跳到主要內容

臺灣博碩士論文加值系統

(18.204.48.64) 您好!臺灣時間:2021/08/04 18:50
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:張鈴婉
研究生(外文):Ling - Wan Chang
論文名稱:神經醯胺誘導神經膠瘤細胞粒線體功能損傷及細胞凋亡
論文名稱(外文):Induced Mitochondrial Dysfunction and Apoptosis of Rat Glioma Cells by C6 Ceramide
指導教授:高淑慧高淑慧引用關係李宏謨李宏謨引用關係
指導教授(外文):Shu - Huei Kao, Ph.D.
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學檢驗生物技術學研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:111
中文關鍵詞:神經醯胺粒線體細胞凋亡細胞色素c神經退化性疾病
外文關鍵詞:ceramidemitochondriaapoptosiscytochrome cneurodegeneration
相關次數:
  • 被引用被引用:0
  • 點閱點閱:235
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
神經醯胺(ceramide)是磷脂質的二級訊號傳遞因子,在細胞生長過程與刺激反應中扮演必要的調節者。此外也被證實為造成細胞氧化壓力的來源之ㄧ,不但參與發展中的神經細胞凋亡,更被證實和神經退化性疾病的生成有關。有文獻指出,ceramide可能經由在粒線體膜上形成通道(channel),造成細胞色素(cytochrome)釋放至細胞質,誘導細胞凋亡的發生。本論文主旨為探討C6 ceramide造成大鼠神經膠瘤細胞(C6 glioma cells)之粒線體功能缺損進而造成細胞色素c (cytochrome c)釋出導致細胞凋亡之研究。從實驗結果得知,在25 ?嵱 C6 ceramide的作用後會降低神經膠瘤細胞的存活率。以25 ?嵱 C6 ceramide培養24小時後,細胞存活率降至對照組的30.8% ± 2.2% (n=3, p<0.001),並且經H2DCFDA染色檢測後發現細胞內活性氧自由基(reactive oxygen species, ROS)的產生於六小時C6 ceramide處理後增加為對照組的209.4% ± 23.3% (n=3, p<0.01),粒線體膜電位(mitochondria membrane potentials, Δ??)在12小時處理後則下降為29.9% ± 2.1% (n=3, p<0.001)。粒線體ATP含量隨刺激時間增加而遞減,在18小時減少為4.4% ± 2.8% (n=3, p<0.001)。此外,C6 ceramide的處理也會造成粒線體DNA的斷損突變(mitochondrial DNA rearragement),於六小時C6 ceramide處理後,其斷損突變情形增加。當以Annexin V-FITC/ Propidium iodide (PI)染色分析偵測細胞死亡情形,發現以25 ?嵱 C6 ceramide培養24小時後,與對照組比較細胞凋亡現象增加了34.7%。當我們以帶有螢光基團的C6 ceramide (NBD-C6 ceramide)與細胞進行培養,利用雷射共軛焦顯微鏡觀察,發現NBD-C6 ceramide與粒線體的螢光影像圖位置相同並重疊在一起,顯示C6 ceramide進入細胞後會在粒線體上形成堆積。以西方墨點法分析細胞凋亡蛋白質變化,結果顯示經25 ?嵱 C6 ceramide處理後,與對照組比較cytochrome c自粒線體釋出到細胞質的情形增加為212.5%,促使細胞走向凋亡,我們添加粒線體膜通透性改變孔(MPT pore) 的抑制劑環孢黴素A (cyclosporin A),看到因C6 ceramide刺激所導致的cytochrome c釋出被部分抑制,與對照組比較減少為115.2%,另外,我們以C6 ceramide的活性抑制物C6 dihydroceramide (DH C6)處理後,發現因25 ?嵱 C6 ceramide刺激所導致的cytochrome c釋出由269.8% ± 28.1%降低為114.0% ± 6.6%,我們推測C6 ceramide除了可能經由傳統的mitochondrial-dependent cell apoptosis 路徑造成細胞死亡,另外,有可能經由C6 ceramide堆積在粒線體上形成cytochrome c釋出的通道(leakage)。當我們以C6 ceramide處理純化後的功能性粒線體,發現C6 ceramide可以直接與粒線體作用,逕自使粒線體的呼吸率下降、cytochrome c釋出。由此我們推測,C6 ceramide經由堆積在大鼠神經膠瘤細胞之粒線體上,引發大量ROS產生造成氧化性傷害,粒線體Δ?擏幭僈P功能缺損,並在粒線體外膜上形成孔洞,誘導儲存於膜間隙的cytochrome c釋出,促使細胞走向凋亡。C6 ceramide進入細胞後在粒線體上形成堆積,可能是造成粒線體功能缺失與細胞凋亡的主因。
Ceramide has been proven an origin of oxidative stress, not only participate in neuron programed cell death, but involve in variety of neurological disorders such as epilepsy, Alzheimer’s and Parkinson’s diseases, and cerebral ischemia. Recent evidence have demonstrated that ceramide-induced apoptosis might be mediated by ceramide-forming mitochondrial membrane channel and cytochrome c release into cytoplasm. In this study, we proposed that ceramide-induced C6 glioma cells apoptosis via mitochondrial dysfunction, forming mitochondrial membrane leakage and induce cytochrome release. We investigated the cytoeffects of C6 ceramide on glioma cells damages including mitochondrial DNA instability, mitochondrial dysfunction and cytochrome c release. We performed several experiments including cell viability by dye exclusion assay, cell apoptosis by Annexin V/PI flow cytometry analysis, ROS generation and mitochondria membrane potentials (Δ??) by flow cytometry, ATP generation by ATP-luciferin assay, mitochondrial DNA rearragement by long-PCR analysis and cytochrome c release by western blotting. In order to identify the cell accumulation of C6 ceramide and ceramide localization, we detected the ceramide marker NBD-C6 ceramide by confocal microscope. A declined cellular viability was found to be 30.8% ± 2.2% in 25 ?