臺灣博碩士論文加值系統

銅 (Copper, Cu) 是地殼中含量最多的金屬元素之一，在工業及日常生活中有相當廣泛的用途，銅在人體是多種酵素的輔因子，亦參與造血功能，故適當攝取銅對生理功能十分重要。然而，銅也是一種對生物有害的環境汙染物，主要來自電鍍、冶煉、廢五金處理等工業汙染及水產養殖用的除藻劑，銅汙染影響最嚴重者為我國西部海岸的「綠牡蠣」。銅的毒性機制與氧化壓力有關，銅離子 Cu2+ 能誘導活性氧物質 (Reactive oxygen species, ROS) 的大量生成，或催化物質的氧化反應，進而干擾細胞的正常運作，使抗氧化系統失衡、細胞受損、酵素活性異常、DNA 斷裂甚至誘導細胞凋亡途徑，銅離子主要對肝臟及腎臟造成毒性，也被指出和阿茲海默症有關，但其詳細機制仍不明瞭，故本研究將以阿茲海默症相關的小鼠海馬迴神經元 (HT-22) 為細胞模式，探討銅離子對腦神經細胞造成的氧化壓力及毒理機制。
研究第一部分探討銅離子之細胞毒性及氧化壓力，先以細胞存活率試驗及乳酸脫氫酶 (Lactate dehydrogenase, LDH) 活性分別為細胞死亡及受損程度指標，發現隨銅濃度上升，細胞存活率呈現穩定的降低。LDH 釋出量亦顯著增加。顯微鏡觀察下同樣發現細胞逐漸萎縮、破碎甚至懸浮。氧化壓力方面，隨著銅離子濃度增加，ROS 及氧化壓力指標總硫醇基含量分別明顯提升及減低。抗氧化酵素超氧歧化酶 (Superoxide dismutase, SOD) 活性則呈現先升後降的趨勢。綜合上述表示銅離子造成 ROS大量增加，細胞內物質氧化及抗氧化系統受抑制，使細胞死亡。
研究第二部分基於上述結果，探討銅離子造成粒線體功能異常和細胞死亡途徑。調控細胞凋亡的鈣離子濃度及粒線體膜電位 (Mitochondrial membrane potential, MMP) 分別顯著提升和降低，表示內質網壓力的提升，進一步影響 MMP 的消散。因為 MMP 和細胞呼吸作用有關，其強弱能影響能量的產出，故 ATP 生成量亦出現顯著下降。細胞死亡途徑方面，發現凋亡細胞的比例明顯較壞死細胞多，且執行凋亡反應的凋亡蛋白酶 (Cysteine dependent aspartate-specific protease-3/7, caspase-3/7) 活性亦有明顯上升，表示銅離子能夠藉由粒線體途徑對神經細胞誘導凋亡作用，在高濃度下亦能造成細胞壞死。

Copper (Cu) is one kind of the most rich metal in the earth. There are also many applications in industry. Copper is a cofactor for many enzymes involving in hematopoietic function in human body. Proper copper intake is important for physiological functions. However, copper is also a harmful environmental pollutant, mainly from industrial pollution such as electroplating, smelting, scrap metal processing and algaecide for aquaculture. The most famous case affected by copper pollution is the "green oysters" in the west coast of Taiwan, and copper pollution in water can affect the farming. The toxicity mechanism of copper is related to oxidative stress. Cu2+ can induce the formation of large amounts of reactive oxygen species (ROS) or be the catalyst of oxidation, which can interfere with the normal operation of cells, imbalance of antioxidant system, cell damage, abnormal enzyme activity, DNA cleavage and even induction of apoptosis. Copper ion is mainly harmful to the liver and kidneys and is also indicated to be associated with Alzheimer's disease, but the detailed mechanism is still unknown. Therefore, this study will use Alzheimer's disease-related mouse hippocampal neurons (HT-22) to investigate the oxidative stress and toxicological mechanism of copper ion on brain.
The chapter 1 of this study intends to investigate the cytotoxicity and oxidative stress induced by copper ion. With the increase of copper ion concentration, the cell survival rate decreased steadily. The release amount of lactate dehydrogenase (LDH) also increased significantly. The cells were also gradually atrophied, broken or even suspended. In terms of oxidative stress, ROS also increases and total thiol content decreases respectively. The antioxidant enzyme superoxide dismutase (SOD) activity shows a trend of increasing first and then decreasing. In summary, copper ion induces a large increase in ROS with neurons, resulting the induction of intracellular substance oxidation, the inhibition of antioxidant system and cells death.
Basing on the results above, the chapter 2 of this study investigates the mitochondrial dysfunction and cell death pathway induced by copper ion. Intracellular calcium concentration and mitochondrial membrane potential (MMP), which regulate apoptosis, are significantly increased and decreased respectively, indicating an increase in endoplasmic reticulum stress (ER stress) and further affecting the dissipation of MMP. Because MMP is related to cellular respiration, its strength can affect energy production, so ATP production also decreases significantly. In term of the cell death pathway, the proportion of apoptotic cells is higher than necrotic cells and the cysteine dependent aspartate-specific protease-3/7 (Caspase-3/7) activity was also increased significantly, indicating that copper ion can induce apoptosis by mitochondrial pathway and necrosis at high concentrations in the neurons.

