臺灣博碩士論文加值系統

黴菌毒素 (mycotoxins) 為真菌類所產生之低分子量的二次代謝物 (secondary metabolites)。赭麴毒素 (ochratoxin, OT) 主要是由麴黴菌屬 (Aspergillus) 和青黴菌屬 (Penicillium) 在黴變的飼料、穀類及咖啡豆中所產生的次級代謝物，其中以赭麴毒素A (ochratoxin A, 簡稱OTA) 的毒性最強，由於OTA廣泛地存在於食物及飼料中，因此，對於人類及動物的健康威脅很大。先前有許多研究證實OTA具有腎臟毒性、肝臟毒性、致畸胎毒性、基因毒性、免疫抑制性及致癌性，由於具有物種及性別特異性，在人類疾病中，OTA被認為可能是造成巴爾幹半島腎病變 (Balkan endemic nephropathy, BEN) 的原因之一，先前文獻指出OTA會經由抑制蛋白質合成、活化氧化壓力、促進細胞凋亡、影響鈣離子平衡等機制進而導致病變，然而對於OTA造成的腎臟傷害多以動物模式為主，在人類腎臟細胞中的詳細分子機制仍有待更多研究來釐清。當細胞受到壓力時，內質網會啟動未摺疊蛋白反應 (unfolded protein response, 簡稱UPR) 來緩解壓力，然而，鮮少有研究去探討OTA與UPR之間的關聯，因此，本實驗欲探討OTA在腎臟中是否會經由UPR去調控後續結果。本實驗以人類腎臟近曲小管上皮細胞 (human renal proximal tubular epithelial cells, 簡稱HK-2) 為實驗對象，首先進行細胞存活率試驗 (MTS assay)，觀察到OTA處理下細胞存活率明顯降低，進一步以流式細胞儀分析細胞週期，可以觀察到HK-2細胞在20 μM OTA處理下sub-G1 phase的細胞數明顯增加，再以西方墨點法分析細胞凋亡指標蛋白PARP的表現量，隨著OTA處理時間增加有上升的趨勢。綜合上述結果，推測OTA在HK-2細胞中會促進細胞凋亡。接著去分析在HK-2細胞中給予OTA是否會活化UPR途徑，以西方墨點法分析UPR路徑之蛋白 (Bip、ATF6、p-eIF2α、p-IRE1α)，實驗結果顯示，在20 μM OTA處理下，上述UPR路徑之蛋白皆有被誘導表現。再以西方墨點法分析UPR相關細胞凋亡路徑 (CHOP、caspase-4及JNK)，實驗結果顯示，只有JNK途徑有被活化。已知活性氧物質 (reactive oxygen species, 簡稱ROS) 的增加會活化JNK途徑，因此，以DCFDA偵測法觀察給予OTA後細胞內ROS的變化，實驗結果顯示ROS隨著OTA濃度增加有上升的趨勢，進一步給予ROS抑制劑－N-acetyl cysteine (NAC) 並分析細胞中ROS含量與細胞凋亡蛋白之變化量，結果顯示，合併NAC處理後能有效降低細胞中因OTA所引起的ROS增加，並能降低PARP的表現，然而，JNK的表現則未受影響。綜合上述結果，本篇研究確認了OTA在HK-2細胞中造成ROS增加最終導致細胞凋亡，然而JNK在這其中所扮演的角色是傾向細胞凋亡或是細胞存活仍有待進一步實驗來釐清。

Mycotoxins are the secondary metabolites produced by certain fungi that are capable of causing disease and death in human and other animals. Ochratoxin (OT) is a mycotoxin produced by Aspergillus and Penicillium. Ochratoxin A (OTA) is the most prevalent and deleterious toxin of this group, it is known to occur in commodities such as animal feeds, cereals and coffee. The exposure of the animal and human population to OTA represents a worldwide problem. Previous studies show that OTA is nephrotoxic, hepatotoxic, teratogenic, genotoxic, immunotoxic and carcinogenic to several species , which characterize in species and sex specificity manner. Epidemiological evidences suggest that OTA may be the risk factor of Balkan endemic nephropathy (BEN). To date, the mechanism of OTA leads to nephropathy remains controversial. Several mechanisms have been reported such as inhibition of protein synthesis, induction of reactive oxygen species (ROS), activation of apoptosis and disruption of calcium homeostasis. When cells counter stress, they will activate unfolded protein response (UPR) to restore normal function by suspending protein synthesis, activation of chaperon expression and degradation of misfolded protein. Overwhelmed stress, will lead to the activation of apoptosis. However, the relation between OTA and UPR in human remains unclear. Thus, the aim of this study is to investigate whether OTA induces UPR in human kidney. We use HK-2 cell as in vitro model. After OTA treatment, cell viability was decreased in a dose-dependent manner. In cell cycle study, OTA increased sub-G1 phase of HK-2 cell. The protein level of PARP, a marker of apoptosis, increased in a time-dependent manner. These results indicated that OTA induce apoptosis in HK-2 cell. To identify the relation between OTA and UPR, we analyzed the protein involved in UPR such as Bip, ATF6, p-eIF2α and p-IRE1α. Expression level of the proteins was increased by OTA treatment. Furthermore, we investigated which apoptosis pathway were induced by OTA treatment. The results showed that OTA induced JNK phosphorylatuin but not CHOP and caspase-4 dependent manner. It is known that increased ROS cause activation of JNK. Thus, we used DCFDA assay to detect ROS level after OTA treatment. The result revealed that ROS level significantly increased after OTA treatment. Next, we used NAC, an inhibitor of ROS, to examine the ROS and protein level. ROS and PARP level were significantly decreased by NAC treatment. Notably, treatment with NAC did not inhibit p-JNK induction. Taken together, our results suggested that OTA induced apoptosis in HK-2 cell through increasing ROS level. However, we need more experiments to examine whether JNK pathway lead to apoptosis or cell survival.