嵱 C6 ceramide-treated cells (p<0.001). A 2.1 folded-increase of ROS generation at 6 h (p<0.01) and 70% reduction of mitochondria membrane potentials at 12 h (p<0.001) were found. In addition, we found the ATP content was declined to 4.4% ± 2.8% (p<0.001) at 18 h and showed a time-dependent reduction. After 25 ?嵱 C6 ceramide treatment, the apoptotic cells were increased 34.7% and raised apoptotic fraction was also detected. We also found NBD-C6 ceramide colocalized with mitochondria. In addition, we also found a 2.1 folded-increase of cytochrome c releasing from mitochondria into cytoplasm followed 25 ?嵱 C6 ceramide treatment. Moreover, the use of cyclosporin A (MPT pore inhibitor, CsA) was found to partially block of cytochrome c release to 115.2% in the ceramide-treated cells. On the other hand, using C6 dihydroceramide (DHC6) as biological inactivator of C6 ceramide was also declined the release of cytochrome c from 269.8% ± 28.1% to 114.0% ± 6.6%. Those evidences indicated that not only C6 ceramide mediated the traditional mitochondrial-dependent cell apoptosis pathway, but accumulation of ceramide in the mitochondria possibly contributing to mitochondrial dysfunction and forming mitochondrial membrane leakage for cytochrome c release. Further more, we isolated the functional mitochondria from glioma cells, the reduced oxygen consumption rates and the induction of cytochrome c release were also revealed in C6 ceramide-treated mitochondria. According to our results, we suggested that ceramide-induced cell apoptosis might be mediated by intramitochondrial ceramide induced mitochondrial malfunction.
縮寫表 1
中文摘要 4
Abstract 6
研究緣起及動機 8
第一章 文獻回顧 9
一、 C6神經醯胺( C6 ceramide ) 10
1. 磷脂質(sphingolipids)的特性 10
2. C6神經醯胺的結構與生合成 11
3. Ceramide調控細胞生理與凋亡 13
4. Ceramide與神經退化性疾病 14
二、 C6神經膠瘤細胞( Glioma cells ) 16
三、 細胞凋亡( Apoptosis ) 17
1. 細胞凋亡的生理意義 17
2. 細胞凋亡的特徵 18
3. 細胞凋亡基因與凋亡蛋白酶(caspase)家族: 18
四、 粒線體( Mitochondria ) 20
1. 粒線體外觀與構造 20
2. 粒線體的功能 21
3. 粒線體DNA (mtDNA) 22
4. 粒線體膜可滲透性(mitochondrial membrane permeabilization, MMP) 23
5. 粒線體呼吸控制率(respiratory control ratio, RCR) 24
五、 活性氧自由基( Reactive oxygen species, ROS ) 25
第二章 實驗材料與方法 29
藥品試劑 30
實驗方法 33
一、 C6神經醯胺( C6 ceramide )的配製 33
二、 C6神經膠瘤細胞株( C6 glioma cell line )培養 33
三、 細胞存活率( Cell viability ) 34
四、 細胞蛋白質製備( Preparation of cell lysate ) 34
五、 細胞質與粒線體的分離( Subcellular fractionation ) 35
六、 蛋白質定量法( Protein assay ) 36
七、 西方墨點法( Western blotting ) 37
八、 流式細胞儀( Flow cytometry )分析 38
九、 粒線體產生ATP能力測定 41
十、 以Lowry方法進行蛋白分析 42
十一、 測定粒線體DNA突變 42
十二、 雷射共軛焦顯微鏡 45
十三、 功能性粒線體的研究 46
十四、 統計分析 48
第三章 實驗結果與分析 50
一、C6 ceramide造成神經膠瘤細胞( C6 glioma cells )的細胞存活率下降 51
二、C6 ceramide促使神經膠瘤細胞走向細胞凋亡( Apoptosis ) 51
三、C6 ceramide誘發神經膠瘤細胞中活性氧自由基( ROS )的增加 52
四、C6 ceramide影響神經膠瘤細胞粒線體的ATP形成能力 53
五、C6 ceramide影響神經膠瘤細胞粒線體膜電位改變 53
六、C6 ceramide引發神經膠瘤細胞粒線體DNA突變、斷裂與斷損 54
七、C6 ceramide在細胞中的粒線體上形成堆積( accumulation ) 54
八、C6 ceramide誘導細胞中粒線體cytochrome c的釋出 55
九、C6 ceramide造成神經膠瘤細胞功能性粒線體呼吸作用下降 57
十、C6 ceramide直接造成功能性粒線體中cytochrome c的釋出 57
第四章 討論 59
第五章 參考文獻 69
第六章 實驗圖表 82
Aliev, G., Smith, M.A., de la Torre, J.C. and Perry, G. (2004) Mitochondria as a primary target for vascular hypoperfusion and oxidative stress in Alzheimer''s disease. Mitochondrion, 4, 649-663.