中文摘要 ....................................................I
Abstract...................................................II
壹、文獻整理.................................................1
一、銅.......................................................2
(一) 銅的歷史及用途...........................................2
(二) 物化性質................................................2
(三) 營養及代謝..............................................3
(四) 暴露來源................................................5
(五) 毒性機制................................................5
(六) 中毒症狀................................................6
(七) 中毒案例...............................................10
(八) 食品中銅含量的檢測......................................12
二、細胞凋亡................................................13
(一) 細胞凋亡的特徵..........................................13
(二) 細胞凋亡訊號...........................................14
(三) 粒線體途徑.............................................14
(四) 死亡受體途徑...........................................15
(五) 凋亡蛋白酶.............................................16
貳、研究內容................................................17
第一章、銅離子對海馬迴神經元造成之細胞毒性及氧化傷害............18
一、前言....................................................18
二、材料及方法..............................................19
三、結果....................................................27
四、討論....................................................29
五、圖表....................................................32
第二章、探討銅離子造成神經元死亡之毒理機制.....................40
一、前言....................................................40
二、材料與方法..............................................41
三、結果....................................................46
四、討論....................................................48
五、圖表....................................................51
參、總結論..................................................59
肆、參考文獻................................................60
謝辭.......................................................73

王麗娟，1995。胺基乙磺酸 (Taurine) 對銅、鉛和鎘在大白鼠毒作用之影響。國立臺灣海洋大學水產食品科學研究所碩士學位論文。基隆。
行政院農業委員會，2017。農作物重金屬等污染監測管制作業程序 (SOP)。行政院農業委員會。台北。
行政院衛生福利部，2013。食用油中銅葉綠素之鑑別方法。行政院衛生福利部。台北。
行政院衛生福利部，2014。重金屬檢驗方法總則。行政院衛生福利部。台北。
行政院衛生福利部，2018a。食品添加物使用範圍及限量暨規格標準。行政院衛生福利部。台北。
行政院衛生福利部，2018b。食品中污染物質及毒素衛生標準。行政院衛生福利部。台北。
行政院環境保護署，2011。土壤汙染監測標準。行政院環境保護署。台北。
李育儒，2015。以細胞模式探討牛磺酸對鋁引起神經毒性之保護效果。國立臺灣海洋大學食品科學系碩士學位論文。基隆。
吳哲豪，2013。橄欖油疑不純 扣千瓶大統油品。中央通訊社。取自https://www.cna.com.tw/news/firstnews/201310160054.aspx
吳尚宜，2017。基隆產珊瑚菟葵種屬的基因鑑定及其毒素對細胞毒性之探討。國立臺灣海洋大學食品科學系碩士學位論文。基隆。
吳柏軒、周敏鴻、薛翰駿、邱奕統、吳為恭、葛祐豪、黃淑莉及羅倩宜，2014。大園工業區海岸野生石蚵 比綠牡蠣還毒。自由時報。取自http://news.ltn.com.tw/news/life/paper/782227。
周建德，2014。以細胞與動物模式探討牛磺酸對於砷中毒引起神經毒性之保護效果。國立臺灣海洋大學食品科學系博士學位論文。基隆。
林易署、陳俊桀及楊純明，2013。簡介農地之重金屬污染及其復育。行政院農業委員會農業試驗所。台中。
邱家蓁，2016。探討牛磺酸與維生素 C 作為肺癌細胞株暴露BaP之預防效果。國立臺灣海洋大學食品科學系碩士學位論文。基隆。
侯力元，2004。香山海域銅污染　牡蠣變綠！聯合報。取自https://news.tvbs.com.tw/entry/463102。
侯千絹，2001。屏縣有毒廢棄物場 變成木瓜園。自由電子新聞網。取自http://old.ltn.com.tw/2001/new/sep/6/today-c6.htm#today。
國家環境毒物研究中心，2013。國家衛生研究院關於銅葉綠素及銅葉綠素鈉等食用人工色素的說明。國家環境毒物研究中心。苗栗。
黃筱庭，2016。腐植酸在高葡萄糖環境下對於小鼠血管內皮細胞 SVEC4-10 中氧化應激反應與訊息傳遞路徑之影響。國立臺灣海洋大學食品科學系碩士學位論文。基隆。
蔡依珍，2017。滲眉埤附近農地銅超標 預防性剷除 5 公頃稻米。中時電子報。取自https://www.chinatimes.com/realtimenews/20170728006160-260405。
蔡智豪，2012。環境污染犯罪：台中又爆發農地遭重金屬汙染事件。台灣生態學會。彰化。
韓柏檉，1988。海洋環境中銅之形態，分佈，生物累積與錯合能力之研究。國立臺灣大學海洋研究所博士論文。臺北。
Al-Chalabi, A. and Leigh, P. N. 2000. Recent advances in amyotrophic lateral sclerosis. Current Opinion in Neurology 13: 397-405.
