 h,顯微鏡下觀察細胞形態(tài)的變化并拍照,One solution法檢測細胞活性。結果顯示,馬度米星銨處理24 h后,H9c2細胞中p-ERK、p-PP2A和demethylated PP2A(De-PP2A)蛋白水平降低,methylated PP2A(Me-PP2A)表達量升高;C2C12細胞中p-JNK和p-c-Jun蛋白水平升高,PP5蛋白水平降低。H9c2細胞中腺病毒干擾表達MKK1-R4F和顯性失活PP2A可削弱馬度米星銨對ERK蛋白磷酸化的抑制及細胞毒性;Okadaic acid預處理可削弱馬度米星銨細胞毒性。C2C12細胞中腺病毒干擾表達顯性失活c-Jun可削弱馬度米星銨細胞毒性;過表達PP5可削弱馬度米星銨對JNK和c-Jun蛋白磷酸化的激活及細胞毒性;SP600125預處理可削弱馬度米星銨細胞毒性。結果表明,馬度米星銨增強H9c2細胞PP2A活性,引起ERK蛋白磷酸化水平降低,導致其對心肌細胞的毒性作用;馬度米星銨抑制C2C12細胞PP5蛋白表達,使JNK和c-Jun磷酸化水平升高,導致其對骨骼肌細胞的毒性作用。6.馬度米星銨對心肌細胞和骨骼肌細胞Akt1-FoxO3a通路的影響不同濃度馬度米星銨處理H9c2細胞和C2C12細胞24 h,Western blot檢測Akt1、p-Akt1(S473)、p-Akt1(T308)、FoxO3a和p-FoxO3a(Thr132)蛋白的表達量,免疫熒光定位細胞內FoxO3a蛋白;腺病毒干擾表達持續(xù)激活Akt,0.5μg/mL和1μg/mL馬度米星銨處理細胞24h或48h,Western blot檢測p-FoxO3a(Thr132)蛋白的表達量,免疫熒光定位細胞內FoxO3a蛋白,顯微鏡下觀察細胞形態(tài)的變化并拍照,One solution法檢測細胞活性。結果顯示,馬度米星銨處理24h后,細胞中p-Akt1(S473)、p-Akt1(T308)和p-FoxO3a(Thr132)蛋白水平降低,細胞核中FoxO3a含量增加。腺病毒干擾表達持續(xù)激活Akt可削弱馬度米星銨對FoxO3a蛋白磷酸化和胞漿轉移的抑制及細胞毒性。結果表明,馬度米星銨抑制H9c2細胞和C2C12細胞中Akt1活性,導致FoxO3a蛋白磷酸化水平降低,抑制其胞漿轉移,從而導致其對心肌細胞和骨骼肌細胞的毒性作用。7.馬度米星銨對心肌細胞和骨骼肌細胞AMPK蛋白的影響不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞：0～1μg/mL)處理24 h,Western blot檢測AMPK和p-AMPK(Thr172)蛋白的表達量;腺病毒干擾表達顯性失活AMPK,0.5μg/mL和1μg/mL馬度米星銨處理細胞24 h或48 h,Western blot檢測AMPK蛋白的表達量,顯微鏡下觀察細胞形態(tài)的變化并拍照,One solution法檢測細胞活性;AMPK抑制劑Compound C預處理1 h,0.5μg/mL和1μg/mL馬度米星銨處理細胞48 h,顯微鏡下觀察細胞形態(tài)的變化并拍照,One solution法檢測細胞活性。結果顯示,馬度米星銨處理24h后,細胞中p-AMPK(Thr172)蛋白水平升高;腺病毒干擾表達顯性失活AMPK和Compound C預處理可削弱馬度米星銨細胞毒性。結果表明,馬度米星銨增加細胞AMPK蛋白磷酸化水平,從而導致其對心肌細胞和骨骼肌細胞的毒性作用。8.馬度米星銨致心肌細胞和骨骼肌細胞氧化應激和內質網應激不同濃度馬度米星銨(H9c2細胞:0～5μg/mL,C2C12細胞:0～1μg/mL)處理24或48 h,利用CM-H2DCFDA檢測細胞內活性氧水平,Western blot檢測PERK、p-PERK(Thr980)、eIF2α、p-eIF2α(Ser51)蛋白表達水平。結果顯示,馬度米星銨處理24或48 h后,細胞內活性氧水平升高;馬度米星銨處理24 h后,細胞內PERK和eIF2α蛋白磷酸化水平升高,呈濃度依賴性。結果表明,馬度米星銨能引起H9c2細胞和C2C12細胞氧化應激和內質網應激。
[Abstract]:In order to investigate the toxic mechanism of ammonium bromide on myocardium and skeletal muscle cells, H9c2 and C2C12 cells were used as a model to investigate the toxicity of ammonium bromide, and to detect the effect of its cell cycle distribution, cell apoptosis and autophagy, and to explore the role of intracellular signaling pathway in the cytotoxicity of makhm ammonium. It is divided into the following parts: 1. the toxic effects of 1. M. M. in cardiomyocytes and skeletal muscle cells are treated with H9c2 cells and C2C12 cells as cardiac myocytes and skeletal muscle cells, with different concentrations of H9c2 cells (0~5 mu g/mL, C2C12 cells: 0~1 mu g/mL) for 5 days, and the morphological changes of cells are observed under microscope. The cell viability was detected by the One solution method and 24,48 or 72h, and the cell viability was detected by trypan blue staining. The results showed that the cell growth was suppressed, the morphology became round and some cells fell off after 5 days after the principle of trypan blue staining, with different concentrations of H9c2 cells (0~5 Mu g/mL, C2C12 cells: 0~1 g/mL). In the culture fluid, vacuoles appeared in the adherent cells, and the number of cells treated in the treatment group was significantly less than that in the untreated group. The cell viability was significantly reduced after 24,48 or 72 h was treated, and the cell survival rate decreased significantly. The results showed that the growth of H9c2 and C2C12 cells was inhibited by mnammonium. Reducing cell activity, increasing cell mortality, the toxic effect of mad ammonium on cardiomyocytes and skeletal muscle cells.2. the effect of mad ammonium on the cell cycle distribution