口試委員會審定書 I
誌謝 II
摘要 III
Abstract V
縮寫表 VII
第一章、緒論 (Introduction) 1
1.1. 慢性腎臟病 (Chronic kidney disease, CKD) 1
1.2. 赭麴毒素A (Ochratoxin A, OTA) 2
1.2.1. OTA的容許攝入限量 5
1.2.2. OTA的毒物動力學 (Toxicokinetics) 5
1.2.3. OTA的生物轉化 (Biotransformation) 7
1.2.4. OTA的腎臟毒性 (Nephrotoxicity) 8
1.2.5. OTA的肝臟毒性 (Hepatotoxicity) 9
1.2.6. OTA的致畸胎毒性 (Teratogenicity) 9
1.2.7. OTA的致癌性 (Carcinogenicity) 10
1.2.8. OTA誘導的細胞凋亡 (Apoptosis) 與氧化應激 (Oxidative stress) 11
1.3. 內質網壓力 (Endoendoplasmic reticulum stress, ER stress) 12
1.4. 細胞凋亡 (Apoptosis) 13
1.4.1. 外來途徑 (Extrinsic pathway) 15
1.4.2. 粒線體調控途徑 (Mitochondrial-mediated pathway) 16
1.4.3. 內質網調控途徑 (Endoplasmic reticulum-mediated pathway) 16
1.4.4. 穿孔素/顆粒溶解酶路徑 (perforin/granzyme pathway) 18
1.4.5. 執行途徑 (Execution pathway) 18
1.5. 研究動機與目的 (Motive and Objective) 19
第二章、材料與方法 (Materials and Methods) 20
2.1. 實驗材料 (Materials) 20
2.1.1. 細胞株 (Cell line) 20
2.1.2. 細胞培養材料 (Materials of cell culture) 20
2.1.3. 化學藥品 (Chemicals) 20
2.1.4. 反應試劑 (Reagents) 21
2.1.5. 儀器與器材 (Instruments and Equipment) 21
2.2. 實驗方法 (Methods) 21
2.2.1. 細胞培養 (Cell culture) 21
2.2.2. 細胞冷凍保存 (Cell freezing) 22
2.2.3. 細胞存活率試驗 (MTS assay) 22
2.2.4. 核糖核酸萃取 (RNA extraction) 23
2.2.5. 反轉錄作用 (Reverse transcription reaction, RT reaction) 23
2.2.6. 半定量聚合酶連鎖反應 (Semi-quantitative Polymerase Chain Reaction, Semi-quantitative PCR) 24
2.2.7. 細胞內活性氧化物 (Intracellular reactive oxygen species, ROS) 測定法 25
2.2.8. 流式細胞儀 (Flow cytometry)－細胞週期分析 25
2.2.9. 蛋白質分析－西方墨點法 (Western blotting assay) 26
2.2.10. 抗體 (Antibody) 27
2.2.11. 統計分析 (Statistical analysis) 27
第三章、結果 (Results) 28
3.1. OTA經由活化細胞凋亡使HK-2細胞的細胞存活率降低 28
3.2. OTA活化HK-2細胞中內質網壓力所誘導的UPR途徑 29
3.3. OTA在HK-2細胞中活化與JNK相關之細胞凋亡途徑 30
3.4. OTA處理下造成HK-2細胞中ROS的活化 31
3.5.以ROS抑制劑－ NAC處理後對OTA在HK-2細胞中造成的影響 31
第四章、討論 (Discussions) 33
4.1. OTA經由JNK訊息傳遞路徑誘導ROS發生之機制探討 33
4.2. OTA未誘導CHOP表現之探討 34
4.3. OTA未誘導XBP1s表現之探討 35
4.4. Caspase-4在內質網壓力誘導的細胞凋亡中所扮演的角色 36
4.5. 以動物模式探討OTA的急毒性對腎臟之影響 37
第五章、結論 (Conclusion) 38
第六章、參考文獻 (Reference) 39
第七章、圖表 (Figures) 49
【圖一】OTA造成人類腎臟近曲小管上皮細胞HK-2的型態改變並降低其 存活率 50
【圖二】OTA經由細胞凋亡造成HK-2細胞密度減低 52
【圖三】OTA改變HK-2細胞ATF6路徑的蛋白表現量 53
【圖四】OTA改變HK-2細胞PERK路徑的蛋白表現量 54
【圖五】OTA改變HK-2細胞IRE1路徑的蛋白表現量 55
【圖六】OTA改變HK-2細胞中XBP1 的mRNA表現量 56
【圖七】OTA改變HK-2細胞中細胞凋亡路徑的蛋白表現量 58
【圖八】OTA處理下造成HK-2細胞中ROS的活化 59
【圖九】NAC處理下抑制OTA所引起的ROS活化 60
【圖十】NAC處理下抑制OTA所引起的PARP活化 61
【圖十一】NAC處理下無法抑制OTA所引起的p-JNK活化 62

Abdu, S. B. (2011). The protective role of Ajwa date against the hepatotoxicity induced by Ochratoxin A. Egyp J Nat Tox, 8, 1-15.