Alfonso, P., Athanase, V., Aldo, P., Vincenzo, D.T., Alessandro, F.C. 2003. The changing faces of glutathione, a cellular protagonist. Biochemical Pharmacology 66: 1499–1503.
Alnemri, E. S., Livingston, D. J., Nicholson, D. W., Salvesen, G., Thornberry, N. A., Wong, W. W. and Yuan, J. 1996. Human ICE/CED-3 protease nomenclature. Cell 87: 171.
Alvarez, A., Opazo, C., Alarcón, R., Garrido, J. and Inestrosa, N. C. 1997. Acetylcholinesterase promotes the aggregation of amyloid-β-peptide fragments by forming a complex with the growing fibrils. Journal of Molecular Biology 272: 348-361.
Aston, N. S., Watt, N., Morton, I. E., Tanner, M. S. and Evans, G. S. 2000. Copper toxicity affects proliferation and viability of human hepatoma cells (HepG2 line). Human & Experimental Toxicology 19: 367-376.
Barceloux, D.G. 1999. Copper. Journal of Toxicology: Clinical Toxicology 37: 217-237.
Barnham, K. J., Masters, C. L. and Bush, A. I. 2004. Neurodegenerative diseases and oxidative stress. Nature Reviews Drug Discovery 3: 205-214.
Belyaeva, E. A., Dymkowska, D., Więckowski, M. R. and Wojtczak, L. 2008. Mitochondria as an important target in heavy metal toxicity in rat hepatoma AS-30D cells. Toxicology and Applied Pharmacology 231: 34-42.
Belyaeva, E. A., Sokolova, T. V., Emelyanova, L. V. and Zakharova, I. O. 2012. Mitochondrial electron transport chain in heavy metal-induced neurotoxicity: effects of cadmium, mercury, and copper. The Scientific World Journal 2012: 1-15.
Bertram, L. and Tanzi, R. E. 2005. The genetic epidemiology of neurodegenerative disease. Journal of Clinical Investigation 115: 1449-1457.
Beshgetoor, D. and Hambidge, M. 1998. Clinical conditions altering copper metabolism in humans. The American Journal of Clinical Nutrition 67: 1017S-1021S.
Birket, M. J., Orr, A. L., Gerencser, A. A., Madden, D. T., Vitelli, C., Swistowski, A., Brand, M., D. and Zeng, X. 2011. A reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cells. Journal of Cell Science 124: 348-358.
Bratton, S. B., MacFarlane, M., Cain, K. and Cohen, G. M. 2000. Protein complexes activate distinct caspase cascades in death receptor and stress-induced apoptosis. Perimental Cell Research 256: 27-33.
Bremner, I., Young, B. W. and Mills, C. F. 1976. Protective effect of zinc supplementation against copper toxicosis in sheep. British Journal of Nutrition 36: 551-561.
Bremner, I. 1998. Manifestations of copper excess. The American Journal of Clinical Nutrition 67: 1069S-1073S.
Brewer, G. J. 1998. Wilson disease and canine copper toxicosis. The American Journal of Clinical Nutrition 67: 1087S-1090S.
Brewer, G. J., Dick, R. D., Johnson, V. D., Fink, J. K., Kluin, K. J. and Daniels, S. 2001. Treatment of Wilson's disease with zinc XVI: treatment during the pediatric years. Journal of Laboratory and Clinical Medicine 137: 191-198.
Budihardjo, I., Oliver, H., Lutter, M., Luo, X. and Wang, X. 1999. Biochemical pathways of caspase activation during apoptosis. Annual Review of Cell and Developmental Biology 15: 269-290.
Bush, A. I. 2000. Metals and neuroscience. Current Opinion in Chemical Biology 4: 184-191.
Cacciuttolo, M. A., Trinh, L., Lumpkin, J. A. and Rao, G. 1993. Hyperoxia induces DNA damage in mammalian cells. Free Radical Biology and Medicine 14: 267-276.
Cantle, J. E. 1986. Atomic Absorption Spectrometry. (5th ed.) Elsevier. Amsterdam, Netherlands.
Chaurio, R. A., Janko, C., Muñoz, L. E., Frey, B., Herrmann, M.and Gaipl, U. S. 2009. Phospholipids: key players in apoptosis and immune regulation. Molecules 14: 4892-4914.
Chen, D., Zhang, D., Jimmy, C. Y., and Chan, K. M. 2011. Effects of Cu2O nanoparticle and CuCl2 on zebrafish larvae and a liver cell-line. Aquatic Toxicology 105: 344-354.
Chen, X. and Yan, S. D. 2006. Mitochondrial Aβ A potential cause of metabolic dysfunction in Alzheimer's disease. IUBMB life 58: 686-694.
Chiao, P. J., Na, R., Niu, J., Sclabas, G. M., Dong, Q. and Curley, S. A. 2002. Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells. Cancer 95: 1696-1705.
Chou, C. T., Lin, H. T., Hwang, P. A., Wang, S. T., Hsieh, C. H. and Hwang, D. F. 2015. Taurine resumed neuronal differentiation in arsenite-treated N2a cells through reducing oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Amino acids 47: 735-744.
