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中文論文名稱 第一部分:以斑馬魚模式探討白藜蘆醇和熊果酸對馬兜鈴酸腎病之防護影響 第二部分:Topiramate對母體卵子形成與子代軟骨發育不良之影響
英文論文名稱 Part I. Nephroprotective role of resveratrol and ursolic acid in aristolochic acid-treated zebrafish Part II. Effects of Topiramate on maternal oogenesis and offspring cartilage dysplasia
校院名稱 淡江大學
系所名稱(中) 化學學系博士班
系所名稱(英) Department of Chemistry
學年度 103
學期 1
出版年 104
研究生中文姓名 丁玉如
研究生英文姓名 Yu-Ju Ding
學號 899160013
學位類別 博士
語文別 中文
口試日期 2015-01-13
論文頁數 188頁
口試委員 指導教授-陳曜鴻
委員-蔡振寧
委員-王芸馨
委員-鄭邑荃
委員-陳銘凱
委員-莊子超
中文關鍵字 腎損傷  白藜蘆醇  雄果酸  卵子形成  癲癇藥  軟骨發育 
英文關鍵字 kidney injury  resveratrol  ursolic acid  oogenesis  Topiramate  cartilage dysplasia 
學科別分類
中文摘要 第一部分:以斑馬魚模式探討白藜蘆醇和熊果酸對馬兜鈴酸腎病之防護影響根據先前研究指出,馬兜鈴酸導致急性腎損傷主要是因為發炎反應所導致,因此選擇白藜蘆醇(Resv)及熊果酸(UA)這兩個具抗發炎功效之成分去進行預防及治療。我們利用3 ppm 馬兜鈴酸引發急性腎損傷,再利用10 ppm Resv 及UA 進行防護實驗,於胚胎發育至48 hpf 觀察其胚胎腎臟損傷比例是否降低。觀察到10 ppm Resv 或UA 腎臟型態與正常對照組型態相似,腎絲球在體軸中線緊靠,且原腎小管也與正常對照組相似達到預防之效果。腎功能檢測的實驗中,發現利用10 ppm 的Resv 或UA 預防後腎絲球過濾率增加22.19 %和25.14%。進一步觀察發現積血的情況明顯的改善且循環系統也較為正常。利用RT-qPCR 分析,顯示預防組發炎基因的表現有顯著減少(TNFα, mpo),也同時減低細胞凋亡情況(bcl2),腎損傷引發之貧血也得到改善(epo, epor)。實驗中設計了腎衰竭指標(TNFα、kim1 或NF-κB)發現其表現量都顯著降低,經過Resv 預防組其表現量分別為0.36,0.28,和3.36 倍;UA 預防組表現量分別為2.77,0.32,和8.10 倍。表示Resv或UA 預防,可顯著降低體內致炎性細胞激素表達減緩發炎反應而達到預防之效果。而體內ROS 的產生也顯著降低,保護腎臟不受發炎介質影響。利用NMR 分析體內代謝產物,發現其穀胺醯胺和許多胺基酸、肌酐酸、膽鹼、乳酸和氧化三甲胺含量近對照組,顯示腎小管再吸收能力的恢復。在這項研究中,我們利用Resv 或UA 預防後,發現能夠抑制炎症反應,恢復腎功能或其他症狀,使腎損傷情況明顯改善。
第二部分:Topiramate 對母體卵子形成與代軟骨發育不良之影響Topiramate 是一種FDA 批准的抗癲癇藥物,適用於成人及二歲以上兒童。然而,根據數據顯示服用Topiramate 之孕婦會產下唇顎裂之幼兒。目前Topiramate 致畸胎毒性仍不清楚,本研究以母斑馬魚灌餵0.5 mg/g/day 藥物連續7 天,收集子代並觀察藥物對母體及子代的影響。結果顯示,在母體,Topiramate 會抑制卵母細胞的成熟。實驗組周邊核仁期及卵黃生成期細胞佔卵巢總細胞數比對照組來得高,且也可觀察到閉鎖細胞之增加由此可以證明Topiramate 會降低卵母細胞成熟速率。在子代中,可以觀察到早期胚胎有16.3±15.6%細胞外包卵黃(epiboly)、聚合移動以及伸展移動畸形之情況。進一步利用顯微注射藥物進入胚胎,發現注射0.5,1 或2 ng/ml 的Topiramate 畸形率分別為4.9%,25%和63.4%,顯示出不論餵食母體藥物或直接注射藥物至胚胎內都可以觀察到胚胎早期細胞移動不同程度的影響。後期則可以利用Alcian blue 染色觀察軟骨發育,發現角鰓骨(ceratobranchial)缺失、密克爾氏軟骨(Meckel’s cartilage)、角舌軟骨(ceratohyal)及篩板(ethmoid plate)變形等軟骨異常。並統計軟骨發育異常之比例為0-50 %,平均後其畸形比例為23.0 % (n=14)。利用茜素紅(Alizarin red)染色則觀察到角舌骨、密克爾氏骨與脊椎骨較明顯之礦化程度減弱。由於Topiramate 組母魚的產率及子代早期細胞分裂的問題,為了確定其機轉,透過RT-qPCR 觀察母體卵巢、未分化及分化中之卵子內runx2b、smad4、smad1 及smad5 基因的表達,結果顯示出Topiramate 可能藉由這些基因過度表現而造成骨骼發育及卵巢細胞異常。