Altura, B.M. and Altura, B.T. (1995) Magnesium and cardiovascular biology: an important link between cardiovascular risk factors and atherogenesis. Cell Mol Biol Res, 41, 347-359.
Altura, B.M., Gebrewold, A., Zheng, T. and Altura, B.T. (2002) Sphingomyelinase and ceramide analogs induce vasoconstriction and leukocyte-endothelial interactions in cerebral venules in the intact rat brain: Insight into mechanisms and possible relation to brain injury and stroke. Brain Res Bull, 58, 271-278.
Ardail, D., Popa, I., Alcantara, K., Pons, A., Zanetta, J.P., Louisot, P., Thomas, L. and Portoukalian, J. (2001) Occurrence of ceramides and neutral glycolipids with unusual long-chain base composition in purified rat liver mitochondria. FEBS Lett, 488, 160-164.
Arora, A.S., Jones, B.J., Patel, T.C., Bronk, S.F. and Gores, G.J. (1997) Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat. Hepatology, 25, 958-963.
Bai, J. and Pagano, R.E. (1997) Measurement of spontaneous transfer and transbilayer movement of BODIPY-labeled lipids in lipid vesicles. Biochemistry, 36, 8840-8848.
Ballou, L.R., Chao, C.P., Holness, M.A., Barker, S.C. and Raghow, R. (1992) Interleukin-1-mediated PGE2 production and sphingomyelin metabolism. Evidence for the regulation of cyclooxygenase gene expression by sphingosine and ceramide. J Biol Chem, 267, 20044-20050.
Bernas, T. and Dobrucki, J. (2002) Mitochondrial and nonmitochondrial reduction of MTT: interaction of MTT with TMRE, JC-1, and NAO mitochondrial fluorescent probes. Cytometry, 47, 236-242.
Bielawska, A., Crane, H.M., Liotta, D., Obeid, L.M. and Hannun, Y.A. (1993) Selectivity of ceramide-mediated biology. Lack of activity of erythro-dihydroceramide. J Biol Chem, 268, 26226-26232.
Bionda, C., Portoukalian, J., Schmitt, D., Rodriguez-Lafrasse, C. and Ardail, D. (2004) Subcellular compartmentalization of ceramide metabolism: MAM (mitochondria-associated membrane) and/or mitochondria? Biochem J, 382, 527-533.
Birbes, H., El Bawab, S., Hannun, Y.A. and Obeid, L.M. (2001) Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. Faseb J, 15, 2669-2679.
Birbes, H., Luberto, C., Hsu, Y.T., El Bawab, S., Hannun, Y.A. and Obeid, L.M. (2005) A mitochondrial pool of sphingomyelin is involved in TNFalpha-induced Bax translocation to mitochondria. Biochem J, 386, 445-451.
Bonini, I.C., Antollini, S.S., Gutierrez-Merino, C. and Barrantes, F.J. (2002) Sphingomyelin composition and physical asymmetries in native acetylcholine receptor-rich membranes. Eur Biophys J, 31, 417-427.
Brenner, C. and Grimm, S. (2006) The permeability transition pore complex in cancer cell death. Oncogene, 25, 4744-4756.
Butron, A., Santiago, R., Mansilla, P., Pintos-Varela, C., Ordas, A. and Malvar, R.A. (2006) Maize (Zea mays L.) genetic factors for preventing fumonisin contamination. J Agric Food Chem, 54, 6113-6117.
Cadenas, E. and Davies, K.J. (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med, 29, 222-230.
Chance, B. and Williams, G.R. (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem, 217, 409-427.
Checkoway, H., Farin, F.M., Costa-Mallen, P., Kirchner, S.C. and Costa, L.G. (1998) Genetic polymorphisms in Parkinson''s disease. Neurotoxicology, 19, 635-643.
Chen, Y., Ginis, I. and Hallenbeck, J.M. (2001) The protective effect of ceramide in immature rat brain hypoxia-ischemia involves up-regulation of bcl-2 and reduction of TUNEL-positive cells. J Cereb Blood Flow Metab, 21, 34-40.
Cheng, A., Arumugam, T.V., Liu, D., Khatri, R.G., Mustafa, K., Kwak, S., Ling, H.P., Gonzales, C., Xin, O., Jo, D.G., Guo, Z., Mark, R.J. and Mattson, M.P. (2007) Pancortin-2 interacts with WAVE1 and Bcl-xL in a mitochondria-associated protein complex that mediates ischemic neuronal death. J Neurosci, 27, 1519-1528.
Clement, M.V. and Pervaiz, S. (1999) Reactive oxygen intermediates regulate cellular response to apoptotic stimuli: an hypothesis. Free Radic Res, 30, 247-252.