Abouzied, M. M., Horvath, A. D., Podlesny, P. M., Regina, N. P., Metodiev, V. D., Kamenova-Tozeva, R. M., . . . Ganev, V. S. (2002). Ochratoxin A concentrations in food and feed from a region with Balkan Endemic Nephropathy. Food Addit Contam, 19(8), 755-764.
Adachi, Y., Yamamoto, K., Okada, T., Yoshida, H., Harada, A., & Mori, K. (2008). ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct, 33(1), 75-89.
Adler, V., Yin, Z., Fuchs, S. Y., Benezra, M., Rosario, L., Tew, K. D., . . . Ronai, Z. (1999). Regulation of JNK signaling by GSTp. Embo j, 18(5), 1321-1334.
Adrain, C., Creagh, E. M., & Martin, S. J. (2001). Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2. Embo j, 20(23), 6627-6636.
Albassam, M. A., Yong, S. I., Bhatnagar, R., Sharma, A. K., & Prior, M. G. (1987). Histopathologic and electron microscopic studies on the acute toxicity of ochratoxin A in rats. Vet Pathol, 24(5), 427-435.
Appelgren, L. E., & Arora, R. G. (1983). Distribution studies of 14C-labelled aflatoxin B1 and ochratoxin A in pregnant mice. Vet Res Commun, 7(1-4), 141-144.
Ashkenazi, A., & Dixit, V. M. (1998). Death receptors: signaling and modulation. Science, 281(5381), 1305-1308.
Assaf, H., Azouri, H., & Pallardy, M. (2004). Ochratoxin A induces apoptosis in human lymphocytes through down regulation of Bcl-xL. Toxicol Sci, 79(2), 335-344.
Atroshi, F., Biese, I., Saloniemi, H., Ali-Vehmas, T., Saari, S., Rizzo, A., & Veijalainen, P. (2000). Significance of apoptosis and its relationship to antioxidants after ochratoxin A administration in mice. J Pharm Pharm Sci, 3(3), 281-291.
Barry, M., & Bleackley, R. C. (2002). Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol, 2(6), 401-409.
Bendele, A. M., Carlton, W. W., Krogh, P., & Lillehoj, E. (1985). Ochratoxin A Carcinogenesis in the (C57BL/6J× C3H) F1 Mouse 2 3. J Natl Cancer Inst, 75(4), 733-742.
Bennett, J. W. (1987). Mycotoxins, mycotoxicoses, mycotoxicology and Mycopathologia. Mycopathologia, 100(1), 3-5.
Bennett, J. W., & Klich, M. (2003). Mycotoxins. Clin Microbiol Rev, 16(3), 497-516.
Bhatt, K., Feng, L., Pabla, N., Liu, K., Smith, S., & Dong, Z. (2008). Effects of targeted Bcl-2 expression in mitochondria or endoplasmic reticulum on renal tubular cell apoptosis. Am J Physiol Renal Physiol, 294(3), F499-507.
Binder, E. M. (2007). Managing the risk of mycotoxins in modern feed production. Anim Feed Sci Technol, 133(1-2), 149-166.