of cardiomyocytes and skeletal muscle cells and its mechanism with different concentrations of mad M ammonium (H9c2 cells: 0~5 mu g/mL, C2C12 cells: 0~1 mu g/mL) treatment 24h or 0.5 mu g/mL horse degree At different time (H9c2 cells: 0,36,48 and 72h, C2C12 cells: 0,24,48 and 72 h), the distribution of cell cycle was detected by flow cytometry after PI staining, and 24 h was treated with different concentrations of mautoman (H9c2 cells: 0~5 micron, C2C12 cells: 0~1 mu g/mL). The results showed that the expression level of the cycle related proteins was different. After the treatment of 24 h, the G_0/G_1 phase ratio of H9c2 cells increased first and then decreased, the proportion of S phase decreased first, the proportion of G_2/M stage decreased gradually, the proportion of G_0/G_1 phase in C2C12 cells gradually increased, the proportion of S phase gradually decreased, and the proportion of G_2/M phase gradually decreased; after the treatment of different time, H9c2 cells and C2C12 cells were treated for different time. The proportion of the 1 phase gradually increased, the proportion of S phase gradually decreased and the proportion of G_2/M phase decreased gradually; the expression of H9c2 Cell Cyclin, CDK6 and CDC25B increased after the treatment of 24 h with different concentrations of MADM ammonium. C2C12 cells Cyclin D1, CDK4, CDK6 and CDC25A expressions increased, the bands appeared displacements and phosphorylation levels decreased. The results showed that H9c2 cells and C2C12 cells have obvious cell cycle blocking effect on H9c2 and C2C12 cells, which inhibit the effect of.3. Ma on cardiomyocyte and skeletal muscle cell apoptosis and its mechanism with different concentrations of mad M ammonium (H9c2 cells: 0~5 mu g/mL, C2C12 cells: 0~1 mu g/mL) to treat 72h, Annexin V-PI double dyed meridian cells The changes in the apoptosis rate were detected by the instrument. The expression of apoptosis related proteins was detected by different concentrations of H9c2 cells (H9c2 cells: 0~5 mu g/mL, C2C12 cells: 0~1 g/mL), and Western blot to detect the expression of apoptosis related proteins; z-VAD-fmk pretreatment of 1H (0.5 mu g/mL and 1 mu g/mL) treated 24 or 48 h. At the same time, trypan blue staining was used to detect the change of cell death rate; different concentrations of H9c2 cells (0~5 mu g/mL, C2C12 cells: 0~1 g/mL) were treated with 24h, Western blot was used to detect the expression of AIF protein, and the intracellular AIF protein was detected by immunofluorescence. The results showed that the apoptosis rate of the cells was significantly increased after the treatment of 72 h. The expression level of TRAIL, DR4, Cleaved caspase 8, Cleaved caspase 3 and Cleaved PARP increased in H9c2 cells after the treatment of 24h, and the expression level of Cleaved caspase 3 and Cleaved PARP increased. Caspase 3 and PARP protein lysis and cell death caused by NH4 were induced. After the treatment of 24 h, the expression of AIF in H9c2 cells increased and more transposition into the nucleus. The expression of AIF in C2C12 cells was unchanged but the AIF in the nucleus increased. The results showed that the apoptosis of H9c2 and C2C12 cells was induced. Toxic effects on cardiac myocytes and skeletal muscle cells.4. mad m star was treated with different concentrations of autophagy to cardiomyocytes and skeletal muscle cells in different concentrations (H9c2 cells: 0~5 mu g/mL, C2C12 cells: 0~1 mu g/mL) to treat 24 h and Western