Cutler, R.G. and Mattson, M.P. (2001) Sphingomyelin and ceramide as regulators of development and lifespan. Mech Ageing Dev, 122, 895-908.
Dai, Q., Liu, J., Chen, J., Durrant, D., McIntyre, T.M. and Lee, R.M. (2004) Mitochondrial ceramide increases in UV-irradiated HeLa cells and is mainly derived from hydrolysis of sphingomyelin. Oncogene, 23, 3650-3658.
Danial, N.N. and Korsmeyer, S.J. (2004) Cell death: critical control points. Cell, 116, 205-219.
Darzynkiewicz, Z., Juan, G., Li, X., Gorczyca, W., Murakami, T. and Traganos, F. (1997) Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis). Cytometry, 27, 1-20.
Davis, C.N., Tabarean, I., Gaidarova, S., Behrens, M.M. and Bartfai, T. (2006) IL-1beta induces a MyD88-dependent and ceramide-mediated activation of Src in anterior hypothalamic neurons. J Neurochem, 98, 1379-1389.
Dbaibo, G.S., Perry, D.K., Gamard, C.J., Platt, R., Poirier, G.G., Obeid, L.M. and Hannun, Y.A. (1997) Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway. J Exp Med, 185, 481-490.
De Marco, C.S. and Caniggia, I. (2002) Mechanisms of oxygen sensing in human trophoblast cells. Placenta, 23 Suppl A, S58-68.
Decraene, C., Brugg, B., Ruberg, M., Eveno, E., Matingou, C., Tahi, F., Mariani, J., Auffray, C. and Pietu, G. (2002) Identification of genes involved in ceramide-dependent neuronal apoptosis using cDNA arrays. Genome Biol, 3, RESEARCH0042.
Desagher, S. and Martinou, J.C. (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol, 10, 369-377.
Di Paola, M., Cocco, T. and Lorusso, M. (2000) Ceramide interaction with the respiratory chain of heart mitochondria. Biochemistry, 39, 6660-6668.
Di Paola, M., Zaccagnino, P., Montedoro, G., Cocco, T. and Lorusso, M. (2004) Ceramide induces release of pro-apoptotic proteins from mitochondria by either a Ca2+ -dependent or a Ca2+ -independent mechanism. J Bioenerg Biomembr, 36, 165-170.
Dickerson, R.E. (1971) The structures of cytochrome c and the rates of molecular evolution. J Mol Evol, 1, 26-45.
Dieter, P., Arlt, U. and Fitzke, E. (1995) Different regulation of the formation of intra- and extracellular oxygen radicals in macrophages. Biol Signals, 4, 331-337.
Douce, R., Bourguignon, J., Macherel, D. and Neuburger, M. (1994) The glycine decarboxylase system in higher plant mitochondria: structure, function and biogenesis. Biochem Soc Trans, 22, 184-188.
Douglas, S., Zauner, S., Fraunholz, M., Beaton, M., Penny, S., Deng, L.T., Wu, X., Reith, M., Cavalier-Smith, T. and Maier, U.G. (2001) The highly reduced genome of an enslaved algal nucleus. Nature, 410, 1091-1096.
El Bawab, S., Roddy, P., Qian, T., Bielawska, A., Lemasters, J.J. and Hannun, Y.A. (2000) Molecular cloning and characterization of a human mitochondrial ceramidase. J Biol Chem, 275, 21508-21513.
Farrant, M. and Nusser, Z. (2005) Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci, 6, 215-229.
Fillet, M., Bentires-Alj, M., Deregowski, V., Greimers, R., Gielen, J., Piette, J., Bours, V. and Merville, M.P. (2003) Mechanisms involved in exogenous C2- and C6-ceramide-induced cancer cell toxicity. Biochem Pharmacol, 65, 1633-1642.
Finkel, T. and Holbrook, N.J. (2000) Oxidants, oxidative stress and the biology of ageing. Nature, 408, 239-247.
Fleury, C., Mignotte, B. and Vayssiere, J.L. (2002) Mitochondrial reactive oxygen species in cell death signaling. Biochimie, 84, 131-141.
France-Lanord, V., Brugg, B., Michel, P.P., Agid, Y. and Ruberg, M. (1997) Mitochondrial free radical signal in ceramide-dependent apoptosis: a putative mechanism for neuronal death in Parkinson''s disease. J Neurochem, 69, 1612-1621.
Fridovich, I. (1999) Fundamental aspects of reactive oxygen species, or what''s the matter with oxygen? Ann N Y Acad Sci, 893, 13-18.
Fubini, B. and Hubbard, A. (2003) Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Radic Biol Med, 34, 1507-1516.
Garcia-Ruiz, C., Colell, A., Mari, M., Morales, A. and Fernandez-Checa, J.C. (1997) Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biol Chem, 272, 11369-11377.
Gotlieb, W.H., Watson, J.M., Rezai, A., Johnson, M., Martinez-Maza, O. and Berek, J.S. (1994) Cytokine-induced modulation of tumor suppressor gene expression in ovarian cancer cells: up-regulation of p53 gene expression and induction of apoptosis by tumor necrosis factor-alpha. Am J Obstet Gynecol, 170, 1121-1128; discussion 1128-1130.