Birkenmeier, E. H., Gwynn, B., Howard, S., Jerry, J., Gordon, J. I., Landschulz, W. H., & McKnight, S. L. (1989). Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev, 3(8), 1146-1156.
Bossy-Wetzel, E., & Green, D. R. (2000). Detection of apoptosis by annexin V labeling. Methods Enzymol, 322, 15-18.
Brown, M. H., Szczech, G. M., & Purmalis, B. P. (1976). Teratogenic and toxic effects of ochratoxin A in rats. Toxicol Appl Pharmacol, 37(2), 331-338.
Bryden, W. L. (2012). Mycotoxin contamination of the feed supply chain: Implications for animal productivity and feed security. Anim Feed Sci Technol, 173(1-2), 134-158.
Cabañes, F. J., Bragulat, M. R., & Castellá, G. (2010). Ochratoxin A Producing Species in the Genus Penicillium. Toxins, 2(5), 1111-1120.
Calfon, M., Zeng, H., Urano, F., Till, J. H., Hubbard, S. R., Harding, H. P., . . . Ron, D. (2002). IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature, 415(6867), 92-96.
Chinnaiyan, A. M. (1999). The apoptosome: heart and soul of the cell death machine. Neoplasia, 1(1), 5-15.
Chopra, M., Link, P., Michels, C., & Schrenk, D. (2010). Characterization of ochratoxin A-induced apoptosis in primary rat hepatocytes. Cell Biol Toxicol, 26(3), 239-254.
Chu, F. S. (1971). Interaction of ochratoxin A with bovine serum albumin. Arch Biochem Biophys, 147(2), 359-366.
Cosyns, J.-P. (2003). Aristolochic acid and''Chinese herbs nephropathy'': a review of the evidence to date. Drug Safety, 26(1), 33-48.
Cross, J. V., & Templeton, D. J. (2004). Oxidative stress inhibits MEKK1 by site-specific glutathionylation in the ATP-binding domain. Biochem J, 381(Pt 3), 675-683.
Dahlmann, A., Dantzler, W. H., Silbernagl, S., & Gekle, M. (1998). Detailed mapping of ochratoxin A reabsorption along the rat nephron in vivo: the nephrotoxin can be reabsorbed in all nephron segments by different mechanisms. J Pharmacol Exp Ther,, 286(1), 157-162.
Dalcero, A., Magnoli, C., Hallak, C., Chiacchiera, S. M., Palacio, G., & Rosa, C. A. R. (2002). Detection of ochratoxin A in animal feeds and capacity to produce this mycotoxin by Aspergillus section Nigri in Argentina. Food Addit Contam, 19(11), 1065-1072.
Davis, R. J. (2000). Signal transduction by the JNK group of MAP kinases. Cell, 103(2), 239-252.
Doster, R. C. (1971). Acute toxicity and carcinogenic activity of ochratoxin in rainbow trout (Salmo gairdneri) (Doctoral dissertation).
Elling, F., Nielsen, J. P., Lillehøj, E. B., Thomassen, M. S., & Størmer, F. C. (1985). Ochratoxin A-induced porcine nephropathy: Enzyme and ultrastructure changes after short-term exposure. Toxicon, 23(2), 247-254.
Elmore, S. (2007). Apoptosis: a review of programmed cell death. Toxicol Pathol, 35(4), 495-516.
Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., & Nagata, S. (1998). A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature, 391(6662), 43-50.
Fan, Z., Beresford, P. J., Oh, D. Y., Zhang, D., & Lieberman, J. (2003). Tumor Suppressor NM23-H1 Is a Granzyme A-Activated DNase during CTL-Mediated Apoptosis, and the Nucleosome Assembly Protein SET Is Its Inhibitor. Cell, 112(5), 659-672.
Ferrufino-Guardia, E., Tangni, E., Larondelle, Y., & Ponchaut, S. (2000). Transfer of ochratoxin A during lactation: exposure of suckling via the milk of rabbit does fed a naturally-contaminated feed. Food Addit Contam, 17(2), 167-175.
Fischer, H., Koenig, U., Eckhart, L., & Tschachler, E. (2002). Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun, 293(2), 722-726.
Fun Sun, C. (1974). A comparative study of the interaction of ochratoxins with bovine serum albumin. Biochem Pharmacol, 23(6), 1105-1113.
Gagliano, N., Donne, I. D., Torri, C., Migliori, M., Grizzi, F., Milzani, A., . . . Gioia, M. (2006). Early cytotoxic effects of ochratoxin A in rat liver: A morphological, biochemical and molecular study. Toxicology, 225(2), 214-224.
Galtier, P. (1977). Contribution of pharmacokinetic studies to mycotoxicology—Ochratoxin A. Vet Res Commun, 1(1), 349-358.