Coloso, R. M., Drake, M. R. and Stipanuk, M. H. 1990. Effect of bathocuproine disulfonate, a copper chelator, on cysteine metabolism by freshly isolated rat hepatocytes. American Journal of Physiology-Endocrinology and Metabolism 259: E443.
Combarros, O., van Duijn, C. M., Hammond, N., Belbin, O., Arias-Vásquez, A., Cortina-Borja, M., Lehmann, G. M., Aulchenko, Y. S., Schuur, M., Heike Kölsch, Heun, R., Wilcock, G. K., Brown, K., Kehoe, P. G., Harrison, R., Coto, E., Alvarez, V., Deloukas, P., Mateo, I., Gwilliam, R., Morgan, K., Warden, D. R., Smith A. D., and Heun, R. 2009. Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer's disease. Journal of Neuroinflammation 6: 22-30.
Conley, S. C. and Kirchner, J. T. 1999. Parkinson's disease-the shaking palsy: Underlying factors, diagnostic considerations, and clinical course. Postgraduate Medicine 106: 39-52.
Cosulich, S. C., Savory, P. J. and Clarke, P. R. 1999. Bcl-2 regulates amplification of caspase activation by cytochrome c. Current Biology 9: 147-150.
Dakshinamurti, K., Sharma, S. K., Sundaram, M. and Watanabe, T. 1993. Hippocampal changes in developing postnatal mice following intrauterine exposure to domoic acid. Journal of Neuroscience 13: 4486-4495.
Danks, D. M. 1988. Copper deficiency in humans. Annual Review of Nutrition 8: 235-257.
Dauer, W. and Przedborski, S. 2003. Parkinson's disease: mechanisms and models. Neuron 39: 889-909.
Dawson, R., Baker, D., Eppler, B., Tang, E., Shih, D., Hern, H. and Hu, M. 2000. Taurine inhibition of metal-stimulated catecholamine oxidation. Neurotoxicity Research 2: 1-15.
Derradji, H. and Baatout, S. 2003. Apoptosis: a mechanism of cell suicide. In Vivo 17: 185-192.
Dickson D. V. 2007. Neuropathology of movement disorders. In Tolosa E. and Jankovic J.J. (Eds) Parkinson's Disease and Movement Disorders. (pp.271–283). Lippincott Williams & Wilkins, Hagerstown, MD.
DiSilvestro, R. A. and Cousins, R. J. 1983. Physiological ligands for copper and zinc. Annual Review of Nutrition 3: 261-288.
Elchuri, S., Oberley, T. D., Qi, W., Eisenstein, R. S., Roberts, L. J., Van Remmen, H., Epstein, C., J. and Huang, T. T. 2005. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24: 367-380.
Elmore, S. 2007. Apoptosis: a review of programmed cell death. Toxicologic Pathology 35: 495-516.
Enghag, P. 2004. Encyclopedia of the Elements. Wiley-Verlag GmbH & Co. KGaA, Weinheim, Germany.
Fadok, V.A., Voelker, D.R., Campbell, P.A., Cohen, J.J., Bratton, D.L., and Henson, P.M. 1992. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. The Journal of Immunology 148: 2207-2216.
Faraci, F., M. and Didson, S., P. 2004. Vascular protection: Superoxide dismutaseisoforms in the vessel wall. Arteriosclerosis, thrombosis, and vascular. Biology 24: 1367-1373.
Fassel, V. A. and Kniseley, R. N. 1974. Inductively coupled plasma. Optical emission spectroscopy. Analytical Chemistry 46: 1110-1120.
Feinstein, D. L., Heneka, M. T., Gavrilyuk, V., Russo, C. D., Weinberg, G. and Galea, E. 2002. Noradrenergic regulation of inflammatory gene expression in brain. Neurochemistry International 41: 357-365.
Fitzgerald, D. J. 1998. Safety guidelines for copper in water. The American Journal of Clinical Nutrition 67: 1098S-1102S.
Fleury, C., Mignotte, B. and Vayssière, J. L. 2002. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 84: 131-141.
Food and Nutrition Board, Institute of Medicine, 2002. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iron, Iodine, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academy Press, Washington, DC.
Förstl, H. and Kurz, A. 1999. Clinical features of Alzheimer’s disease. European Archives of Psychiatry and Clinical Neuroscience 249: 288-290.
Friedman, S. and Kaufman, S. 1966. An electron paramagnetic resonance study of 3, 4-dihydroxyphenylethylamine β-hydroxylase. Journal of Biological Chemistry 241: 2256-2259.
Gaetke, L. M. and Chow, C. K. 2003. Copper toxicity, oxidative stress, and antioxidant nutrients. Toxicology 189: 147-163.
Gaggelli, E., Kozlowski, H., Valensin, D. and Valensin, G. 2006. Copper homeostasis and neurodegenerative disorders (Alzheimer's, prion, and Parkinson's diseases and amyotrophic lateral sclerosis). Chemical Reviews 106: 1995-2044.