Grassme, H., Jekle, A., Riehle, A., Schwarz, H., Berger, J., Sandhoff, K., Kolesnick, R. and Gulbins, E. (2001) CD95 signaling via ceramide-rich membrane rafts. J Biol Chem, 276, 20589-20596.
Green, D. and Kroemer, G. (1998) The central executioners of apoptosis: caspases or mitochondria? Trends Cell Biol, 8, 267-271.
Gudz, T.I., Tserng, K.Y. and Hoppel, C.L. (1997) Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem, 272, 24154-24158.
Gulbins, E. and Grassme, H. (2002) Ceramide and cell death receptor clustering. Biochim Biophys Acta, 1585, 139-145.
Gumireddy, K., Sutton, L.N., Phillips, P.C. and Reddy, C.D. (2003) All-trans-retinoic acid-induced apoptosis in human medulloblastoma: activation of caspase-3/poly(ADP-ribose) polymerase 1 pathway. Clin Cancer Res, 9, 4052-4059.
Gutteridge, J.M. and Halliwell, B. (1989) Iron toxicity and oxygen radicals. Baillieres Clin Haematol, 2, 195-256.
Halestrap, A.P. and Brennerb, C. (2003) The adenine nucleotide translocase: a central component of the mitochondrial permeability transition pore and key player in cell death. Curr Med Chem, 10, 1507-1525.
Halestrap, A.P., Connern, C.P., Griffiths, E.J. and Kerr, P.M. (1997) Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury. Mol Cell Biochem, 174, 167-172.
Halliwell, B. and Chirico, S. (1993) Lipid peroxidation: its mechanism, measurement, and significance. Am J Clin Nutr, 57, 715S-724S; discussion 724S-725S.
Hannun, Y.A. (1994) The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem, 269, 3125-3128.
Hannun, Y.A. (1996) Functions of ceramide in coordinating cellular responses to stress. Science, 274, 1855-1859.
Hannun, Y.A. and Luberto, C. (2000) Ceramide in the eukaryotic stress response. Trends Cell Biol, 10, 73-80.
Hayashi, J. (1995) [Human mitochondria and mitochondrial genome function as a single dynamic cellular unit]. Tanpakushitsu Kakusan Koso, 40, 143-150.
Herr, I., Martin-Villalba, A., Kurz, E., Roncaioli, P., Schenkel, J., Cifone, M.G. and Debatin, K.M. (1999) FK506 prevents stroke-induced generation of ceramide and apoptosis signaling. Brain Res, 826, 210-219.
Huang, P., Feng, L., Oldham, E.A., Keating, M.J. and Plunkett, W. (2000) Superoxide dismutase as a target for the selective killing of cancer cells. Nature, 407, 390-395.
Isashiki, Y., Nakagawa, M., Ohba, N., Kamimura, K., Sakoda, Y., Higuchi, I., Izumo, S. and Osame, M. (1998) Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scand, 76, 6-13.
Jonas, S., Bechstein, W.O., Lemmens, H.P., Neuhaus, R., Thalmann, U. and Neuhaus, P. (1996) Liver graft-transmitted glioblastoma multiforme. A case report and experience with 13 multiorgan donors suffering from primary cerebral neoplasia. Transpl Int, 9, 426-429.
Kerr, J.F., Wyllie, A.H. and Currie, A.R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer, 26, 239-257.
Kim, M.Y., Linardic, C., Obeid, L. and Hannun, Y. (1991) Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor alpha and gamma-interferon. Specific role in cell differentiation. J Biol Chem, 266, 484-489.
Kim, W.H., Choi, C.H., Kang, S.K., Kwon, C.H. and Kim, Y.K. (2005) Ceramide induces non-apoptotic cell death in human glioma cells. Neurochem Res, 30, 969-979.
Kolesnick, R. (2002) The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J Clin Invest, 110, 3-8.
Kolesnick, R.N., Goni, F.M. and Alonso, A. (2000) Compartmentalization of ceramide signaling: physical foundations and biological effects. J Cell Physiol, 184, 285-300.
Kong, J.Y., Klassen, S.S. and Rabkin, S.W. (2005) Ceramide activates a mitochondrial p38 mitogen-activated protein kinase: a potential mechanism for loss of mitochondrial transmembrane potential and apoptosis. Mol Cell Biochem, 278, 39-51.
Kong, W., Hu, Y., Wang, Q., Xu, L., Wang, Y., Han, Y., Li, J., Liu, B. and Kong, W. (2006) [Establishment of model with inner ear mimetic aging and mtDNA 4834 bp deletion in rats]. Lin Chuang Er Bi Yan Hou Ke Za Zhi, 20, 888-890, 893.
Koroshetz, W.J., Jenkins, B.G., Rosen, B.R. and Beal, M.F. (1997) Energy metabolism defects in Huntington''s disease and effects of coenzyme Q10. Ann Neurol, 41, 160-165.