blot to detect the expression of autophagy protein; adenovirus interference 24 h expression GFP The labeled LC3 protein was treated with 24 h by (H9c2 cells: 0~5 mu g/mL, C2C12 cells: 0~1 mu g/mL). The intracellular LC3 protein was observed under the fluorescence microscope. The results showed that the level of LC3 II and p62 protein in the cells increased after 24 h treatment. After 24h, it was observed under the fluorescence microscope that there were a large number of green fluorescence points in the cells compared with the control group. The results showed that the LC3 protein could induce autophagy in H9c2 cells and C2C12 cells and blocked the autophagy,.5. mad, and the MAPK pathway protein and protein phosphatase of cardiomyocytes and skeletal muscle cells. The expression of MAPK pathway related protein and protein phosphatase in H9c2 cells and C2C12 cells was measured by (0~1 mu g/mL), and the expression of MAPK pathway related protein and protein phosphatase was detected by Western blot. The adenovirus interfered with the expression of MKK1-R4F and dominant inactivation PP2A, 0.5 mu g/mL and 1 mu g/mL Malayan ammonium treatment H9c2 cells 24 or 48 The cell morphologic changes were observed under the microscope and the cell activity was taken by the One solution method. The PP2A inhibitor Okadaic acid was pretreated with 1 h, 0.5 mu g/mL and 1 micron ammonium bromide treated H9c2 cell 48 h. The morphological changes of the cells were observed under the microscope and the cell activity was photographed by the One solution method; the adenovirus interfered with the expression of dominant inactivation. C-Jun, 0.5 mu g/mL and 1 g/mL M. M. NH4 treated C2C12 cells 24h or 48h, Western blot detected the expression of c-Jun protein, observed cell morphological changes under microscope and photographed, One solution method was used to detect cell activity; adenovirus interfered over expression PP5,0.5 muon and 1 mu ammonium bromide treated 24 or 48 cells The expression of p-JNK and p-c-Jun protein was measured, the morphological changes of cells were observed under microscope and the cell activity was detected by One solution method. The JNK inhibitor SP600125 pretreated 1 h, 0.5 mu g/mL and 1 micron ammonium bromide treated C2C12 cells 48 h. The cell morphology was observed under microscope and photographed. The cell activity was detected by One assay. After the treatment of 24 h, the level of p-ERK, p-PP2A and demethylated PP2A (De-PP2A) protein in H9c2 cells decreased, and the expression of methylated PP2A (Me-PP2A) increased, and the level of p-JNK and protein in C2C12 cells increased. The inhibition and cytotoxicity of ERK protein phosphorylation by stellar ammonium, Okadaic acid pretreatment can weaken the interference expression of adenovirus in.C2C12 cells of madeimatin cytotoxic c-Jun to weaken the toxicity of the cytotoxicity of the cytotoxicity of madeimatin; overexpression of PP5 can weaken the activation and cytotoxicity of JNK and c-Jun protein phosphorylation by the overexpression of PP5; SP600125 The pretreatment could weaken the cytotoxicity of the H9c2 cells. The results showed that the PP2A activity of H9c2 cells was enhanced and the level of phosphorylation of ERK protein decreased, which resulted in its toxic effect on cardiac myocytes; the expression of PP5 protein in C2C12 cells was inhibited by M. marem, and the level of JNK and c-Jun phosphorylation was increased, resulting in its toxicity to skeletal muscle