Gill, S. S., Hou, Y., Ghane, T. and Pulido, O. M. 2008. Regional susceptibility to domoic acid in primary astrocyte cells cultured from the brain stem and hippocampus. Marine Drugs 6: 25-38.
Groner, Y., Elroy-Sterol, O., Avraham, K. B., Schickler, M., Knobler, H., Minc-Golomb, D., Bar-Peled, O., Yarom, R. and Rotshenker, S. 1994. Cell damage by excess CuZnSOD and Down's syndrome. Biomedicine & Pharmacotherapy 48: 231-240.
Halliwell, B. and Gutteridge, J. M. 1990. [1] Role of free radicals and catalytic metal ions in human disease: An overview. In Methods in Enzymology (pp. 1-85). Academic Press, Cambridge, MA.
Heath, C. J. and Picciotto, M. R. 2009. Nicotine-induced plasticity during development: modulation of the cholinergic system and long-term consequences for circuits involved in attention and sensory processing. Neuropharmacology 56: 254-262.
Hengartner, M. O. 2000. The biochemistry of apoptosis. Nature 407: 770-776.
Hernández F. and Avila J. 2007. Tauopathies. Cellular and Molecular Life Sciences. 64: 2219–33.
Holleman, A. F. and Wiberg, N. 2001. Inorganic Chemistry. Academic Press, Cambridge, MA.
Inestrosa, N. C., Alvarez, A., Perez, C. A., Moreno, R. D., Vicente, M., Linker, C., Casanueva, O. I., Soto, C. and Garrido, J. 1996. Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme. Neuron 16: 881-891.
Jacob, R. A., Skala, J. H., Omaye, S. T. and Turnlund, J. R. 1987. Effect of varying ascorbic acid intakes on copper absorption and ceruloplasmin levels of young men. The Journal of Nutrition 117: 2109-2115.
Jacobson, M. D. 1996. Reactive oxygen species and programmed cell death. Trends in Biochemical Sciences 21: 83-86.
JECFA (The Joint FAO/WHO Expert Committee on Food Additives). 1978. Chlorophyllins, Copper Complexes Sodium and Potassium Salts. World Health Organization, Geneva, Switzerland.
Johnson, V. J., Kim, S. H. and Sharma, R. P. 2005. Aluminum-maltolate induces apoptosis and necrosis in neuro-2a cells: Potential role for p53 signaling. Toxicological Sciences 83: 329-339.
Jung, Y. J. and Surh, Y. J. 2001. Oxidative DNA damage and cytotoxicity induced by copper-stimulated redox cycling of salsolinol, a neurotoxic tetrahydroisoquinoline alkaloid. Free Radical Biology and Medicine 30: 1407-1417.
Jürgensmeier, J. M., Xie, Z., Deveraux, Q., Ellerby, L., Bredesen, D. and Reed, J. C. 1998. Bax directly induces release of cytochrome c from isolated mitochondria. Proceedings of the National Academy of Sciences 95: 4997-5002.
Kadiiska, M. B., Hanna, P. M., Jordan, S. J. and Mason, R. P. 1993. Electron spin resonance evidence for free radical generation in copper-treated vitamin E-and selenium-deficient rats: in vivo spin-trapping investigation. Molecular Pharmacology 44: 222-227.
Kehrer, J. P. 1993. Free radicals as mediators of tissue injury and disease. Critical
Reviews in Toxicology 23: 21-48.
Kim, D. K., Song, J. W., Park, J. D. and Choi, B. S. 2013. Copper induces the accumulation of amyloid-beta in the brain. Molecular & Cellular Toxicology 9: 57-66.
Kleizen, B. and Braakman, I. 2004. Protein folding and quality control in the endoplasmic reticulum. Current Opinion in Cell Biology 16: 343-349.
Klevay, L. M. 1997. Copper as a supplement to iron for hemoglobin building in the rat. Journal of Nutrition 127: 1034S-1036S.
Knobeloch, L., Schubert, C., Hayes, J., Clark, J., Fitzgerald, C. and Fraundorff, A. 1998. Gastrointestinal upsets and new copper plumbing--is there a connection?. Wisconsin Medical Journal 97: 49-53.
Kowaltowski, A. J., Castilho, R. F. and Vercesi, A. E. 1996. Opening of the mitochondrial permeability transition pore by uncoupling or inorganic phosphate in the presence of Ca2+ is dependent on mitochondrial‐generated reactive oxygen species. FEBS Letters 378: 150-152.
Kowaltowski, A. J., Castilho, R. F. and Vercesi, A. E. 2001. Mitochondrial permeability transition and oxidative stress. FEBS Letters 495: 12-15.
Kroemer, G., Petit, P. A. T. R. I. C. E., Zamzami, N. A. O. U. F. A. L., Vayssiere, J. L., and Mignotte, B. 1995. The biochemistry of programmed cell death. The FASEB Journal 9: 1277-1287.
Kumar, V., Abbas, A., Nelson, F. and Mitchell, R. 2007. Robbins Basic Pathology (8th ed.). Elsevier Science Health Science, Amsterdam, Netherlands.