Kroemer, G., El-Deiry, W.S., Golstein, P., Peter, M.E., Vaux, D., Vandenabeele, P., Zhivotovsky, B., Blagosklonny, M.V., Malorni, W., Knight, R.A., Piacentini, M., Nagata, S. and Melino, G. (2005) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ, 12 Suppl 2, 1463-1467.
Kroemer, G., Zamzami, N., Marchetti, P. and Castedo, M. (1995) Maintenance of the T lymphocyte pool by inhibition of apoptosis: a novel strategy of immunostimulation? Curr Top Microbiol Immunol, 200, 223-235.
Kroemer, G., Zamzami, N. and Susin, S.A. (1997) Mitochondrial control of apoptosis. Immunol Today, 18, 44-51.
Lee, J.T., Xu, J., Lee, J.M., Ku, G., Han, X., Yang, D.I., Chen, S. and Hsu, C.Y. (2004) Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol, 164, 123-131.
Lee, J.Y., Hannun, Y.A. and Obeid, L.M. (1996) Ceramide inactivates cellular protein kinase Calpha. J Biol Chem, 271, 13169-13174.
Lee, W.Y. and Lee, S.M. (2005) Ischemic preconditioning protects post-ischemic oxidative damage to mitochondria in rat liver. Shock, 24, 370-375.
Lin, C.F., Chen, C.L. and Lin, Y.S. (2006) Ceramide in apoptotic signaling and anticancer therapy. Curr Med Chem, 13, 1609-1616.
Lopez-Montero, I., Rodriguez, N., Cribier, S., Pohl, A., Velez, M. and Devaux, P.F. (2005) Rapid transbilayer movement of ceramides in phospholipid vesicles and in human erythrocytes. J Biol Chem, 280, 25811-25819.
lRuiz-Arguello, M.B., Basanez, G., Goni, F.M. and Alonso, A. (1996) Different effects of enzyme-generated ceramides and diacylglycerols in phospholipid membrane fusion and leakage. J Biol Chem, 271, 26616-26621.
Malaplate-Armand, C., Florent-Bechard, S., Youssef, I., Koziel, V., Sponne, I., Kriem, B., Leininger-Muller, B., Olivier, J.L., Oster, T. and Pillot, T. (2006) Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol Dis, 23, 178-189.
Marchesini, N. and Hannun, Y.A. (2004) Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol, 82, 27-44.
Martin, S.F., Williams, N. and Chatterjee, S. (2006) Lactosylceramide is required in apoptosis induced by N-Smase. Glycoconj J, 23, 147-157.
Mate, M.J., Ortiz-Lombardia, M., Boitel, B., Haouz, A., Tello, D., Susin, S.A., Penninger, J., Kroemer, G. and Alzari, P.M. (2002) The crystal structure of the mouse apoptosis-inducing factor AIF. Nat Struct Biol, 9, 442-446.
Mathias, S., Younes, A., Kan, C.C., Orlow, I., Joseph, C. and Kolesnick, R.N. (1993) Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1 beta. Science, 259, 519-522.
Matsko, C.M., Hunter, O.C., Rabinowich, H., Lotze, M.T. and Amoscato, A.A. (2001) Mitochondrial lipid alterations during Fas- and radiation-induced apoptosis. Biochem Biophys Res Commun, 287, 1112-1120.
Merrill, A.H., Jr. (2002) De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J Biol Chem, 277, 25843-25846.
Merrill, A.H., Jr., Sullards, M.C., Wang, E., Voss, K.A. and Riley, R.T. (2001) Sphingolipid metabolism: roles in signal transduction and disruption by fumonisins. Environ Health Perspect, 109 Suppl 2, 283-289.
Mevorach, D. (2003a) [Apoptosis: death is part of life]. Harefuah, 142, 832-833, 878.
Mevorach, D. (2003b) Systemic lupus erythematosus and apoptosis: a question of balance. Clin Rev Allergy Immunol, 25, 49-60.
Mitoma, J., Ito, M., Furuya, S. and Hirabayashi, Y. (1998) Bipotential roles of ceramide in the growth of hippocampal neurons: promotion of cell survival and dendritic outgrowth in dose- and developmental stage-dependent manners. J Neurosci Res, 51, 712-722.
Moffat, B.A., Reddy, G.R., McConville, P., Hall, D.E., Chenevert, T.L., Kopelman, R.R., Philbert, M., Weissleder, R., Rehemtulla, A. and Ross, B.D. (2003) A novel polyacrylamide magnetic nanoparticle contrast agent for molecular imaging using MRI. Mol Imaging, 2, 324-332.
Morales, A., Lee, H., Goni, F.M., Kolesnick, R. and Fernandez-Checa, J.C. (2007) Sphingolipids and cell death. Apoptosis, 12, 923-939.
Muriel, M.P., Lambeng, N., Darios, F., Michel, P.P., Hirsch, E.C., Agid, Y. and Ruberg, M. (2000) Mitochondrial free calcium levels (Rhod-2 fluorescence) and ultrastructural alterations in neuronally differentiated PC12 cells during ceramide-dependent cell death. J Comp Neurol, 426, 297-315.
Murphy, A.N., Fiskum, G. and Beal, M.F. (1999) Mitochondria in neurodegeneration: bioenergetic function in cell life and death. J Cereb Blood Flow Metab, 19, 231-245.