cells. Effects of.6. on Akt1-FoxO3a pathway in cardiac myocytes and skeletal muscle cells with different concentrations of H9c2 cells and C2C12 cells in H9c2 cells and C2C12 cells, Western blot to detect Akt1, p-Akt1 (S473), p-Akt1 (T308), protein expression, immunofluorescent localization of intracellular proteins; adenovirus interference expression Continuous activation of Akt, 0.5 mu g/mL and 1 g/mL Ma ammonium ammonium treated cells 24h or 48h, Western blot to detect the expression of p-FoxO3a (Thr132) protein, immunofluorescence localization of intracellular FoxO3a protein, microscopic observation of cell morphology changes and photographing, One solution method detection of cell activity. The level of -Akt1 (S473), p-Akt1 (T308) and p-FoxO3a (Thr132) protein decreased, and the content of FoxO3a in the nucleus increased. The interference of adenovirus to continuously activate Akt could weaken the inhibition and cytotoxicity of marem ammonium on the phosphorylation and cytoplasmic transfer of FoxO3a protein. The results showed that the activity of Akt1 activity in H9c2 and C2C12 cells was inhibited. The level of phosphorylation of 3a protein decreased and the cytoplasmic transfer inhibited its cytoplasmic transfer, resulting in its toxic effect on cardiac myocytes and skeletal muscle cells.7.. The effect of mad m on AMPK protein of myocardial cells and skeletal muscle cells was different at different concentrations (H9c2 cells: 0~5 mu g/mL, C2C12 fine cell: 0~1 Mu g/mL) treatment 24 h, Western blot detection AMPK and P. The expression of -AMPK (Thr172) protein; adenovirus interfered with the expression of dominant inactivation AMPK, 0.5 g/mL and 1 mu g/mL treated cells 24 h or 48 h, Western blot detected the expression of AMPK protein, observed cell morphological changes under microscope and photographed, One solution method was used to detect cell activity. 1 The cell morphology was observed under microscope and the cell activity was photographed under the microscope and the cell activity was photographed under the microscope. The results showed that the level of p-AMPK (Thr172) protein in the cells increased after the treatment of 24h by One solution, and the preconditioning of adenovirus to express the dominant inactivation AMPK and Compound C could weaken the madeimonammonium cell. The results showed that the preprocessing of One and Compound C could weaken the madeimonammonium cell. Toxicity. The results showed that marem ammonium increased the level of phosphorylation of AMPK protein, resulting in its toxic effect on cardiomyocytes and skeletal muscle cells.8. mad M ammonium induced oxidative stress in cardiomyocytes and skeletal muscle cells and endoplasmic reticulum stress at different concentrations of H9c2 cells (H9c2 cells: 0~5 mu g/mL, C2C12 cells: 0~1 Mu g/mL) treatment 2 4 or 48 h, using CM-H2DCFDA to detect the intracellular reactive oxygen level, and Western blot to detect the expression level of PERK, p-PERK (Thr980), eIF2 a, and p-eIF2 alpha (Ser51) protein. The results showed that the intracellular active oxygen level was increased after the treatment of 24 or 48 h, and the level of phosphorylation of intracellular and alpha protein was increased after 24 h. The results showed that the treatment of H9c2 and C2C12 cells induced oxidative stress and endoplasmic reticulum stress.
【學位授予單位】：南京農業(yè)大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：S859.795

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