Landner, L. and Lindeström, L. 1999. Copper in Society and in the Environment. Swedish Environmental Research Group, Stockholm, Sweden.
Lee, A. S. 2005. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 35: 373-381.
Liang, Q., Jing, H. and Gregoire, D. C. 2000. Determination of trace elements in granites by inductively coupled plasma mass spectrometry. Talanta 51: 507-513.
Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L. and Markesbery, W. R. 1998. Copper, iron and zinc in Alzheimer's disease senile plaques. Journal of the Neurological Sciences 158: 47-52.
Lushchak V. I. 2012. Glutathione homeostasis and function: Potential targets for medical interventions. Journal of Amino Acids 2012: 1-26.
Luza, S. C. and Speisky, H. C. 1996. Liver copper storage and transport during development: implications for cytotoxicity. The American Journal of Clinical Nutrition 63: 812S-820S.
Moser, C. C., Farid, T. A., Chobot, S. E. and Dutton, P. L. 2006. Electron tunneling chains of mitochondria. Biochimica et Biophysica Acta (BBA)-Bioenergetics 1757: 1096-1109.
Mravec, B. 2006. Salsolinol, a derivate of dopamine, is a possible modulator of catecholaminergic transmission: A review of recent developments. Physiological Research 55: 353-364.
Muller, F. L., Song, W., Liu, Y., Chaudhuri, A., Pieke-Dahl, S., Strong, R., Huang, T. T., Epsteing, C., J., Roberts II, J., Csete M. and Faulkner, J. A. 2006. Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radical Biology and Medicine 40: 1993-2004.
Multhaup, G., Hesse, L., Borchardt, T., Ruppert, T., Cappai, R., Masters, C. L. and Beyreuther, K. 1999. Autoxidation of amyloid precursor protein and formation of reactive oxygen species. In Linder, M., C. (Ed.) Copper Transport and Its Disorders (pp. 183-192). Springer, Boston, MA.
Murakami, H. and Nurse, P. 2000. DNA replication and damage checkpoints and meiotic cell cycle controls in the fission and budding yeasts. The Biochem Journal 349: 1-12.
Murphy, A. N. 1999. Ca2+ -mediated mitochondrial dysfunction and the protective effects of Bcl-2. Annals of the New York Academy of Sciences 893: 19-32.
Murrell, J., Farlow, M., Ghetti, B. and Benson, M. D. 1991. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254: 97-99.
Myers, B. M., Prendergast, F. G., Holman, R., Kuntz, S. M., & Larusso, N. F. 1993. Alterations in hepatocyte lysosomes in experimental hepatic copper overload in rats. Gastroenterology 105: 1814-1823.
Nachlas, M. M., Margulies, S. I., Goldberg, J. D. and Seligman, A. M. 1960. The determination of lactic dehydrogenase with a tetrazolium salt. Analytical Biochemistry 1: 317-326.
Nicholson, D. W. and Thornberry, N. A. 1997. Caspases: Killer proteases. Trends in Biochemical Sciences 22: 299-306.
Nicotera, P., Leist, M. and Ferrando-May, E. 1999. Apoptosis and necrosis: Different execution of the same death. In Baldwin, B. (Ed.) Biochemical Society Symposia (Vol. 66, pp. 69-73). Portland Press Limited, London, UK.
Parone, P. A., James, D., and Martinou, J. C. 2002. Mitochondria: Regulating the inevitable. Biochimie 84: 105-111.
Perry, J. J. P., Shin, D. S. and Tainer, J. A. 2010. Amyotrophic lateral sclerosis. In Shamim, M., I. (Ed.) Diseases of DNA Repair (pp. 9-20). Springer, New York, USA.
Pinton P, Brini M, Bastianutto C, Tuft RA, Pozzan T and Rizzuto R. 1998. New light on mitochondrial calcium. Biofactors 8: 243–253.
Pinton, P., Giorgi, C., Siviero, R., Zecchini, E., & Rizzuto, R. 2008. Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene 27: 350-358.
Ponsoda, X., Jover, R., Castell, J. V. and Gómez-Lechón, M. J. 1991. Measurement of intracellular LDH activity in 96-well cultures: A rapid and automated assay for cytotoxicity studies. Journal of Tissue Culture Methods 13: 21-24.
Powell, S. R. 2000. The antioxidant properties of zinc. The Journal of Nutrition 130: 1447S-1454S.
Puri, S. C. and Mullen, K. 1980. Applied Statistics for Food and Agricultural Scientists. GK Hall, Boston, MA.
Purves, D., Augustine, G. J., Fitzpatrick, D., Katz, L. C., LaMantia, A. S., McNamara, J. O. and Williams, S. M. 2001. Neuroscience (2nd ed.). Sunderland, MA: Sinauer Associates.
Rai, K. S., Hattiangady, B. and Shetty, A. K. 2007. Enhanced production and dendritic growth of new dentate granule cells in the middle‐aged hippocampus following intracerebroventricular FGF‐2 infusions. European Journal of Neuroscience 26: 1765-1779.