Nicholls, D.G. (2002) Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease. Int J Biochem Cell Biol, 34, 1372-1381.
Nishimura, G., Proske, R.J., Doyama, H. and Higuchi, M. (2001) Regulation of apoptosis by respiration: cytochrome c release by respiratory substrates. FEBS Lett, 505, 399-404.
Nordberg, J. and Arner, E.S. (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med, 31, 1287-1312.
Ogretmen, B. and Hannun, Y.A. (2004) Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer, 4, 604-616.
Okazaki, T., Bell, R.M. and Hannun, Y.A. (1989) Sphingomyelin turnover induced by vitamin D3 in HL-60 cells. Role in cell differentiation. J Biol Chem, 264, 19076-19080.
Parihar, M.S. and Brewer, G.J. (2007) Simultaneous age-related depolarization of mitochondrial membrane potential and increased mitochondrial reactive oxygen species production correlate with age-related glutamate excitotoxicity in rat hippocampal neurons. J Neurosci Res, 85, 1018-1032.
Pascher, I. (1976) Molecular arrangements in sphingolipids. Conformation and hydrogen bonding of ceramide and their implication on membrane stability and permeability. Biochim Biophys Acta, 455, 433-451.
Pettus, B.J., Chalfant, C.E. and Hannun, Y.A. (2002) Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta, 1585, 114-125.
Pinton, P., Ferrari, D., Rapizzi, E., Di Virgilio, F., Pozzan, T. and Rizzuto, R. (2001) The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. Embo J, 20, 2690-2701.
Reed, J.C. (2002) Apoptosis-based therapies. Nat Rev Drug Discov, 1, 111-121.
Rodel, G. (1994) [Mutations of the mitochondria genome. Diagnosis and pathogenetic significance]. Pathologe, 15, 315-320.
Ruberg, M., France-Lanord, V., Brugg, B., Lambeng, N., Michel, P.P., Anglade, P., Hunot, S., Damier, P., Faucheux, B., Hirsch, E. and Agid, Y. (1997) [Neuronal death caused by apoptosis in Parkinson disease]. Rev Neurol (Paris), 153, 499-508.
Schafer, P., Scholz, S.R., Gimadutdinow, O., Cymerman, I.A., Bujnicki, J.M., Ruiz-Carrillo, A., Pingoud, A. and Meiss, G. (2004) Structural and functional characterization of mitochondrial EndoG, a sugar non-specific nuclease which plays an important role during apoptosis. J Mol Biol, 338, 217-228.
Schneider-Brachert, W., Tchikov, V., Neumeyer, J., Jakob, M., Winoto-Morbach, S., Held-Feindt, J., Heinrich, M., Merkel, O., Ehrenschwender, M., Adam, D., Mentlein, R., Kabelitz, D. and Schutze, S. (2004) Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity, 21, 415-428.
Sherratt, H.S. (1991) Mitochondria: structure and function. Rev Neurol (Paris), 147, 417-430.
Shiio, Y., Donohoe, S., Yi, E.C., Goodlett, D.R., Aebersold, R. and Eisenman, R.N. (2002) Quantitative proteomic analysis of Myc oncoprotein function. Embo J, 21, 5088-5096.
Shimeno, H., Soeda, S., Sakamoto, M., Kouchi, T., Kowakame, T. and Kihara, T. (1998) Partial purification and characterization of sphingosine N-acyltransferase (ceramide synthase) from bovine liver mitochondrion-rich fraction. Lipids, 33, 601-605.
Simon, H.U., Haj-Yehia, A. and Levi-Schaffer, F. (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis, 5, 415-418.
Siskind, L.J. (2005) Mitochondrial ceramide and the induction of apoptosis. J Bioenerg Biomembr, 37, 143-153.
Siskind, L.J., Davoody, A., Lewin, N., Marshall, S. and Colombini, M. (2003) Enlargement and contracture of C2-ceramide channels. Biophys J, 85, 1560-1575.
Siskind, L.J., Fluss, S., Bui, M. and Colombini, M. (2005) Sphingosine forms channels in membranes that differ greatly from those formed by ceramide. J Bioenerg Biomembr, 37, 227-236.
Siskind, L.J., Kolesnick, R.N. and Colombini, M. (2002) Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J Biol Chem, 277, 26796-26803.
Smiley, S.T., Reers, M., Mottola-Hartshorn, C., Lin, M., Chen, A., Smith, T.W., Steele, G.D., Jr. and Chen, L.B. (1991) Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci U S A, 88, 3671-3675.
Song, M.S. and Posse de Chaves, E.I. (2003) Inhibition of rat sympathetic neuron apoptosis by ceramide. Role of p75NTR in ceramide generation. Neuropharmacology, 45, 1130-1150.
Soriano, J.M., Gonzalez, L. and Catala, A.I. (2005) Mechanism of action of sphingolipids and their metabolites in the toxicity of fumonisin B1. Prog Lipid Res, 44, 345-356.
Srinivasula, S.M., Hegde, R., Saleh, A., Datta, P., Shiozaki, E., Chai, J., Lee, R.A., Robbins, P.D., Fernandes-Alnemri, T., Shi, Y. and Alnemri, E.S. (2001) A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature, 410, 112-116.