Galtier, P., Alvinerie, M., & Charpenteau, J. L. (1981). The pharmacokinetic profiles of ochratoxin A in pigs, rabbits and chickens. Food Cosmet Toxicol, 19, 735-738.
Gekle, M., Gaßner, B., Freudinger, R., Mildenberger, S., Silbernagl, S., Pfaller, W., & Schramek, H. (1998). Characterization of an Ochratoxin-A-Dedifferentiated and Cloned Renal Epithelial Cell Line. Toxicol Appl Pharmacol, 152(1), 282-291.
Gilani, S. H., Bancroft, J., & Reily, M. (1978). Teratogenicity of ochratoxin A in chick embryos. Toxicol Appl Pharmacol, 46(2), 543-546.
Grollman, A. P., Shibutani, S., Moriya, M., Miller, F., Wu, L., Moll, U., . . . Jelakovic, B. (2007). Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A, 104(29), 12129-12134.
Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H., & Ron, D. (2000). Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell, 5(5), 897-904.
Hayes, A. W., Hood, R. D., & Lee, H. L. (1974). Teratogenic effects of ochratoxin A in mice. Teratology, 9(1), 93-97.
Hetz, C. (2012). The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol, 13(2), 89-102.
Hibi, M., Lin, A., Smeal, T., Minden, A., & Karin, M. (1993). Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev, 7(11), 2135-2148.
Hitomi, J., Katayama, T., Eguchi, Y., Kudo, T., Taniguchi, M., Koyama, Y., . . . Tohyama, M. (2004). Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol, 165(3), 347-356.
Hood, R. D., Naughton, M. J., & Hayes, A. W. (1976). Prenatal effects of ochratoxin A in hamsters. Teratology, 13(1), 11-14.
Inagi, R. (2009). Endoplasmic reticulum stress in the kidney as a novel mediator of kidney injury. Nephron Exp Nephrol, 112(1), e1-9.
Jorgensen, K., Rasmussen, G., & Thorup, I. (1996). Ochratoxin A in Danish cereals 1986-1992 and daily intake by the Danish population. Food Addit Contam, 13(1), 95-104.
Joza, N., Susin, S. A., Daugas, E., Stanford, W. L., Cho, S. K., Li, C. Y., . . . Penninger, J. M. (2001). Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature, 410(6828), 549-554.
Jung, K. Y., Takeda, M., Kim, D. K., Tojo, A., Narikawa, S., Yoo, B. S., . . . Endou, H. (2001). Characterization of ochratoxin A transport by human organic anion transporters. Life Sciences, 69(18), 2123-2135.
Kamp, H. G., Eisenbrand, G., Schlatter, J., Würth, K., & Janzowski, C. (2005). Ochratoxin A: induction of (oxidative) DNA damage, cytotoxicity and apoptosis in mammalian cell lines and primary cells. Toxicology, 206(3), 413-425.
Kanisawa, M., & Suzuki, S. (1978). Induction of renal and hepatic tumors in mice by ochratoxin A, a mycotoxin. Gan, 69(4), 599-600.
Kaufman, R. J. (2002). Orchestrating the unfolded protein response in health and disease. J Clin Invest, 110(10), 1389-1398.
Kerr, J. F., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer, 26(4), 239-257.
Kischkel, F. C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P. H., & Peter, M. E. (1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. Embo j, 14(22), 5579-5588.
Knasmuller, S., Cavin, C., Chakraborty, A., Darroudi, F., Majer, B. J., Huber, W. W., & Ehrlich, V. A. (2004). Structurally related mycotoxins ochratoxin A, ochratoxin B, and citrinin differ in their genotoxic activities and in their mode of action in human-derived liver (HepG2) cells: implications for risk assessment. Nutr Cancer, 50(2), 190-197.
Koszegi, T., & Poor, M. (2016). Ochratoxin A: Molecular Interactions, Mechanisms of Toxicity and Prevention at the Molecular Level. Toxins (Basel), 8(4), 111.
Krogh, P. (1980). Causal associations of mycotoxic nephropathy. Acta Pathol Microbiol Scand Suppl, 291-300.
Kuan, C. Y., Yang, D. D., Samanta Roy, D. R., Davis, R. J., Rakic, P., & Flavell, R. A. (1999). The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron, 22(4), 667-676.
Kumagai, S., & Aibara, K. (1982). Intestinal absorption and secretion of ochratoxin A in the rat. Toxicol Appl Pharmacol, 64(1), 94-102.