Rajput, V. S., Gupta, S. N., Sur, B. K., Pandey, R. P. and Singh, S. 1979. An evaluation of serum copper levels in diagnosis of various malignancies. Indian Journal of Surgery 5: 515-519.
Rayner W. H. 2007. Jewelrymaking Through History: an Encyclopedia. Greenwood Publishing Group, Westport, CT.
Richter, C., Gogvadze, V., Laffranchi, R., Schlapbach, R., Schweizer, M., Suter, M., -Walter, P. and Yaffee, M. 1995. Oxidants in mitochondria: from physiology to diseases. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1271: 67-74.
Rodhe, Y., Skoglund, S., Wallinder, I. O., Potácová, Z. and Möller, L. 2015. Copper-based nanoparticles induce high toxicity in leukemic HL60 cells. Toxicology in Vitro 29: 1711-1719.
Ron, D. 2002. Translational control in the endoplasmic reticulum stress response. The Journal of Clinical Investigation 110: 1383-1388.
Rossi, A., Poverini, R., Di Lullo, G., Modesti, A., Modica, A. and Scarino, M. L. 1996. Heavy metal toxicity following apical and basolateral exposure in the human intestinal cell line Caco-2. Toxicology in Vitro 10: 27-36.
Scanni, A., Licciardello, L., Trovato, M., Tomirotti, M. and Biraghi, M. 1977. Serum copper and ceruloplasmin levels in patients with neoplasias localized in the stomach, large intestine or lung. Tumori Journal 63:175-180.
Schröder, M. and Kaufman, R. J. 2005. ER stress and the unfolded protein response. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 569: 29-63.
Searle, J. 1982. Necrosis and apoptosis: distinct modes of cell death with fundamentally different significance. Pathology Annual 17: 229-259.
Sedlak, J. and Lindsay, R. H. 1968. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Analytical Biochemistry 25: 192-205.
Semple, A. B., Parry, W. H. and Phillips, D. E. 1960. Acute copper poisoning. An outbreak traced to contaminated water from a corroded geyser. Lancet 700-701.
Senard, J. M. and Rouet, P. 2006. Dopamine beta-hydroxylase deficiency. Orphanet Journal of Rare Diseases: 1: 1-7.
Shen, H. M., Dong, S. Y. and Ong, C. N. 2001. Critical role of calcium overloading in cadmium-induced apoptosis in mouse thymocytes. Toxicology and Applied Pharmacology 171: 12-19.
Sherr, C. J. and Roberts, J. M. 1999. CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes and Development 13: 1501-1512.
Shriner, R. L., Hermann, C. K. F., Morrill, T. C., Curtin, D. Y. and Fuson, R. C. 2003. Thesystematic Identification of Organic Compounds. John Wiley and Sons, New York, USA.
Simizu, S., Takada, M., Umezawa, K. amd Imoto, M. 1998. Requirement of caspase-3 (-like) protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs. Journal of Biological Chemistry 273: 26900-26907.
Sinha, M., Manna, P. and Sil, P. C. 2008. Arjunolic acid attenuates arsenic-induced nephrotoxicity. Pathophysiology 15: 147-156.
Smaili, S., Hsu, Y.-T., Carvalho, A., Rosenstock, T., Sharpe, J. and Youle, R. 2003. Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling. Brazilian Journal of Medical and Biological Research 36: 183-190.
Sokol, R. J., Devereaux, M. W., Traber, M. G. and Shikes, R. H. 1989. Copper toxicity and lipid peroxidation in isolated rat hepatocytes: effect of vitamin E. Pediatric Research 25: 55-62.
Sokol, R. J., Deverbaux, M., Mierau, G. W., Hambidge, K. M. and Shikes, R. H. 1990. Oxidant injury to hepatic mitochondrial lipids in rats with dietary copper overload: modification by vitamin E deficiency. Gastroenterology 99: 1061-1071.
Sokol, R. J., Deverbaux, M. W., O'Brien, K., Khandwala, R. A. and Loehr, J. P. 1993. Abnormal hepatic mitochondrial respiration and cytochrome C oxidase activity in rats with long-term copper overload. Gastroenterology 105: 178-187.
Spencer, W. A., Jeyabalan, J., Kichambre, S. and Gupta, R. C. 2011. Oxidatively generated DNA damage after Cu (II) catalysis of dopamine and related catecholamine neurotransmitters and neurotoxins: Role of reactive oxygen species. Free Radical Biology and Medicine 50: 139-147.
Spitalny, K. C., Brondum, J., Vogt, R. L., Sargent, H. E. and Kappel, S. 1984. Drinking-water-induced copper intoxication in a Vermont family. Pediatrics 74: 1103-1106.
Stumm, W. and Morgan, J. J. 1996. Aquatic Chemistry. Wiley Interscience, New York, NY.
Suh, J. and Rabson, A. B. 2004. NF‐κB activation in human prostate cancer: Important mediator or epiphenomenon?. Journal of Cellular Biochemistry 91: 100-117.
Sveinbjornsdottir, S. 2016. The clinical symptoms of Parkinson's disease. Journal of Neurochemistry 139: 318–324.