Stockmann-Juvala, H., Mikkola, J., Naarala, J., Loikkanen, J., Elovaara, E. and Savolainen, K. (2004a) Fumonisin B1-induced toxicity and oxidative damage in U-118MG glioblastoma cells. Toxicology, 202, 173-183.
Stockmann-Juvala, H., Mikkola, J., Naarala, J., Loikkanen, J., Elovaara, E. and Savolainen, K. (2004b) Oxidative stress induced by fumonisin B1 in continuous human and rodent neural cell cultures. Free Radic Res, 38, 933-942.
Stockmann-Juvala, H., Naarala, J., Loikkanen, J., Vahakangas, K. and Savolainen, K. (2006) Fumonisin B1-induced apoptosis in neuroblastoma, glioblastoma and hypothalamic cell lines. Toxicology, 225, 234-241.
Stoica, B.A., Movsesyan, V.A., Lea, P.M.t. and Faden, A.I. (2003) Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci, 22, 365-382.
Susin, S.A., Zamzami, N., Castedo, M., Daugas, E., Wang, H.G., Geley, S., Fassy, F., Reed, J.C. and Kroemer, G. (1997a) The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J Exp Med, 186, 25-37.
Susin, S.A., Zamzami, N., Larochette, N., Dallaporta, B., Marzo, I., Brenner, C., Hirsch, T., Petit, P.X., Geuskens, M. and Kroemer, G. (1997b) A cytofluorometric assay of nuclear apoptosis induced in a cell-free system: application to ceramide-induced apoptosis. Exp Cell Res, 236, 397-403.
Therade-Matharan, S., Laemmel, E., Carpentier, S., Obata, Y., Levade, T., Duranteau, J. and Vicaut, E. (2005) Reactive oxygen species production by mitochondria in endothelial cells exposed to reoxygenation after hypoxia and glucose depletion is mediated by ceramide. Am J Physiol Regul Integr Comp Physiol, 289, R1756-1762.
Thompson, C.B. (1995) Apoptosis in the pathogenesis and treatment of disease. Science, 267, 1456-1462.
Toman, R.E., Movsesyan, V., Murthy, S.K., Milstien, S., Spiegel, S. and Faden, A.I. (2002) Ceramide-induced cell death in primary neuronal cultures: upregulation of ceramide levels during neuronal apoptosis. J Neurosci Res, 68, 323-330.
Tripathi, P. and Hildeman, D. (2004) Sensitization of T cells to apoptosis--a role for ROS? Apoptosis, 9, 515-523.
Trounce, I.A., Kim, Y.L., Jun, A.S. and Wallace, D.C. (1996) Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines. Methods Enzymol, 264, 484-509.
Wang, X. (2001) The expanding role of mitochondria in apoptosis. Genes Dev, 15, 2922-2933.
Wei, Y.H. (1998) Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med, 217, 53-63.
Willaime, S., Vanhoutte, P., Caboche, J., Lemaigre-Dubreuil, Y., Mariani, J. and Brugg, B. (2001) Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation. Eur J Neurosci, 13, 2037-2046.
Wolff, R.A., Dobrowsky, R.T., Bielawska, A., Obeid, L.M. and Hannun, Y.A. (1994) Role of ceramide-activated protein phosphatase in ceramide-mediated signal transduction. J Biol Chem, 269, 19605-19609.
Wong, M.L., Xie, B., Beatini, N., Phu, P., Marathe, S., Johns, A., Gold, P.W., Hirsch, E., Williams, K.J., Licinio, J. and Tabas, I. (2000) Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: a possible link between inflammatory cytokines and atherogenesis. Proc Natl Acad Sci U S A, 97, 8681-8686.
Yu, Z.F., Nikolova-Karakashian, M., Zhou, D., Cheng, G., Schuchman, E.H. and Mattson, M.P. (2000) Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis. J Mol Neurosci, 15, 85-97.
Yuan, H., Williams, S.D., Adachi, S., Oltersdorf, T. and Gottlieb, R.A. (2003) Cytochrome c dissociation and release from mitochondria by truncated Bid and ceramide. Mitochondrion, 2, 237-244.
Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T., Susin, S.A., Petit, P.X., Mignotte, B. and Kroemer, G. (1995) Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med, 182, 367-377.
Zhang, D. and Armstrong, J.S. (2007) Bax and the mitochondrial permeability transition cooperate in the release of cytochrome c during endoplasmic reticulum-stress-induced apoptosis. Cell Death Differ, 14, 703-715.
Zheng, T., Li, W., Wang, J., Altura, B.T. and Altura, B.M. (2000) Sphingomyelinase and ceramide analogs induce contraction and rises in [Ca(2+)](i) in canine cerebral vascular muscle. Am J Physiol Heart Circ Physiol, 278, H1421-1428.
Zoratti, M. and Szabo, I. (1994) Electrophysiology of the inner mitochondrial membrane. J Bioenerg Biomembr, 26, 543-553.
Zoratti, M. and Szabo, I. (1995) The mitochondrial permeability transition. Biochim Biophys Acta, 1241, 139-176.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