Le-Niculescu, H., Bonfoco, E., Kasuya, Y., Claret, F. X., Green, D. R., & Karin, M. (1999). Withdrawal of Survival Factors Results in Activation of the JNK Pathway in Neuronal Cells Leading to Fas Ligand Induction and Cell Death. Mol Cell Biol, 19(1), 751-763.
Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., & Wang, X. (1997). Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 91(4), 479-489.
Li, Y., Guo, Y., Tang, J., Jiang, J., & Chen, Z. (2014). New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim Biophys Sin (Shanghai), 46(8), 629-640.
Madhyastha, M. S., Marquardt, R. R., & Frohlich, A. A. (1992). Hydrolysis of ochratoxin A by the microbial activity of digesta in the gastrointestinal tract of rats. Arch Environ Contam Toxicol, 23(4), 468-472.
Madsen, A., Mortensen, H. P., & Hald, B. (1982). Feeding Experiments with Ochratoxin a Contaminated Barley for Bacon Pigs. Acta Agric Scand, 32(2), 225-239.
Martinvalet, D., Zhu, P., & Lieberman, J. (2005). Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity, 22(3), 355-370.
Matsumoto, M., Minami, M., Takeda, K., Sakao, Y., & Akira, S. (1996). Ectopic expression of CHOP (GADD153) induces apoptosis in M1 myeloblastic leukemia cells. FEBS Lett, 395(2-3), 143-147.
Mayura, K., Reddy, R. V., Hayes, A. W., & Berndt, W. O. (1982). Embryocidal, fetotoxic and teratogenic effects of ochratoxin A in rats. Toxicology, 25(2-3), 175-185.
Meeting, J. F. W. E. C. o. F. A. (2001). Safety evaluation of certain mycotoxins in food: Food & Agriculture Org.
Nakagawa, T., & Yuan, J. (2000). Cross-Talk between Two Cysteine Protease Families: Activation of Caspase-12 by Calpain in Apoptosis. J Cell Biol, 150(4), 887-894.
Nangaku, M. (2004). Mechanisms of tubulointerstitial injury in the kidney: final common pathways to end-stage renal failure. Intern Med, 43(1), 9-17.
Nishitoh, H., Saitoh, M., Mochida, Y., Takeda, K., Nakano, H., Rothe, M., . . . Ichijo, H. (1998). ASK1 is essential for JNK/SAPK activation by TRAF2. Mol Cell, 2(3), 389-395.
Organization, W. H. (1999). High-Dose Irradiation: Wholesomeness of Food Irradiatied with Doses above 10 kGy: World Health Organization.
Organization, W. H., & Cancer, I. A. f. R. o. (1993). Some naturally occurring substances: food items and constituents, heterocyclic aromatic amines and mycotoxins. IARC Monogr Eval Carcinog Risks Hum, 56.
Parkinson, A., & Ogilvie, B. W. (2001). Biotransformation of xenobiotics: McGraw-Hill New York.
Patil, R. D., Dwivedi, P., & Sharma, A. K. (2006). Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats. Reprod Toxicol, 22(4), 679-687.
Pavlović, N. M. (2013). Balkan endemic nephropathy—current status and future perspectives. Clin Kidney J, 6(3), 257-265.
Petkova-Bocharova, T., & Castegnaro, M. (1991). Ochratoxin A in human blood in relation to Balkan endemic nephropathy and urinary tract tumours in Bulgaria. IARC scientific publications(115), 135-137.
Petrik, J., Žanić-Grubišić, T., Barišić, K., Pepeljnjak, S., Radić, B., Ferenčić, Ž., & Čepelak, I. (2003). Apoptosis and oxidative stress induced by ochratoxin A in rat kidney. Arch Toxicol, 77(12), 685-693.
Petzinger, E., & Ziegler, K. (2000). Ochratoxin A from a toxicological perspective. J Vet Pharmacol Ther, 23(2), 91-98.
Pfohl‐Leszkowicz, A., & Manderville, R. A. (2007). Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans. Mol Nutr Food Res, 51(1), 61-99.
Pitout, M. J. (1969). The hydrolysis of ochratoxin a by some proteolytic enzymes. Biochemical Pharmacology, 18(2), 485-491.
PLESTINA, R. (1988). Enterohepatic circulation of ochratoxin A in rats. Period Biol, 90(1), 39-42.
Pohland, A., Nesheim, S., & Friedman, L. (1992). Ochratoxin A: a review (technical report). Pure Appl Chem, 64(7), 1029-1046.
Pohland, A., Schuller, P., Steyn, P., & Van Egmond, H. (1982). Physicochemical data for some selected mycotoxins. Pure Appl Chem, 54(11), 2219-2284.
Program, N. T. (1989). Toxicology and Carcinogenesis Studies of Ochratoxin A (CAS No. 303-47-9) in F344/N Rats (Gavage Studies). Natl Toxicol Program Tech Rep Ser, 358, 1.