Szalai G, Krishnamurthy R and Hajnoczky G. 1999. Apoptosis driven by IP(3)-linked mitochondrial calcium signals. EMBO Journal 18: 6349–6361.
Tainer, J. A., Getzoff, E. D., Richardson, J. S. and Richardson, D. C. 1983. Structure and mechanism of copper, zinc superoxide dismutase. Nature 306: 284-287.
Taylor, K. B. 1974. Dopamine-β-hydroxylase Stereochemical course of the reaction. Journal of Biological Chemistry 249: 454-458.
Teif, V. B. and Rippe, K. 2009. Predicting nucleosome positions on the DNA: combining intrinsic sequence preferences and remodeler activities. Nucleic acids research 37: 5641-5655.
Thornberry, N. A., Rosen, A. and Nicholson, D. W. 1997. Control of apoptosis by proteases. Advances in Pharmacology: 41 155-177.
Tsukihara T., Aoyama H., Yamashita E., Tomizaki T., Yamaguchi H., Shinzawa-Itoh K., Nakashima R., Yaono R., Yoshikawa S. 1995. Structures of metal sites of oxidized bovine heart cytochrome c oxidase at 2.8 Å. Science 269: 1069-1074.
Turnlund, J. R., Scott, K. C., Peiffer, G. L., Jang, A. M., Keyes, W. R., Keen, C. L and Sakanashi, T. M. 1997. Copper status of young men consuming a low-copper diet. The American Journal of Clinical Nutrition 65: 72-78.
Turnlund, J. R. 1988. Copper nutriture, bioavailability, and the influence of dietary factors. Journal of the American Dietetic Association 88: 303-308.
Turnlund, J.R. 1999. Copper. In Shils, M.E. et al. (Eds). Modern Nutrition in Health and Disease. Lippincott Williams and Wilkins, Baltimore, MD.
Van Meerloo, J., Kaspers, G. J. and Cloos, J. 2011. Cell sensitivity assays: The MTT assay. In Abbott, A. (Ed.) Cancer Cell Culture (pp. 237-245). Humana Press, New York, NY.
Vessoni, A. T., Quinet, A., de Andrade-Lima, L. C., Martins, D. J., Garcia, C. C. M., Rocha, C. R. R., and Menck, C. F. M. 2016. Chloroquine-induced glioma cells death is associated with mitochondrial membrane potential loss, but not oxidative stress. Free Radical Biology and Medicine 90: 91-100.
Vilaplana, J., Romaguera, C., Grimalt, F. Cornellana, F. 1991. New trends in the use of metals in jewellery. Contact Dermatitis 25: 145-148.
Wang, H. Y., Lee, D. H., D'Andrea, M. R., Peterson, P. A., Shank, R. P. and Reitz, A. B. 2000. β-Amyloid1–42 binds to α7 nicotinic acetylcholine receptor with high affinity implications for Alzheimer's disease pathology. Journal of Biological Chemistry 275: 5626-5632.
Wang, W., Esbensen, Y., Kunke, D., Suganthan, R., Rachek, L., Bjørås, M. and Eide, L. 2011. Mitochondrial DNA damage level determines neural stem cell differentiation fate. Journal of Neuroscience 31: 9746-9751.
Weil, M., Jacobson, M., Coles, H., Davies, T., Gardner, R., Raff, K. and Raff, M. 1996. Constitutive expression of the machinery for programmed cell death. Journal of Cell Biology 133: 1053-1059.
WHO (World Health Organization). 1996a. Copper in Drinking-water (pp. 1-23). World Health Organization, Geneva, Switzerland.
WHO (World Health Organization). 1996b. Cu. In: Trace Elements in Human Nutrition and Health (pp. 123-143). World Health Organization, Geneva, Switzerland.
Wijesekera, L. C. and Leigh, P. N. 2009. Amyotrophic lateral sclerosis. Orphanet Journal of Rare Diseases 4: 3-24.
Wikström, M. 2000. Proton translocation by cytochrome c oxidase: a rejoinder to recent criticism. Biochemistry 39: 3515-3519.
Wimmer, T., Cohen, G., Saemann, M. D. and Hörl, W. H. 2004. Effects of Tamm–Horsfall protein on polymorphonuclear leukocyte function. Nephrology Dialysis Transplantation 19: 2192-2197.
Winge, D. R. and Mehra, R. K. 1990. Host defenses against copper toxicity. In David R., K. (Ed.) International Review of Experimental Pathology (pp. 47-83). Academic Press, Cambridge, MA.
Xia, Z., Lundgren, B., Bergstrand, A., DePierre, J. W. and Nässberger, L. 1999. Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-XL. Biochemical Pharmacology 57: 1199-1208.
Zhang, J., Mori, A., Chen, Q. and Zhao, B. 2006. Fermented papaya preparation attenuates β-amyloid precursor protein: β-Amyloid–mediated copper neurotoxicity in β-amyloid precursor protein and β-amyloid precursor protein Swedish mutation overexpressing SH-SY5Y cells. Neuroscience 143: 63-72.