Purchase, I. F., & Van der Watt, J. J. (1971). The long-term toxicity of Ochratoxin A to rats. Food Cosmet Toxicol, 9(5), 681-682.
Rao, R. V., Hermel, E., Castro-Obregon, S., del Rio, G., Ellerby, L. M., Ellerby, H. M., & Bredesen, D. E. (2001). Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem, 276(36), 33869-33874.
Reddy, K. R. N., Salleh, B., Saad, B., Abbas, H. K., Abel, C. A., & Shier, W. T. (2010). An overview of mycotoxin contamination in foods and its implications for human health. Toxin Rev, 29(1), 3-26.
Ringot, D., Chango, A., Schneider, Y. J., & Larondelle, Y. (2006). Toxicokinetics and toxicodynamics of ochratoxin A, an update. Chem Biol Interact, 159(1), 18-46.
Roth, A., Chakor, K., Creppy, E. E., Kane, A., Roschenthaler, R., & Dirheimer, G. (1988). Evidence for an enterohepatic circulation of ochratoxin A in mice. Toxicology, 48(3), 293-308.
Sabapathy, K., Jochum, W., Hochedlinger, K., Chang, L., Karin, M., & Wagner, E. F. (1999). Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech Dev, 89(1-2), 115-124.
Saelens, X., Festjens, N., Vande Walle, L., van Gurp, M., van Loo, G., & Vandenabeele, P. (2004). Toxic proteins released from mitochondria in cell death. Oncogene, 23(16), 2861-2874.
Sage, L., Krivobok, S., Delbos, E., Seigle-Murandi, F., & Creppy, E. E. (2002). Fungal flora and ochratoxin a production in grapes and musts from france. J Agric Food Chem, 50(5), 1306-1311.
Salvesen, G. S., & Dixit, V. M. (1997). Caspases: intracellular signaling by proteolysis. Cell, 91(4), 443-446.
Santabarbara-Ruiz, P., Lopez-Santillan, M., Martinez-Rodriguez, I., Binagui-Casas, A., Perez, L., Milan, M., . . . Serras, F. (2015). ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration. PLoS Genet, 11(10), e1005595.
Saraste, A., & Pulkki, K. (2000). Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res, 45(3), 528-537.
Schwerdt, G., Freudinger, R., Schuster, C., Silbernagl, S., & Gekle, M. (2004). Inhibition of mitochondria and extracellular acidification enhance ochratoxin A-induced apoptosis in renal collecting duct-derived MDCK-C7 cells. Cell Physiol Biochem, 14(1-2), 47-56.
Seegers, J. C., Bohmer, L. H., Kruger, M. C., Lottering, M. L., & de Kock, M. (1994). A comparative study of ochratoxin A-induced apoptosis in hamster kidney and HeLa cells. Toxicol Appl Pharmacol, 129(1), 1-11.
Sevrioukova, I. F. (2011). Apoptosis-Inducing Factor: Structure, Function, and Redox Regulation. Antioxid Redox Signal, 14(12), 2545-2579. d
Shi, Y., Nikulenkov, F., Zawacka-Pankau, J., Li, H., Gabdoulline, R., Xu, J., . . . Selivanova, G. (2014). ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis. Cell Death Differ, 21(4), 612-623.
Shreeve, B. J., Patterson, D. S. P., Pepin, G. A., Roberts, B. A., & Wrathall, A. E. (1977). Effect of Feeding Ochratoxin to Pigs During Early Pregnancy. Br Vet J , 133(4), 412-417.
Slee, E. A., Adrain, C., & Martin, S. J. (2001). Executioner caspase-3,-6, and-7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem, 276(10), 7320-7326.
Sreemannarayana, O., Frohlich, A. A., Vitti, T. G., Marquardt, R. R., & Abramson, D. (1988). Studies of the tolerance and disposition of ochratoxin A in young calves. J Anim Sci, 66(7), 1703-1711.
Stoev, S. D., Grozeva, N., & Hald, B. (1998). Ultrastructural and toxicological investigations in spontaneous cases of porcine nephropathy in Bulgaria. Veterinarski Arhiv, 68(2), 39-49.
Stormer, F. C., Hansen, C. E., Pedersen, J. I., Hvistendahl, G., & Aasen, A. J. (1981). Formation of (4R)- and (4S)-4-hydroxyochratoxin A from ochratoxin A by liver microsomes from various species. Appl Environ Microbiol, 42(6), 1051-1056.
Studer-Rohr, I., Schlatter, J., & Dietrich, D. R. (2000). Kinetic parameters and intraindividual fluctuations of ochratoxin A plasma levels in humans. Archives of Toxicology, 74(9), 499-510.
Suzuki, S., Kozuka, Y., Satoh, T., & Yamazaki, M. (1975). Studies on the nephrotoxicity of ochratoxin A in rats. Toxicol Appl Pharmacol, 34(3), 479-490.
Taniwaki, M. H., Pitt, J. I., Teixeira, A. A., & Iamanaka, B. T. (2003). The source of ochratoxin A in Brazilian coffee and its formation in relation to processing methods. Int J Food Microbiol, 82(2), 173-179.
Thornberry, N. A., & Lazebnik, Y. (1998). Caspases: enemies within. Science, 281(5381), 1312-1316.
Tirasophon, W., Welihinda, A. A., & Kaufman, R. J. (1998). A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev, 12(12), 1812-1824.
Tournier, C., Hess, P., Yang, D. D., Xu, J., Turner, T. K., Nimnual, A., . . . Davis, R. J. (2000). Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science, 288(5467), 870-874.
Trapani, J. A., & Smyth, M. J. (2002). Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol, 2(10), 735-747.
Trivedi, A. B., Doi, E., & Kitabatake, N. (1992). Detoxification of Ochratoxin A on Heating under Acidic and Alkaline Conditions. Biosci Biotechnol Biochem, 56(5), 741-745.
Ubeda, M., Wang, X. Z., Zinszner, H., Wu, I., Habener, J. F., & Ron, D. (1996). Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element. Mol Cell Biol, 16(4), 1479-1489.
Ueno, Y., Umemori, K., Niimi, E., Tanuma, S., Nagata, S., Sugamata, M., . . . et al. (1995). Induction of apoptosis by T-2 toxin and other natural toxins in HL-60 human promyelotic leukemia cells. Nat Toxins, 3(3), 129-137.
Umek, R. M., Friedman, A. D., & McKnight, S. L. (1991). CCAAT-enhancer binding protein: a component of a differentiation switch. Science, 251(4991), 288-292.
Urano, F., Bertolotti, A., & Ron, D. (2000). IRE1 and efferent signaling from the endoplasmic reticulum. J Cell Sci, 113 Pt 21, 3697-3702.
Vanherweghem, J. L., Depierreux, M., Tielemans, C., Abramowicz, D., Dratwa, M., Jadoul, M., . . . et al. (1993). Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet, 341(8842), 387-391.
Vembar, S. S., & Brodsky, J. L. (2008). One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol, 9(12), 944-957.
Vidal, A., Sanchis, V., Ramos, A. J., & Marin, S. (2015). Thermal stability and kinetics of degradation of deoxynivalenol, deoxynivalenol conjugates and ochratoxin A during baking of wheat bakery products. Food Chem, 178, 276-286.
Wangikar, P., Dwivedi, P., & Sinha, N. (2010). Teratogenic effects of ochratoxin a in rabbits. World Rabbit Sci, 12(3), 159-171.
Wei, X., & Sulik, K. K. (1993). Pathogenesis of craniofacial and body wall malformations induced by ochratoxin A in mice. Am J Med Genet, 47(6), 862-871.
Wei, X., & Sulik, K. K. (1996). Pathogenesis of caudal dysgenesis/sirenomelia induced by ochratoxin A in chick embryos. Teratology, 53(6), 378-391.
Wu, Q., Dohnal, V., Huang, L., Kuca, K., Wang, X., Chen, G., & Yuan, Z. (2011). Metabolic pathways of ochratoxin A. Curr Drug Metab, 12(1), 1-10.
Xiao, H., Madhyastha, S., Marquardt, R. R., Li, S., Vodela, J. K., Frohlich, A. A., & Kemppainen, B. W. (1996). Toxicity of Ochratoxin A, Its Opened Lactone Form and Several of Its Analogs: Structure–Activity Relationships. Appl Environ Microbiol, 137(2), 182-192.
Xiao, H., Marquardt, R. R., Abramson, D., & Frohlich, A. A. (1996). Metabolites of ochratoxins in rat urine and in a culture of Aspergillus ochraceus. Appl Environ Microbiol, 62(2), 648-655.
Yoshizumi, M., Abe, J., Haendeler, J., Huang, Q., & Berk, B. C. (2000). Src and Cas mediate JNK activation but not ERK1/2 and p38 kinases by reactive oxygen species. J Biol Chem, 275(16), 11706-11712.
Yu, C., Minemoto, Y., Zhang, J., Liu, J., Tang, F., Bui, T. N., . . . Lin, A. (2004). JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Mol Cell, 13(3), 329-340.
Zou, H., Henzel, W. J., Liu, X., Lutschg, A., & Wang, X. (1997). Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c–Dependent Activation of Caspase-3. Cell, 90(3), 405-413.