英文摘要 Part I. Nephroprotective role of resveratrol and ursolic acid in aristolochic acid-treated zebrafish Aim of this study was to study the nephroprotective effects of resveratrol (Resv) and ursolic acid (UA) in a zebrafish model. Using two transgenic lines, Tg(wt1b:GFP) and Tg(gata1:dsRed) the subtle changes in the kidney and the red blood cells circulation can be easily recorded. Results showed that both Resv and UA treatment can attenuate AA-induced kidney injury and improve the blood circulation. We used glomerular filtration rate assays to evaluate zebrafish's renal function and found that both Resv and UA treatment can restore renal function (100% for Mock; 56.1±17.3% for AA-treated; 80.2± 11.3% for Resv+AA; and 83.1± 8.1% for UA+AA, n=15). Furthermore, real time RT-PCR experiments show that pre-treatment with either Resv or UA suppresses pro-inflammatory gene expressions. NMR results revealed that tubular amino acid reabsorption can be improved by Resv or UA treated. In conclusion, our findings reveal that AA-induced nephrotoxicities can be attenuated by pre-treatment with either Resv or UA.
Part II. Effects of Topiramate on maternal oogenesis and offspring cartilage dysplasia Topiramate is used to treat epilepsy in children and adults. In children, it is indicated for the treatment of Lennox-Gastaut syndrome, a disorder that causes seizures and developmental retardation. Recent clinical data showed that administration of Topiramate in pregnant women caused an increased risk of oral clefts on their new born babies. To further understand the adverse effects of Topiramate, we dosed adult female zebrafish with 0.5 mg/g/day for 7 days, and recorded the phenotypic changes of adult females as well as their offspring. In adults, histopathological examination showed that Topiramate treatment reduced oocyte maturation. Meanwhile, around 23.0% (n=14) of offspring derived from Topiramate-treated adults displayed cartilage deformity, such as ceratobranchial missing, ceratohyal, Meckel’s cartilage and ethmoid plate deformation. Alizarin red staining revealed that the mineralization of ceratohyal, Meckel’s cartilage, and vertebrae were downregulated. From the molecular points of view, real-time PCR demonstrated that the expression levels of smad 1/4/5 and runx2b were upregulated in the Topiramate-treated groups at different sites (ovaries, eggs and 1-cell-stage embryos) in comparison with those of mock-treated controls. Finally, whole-mount in situ hybridization on 8 hpf embryos indicated that endogenous runx2b levels were upregulated. Taken together, we concluded that Topiramate might induce maternal smad1/4/5 and runx2b genes overexpression, and then caused offspring skeletal dysplasia.
論文目次 目錄
中文摘要 I
英文摘要 III
目錄 V
圖索引 XI
表索引 XIII
縮寫表 XIV
第一部分:以斑馬魚模式探討白藜蘆醇和熊果酸對馬兜鈴酸腎病之防護影響 1
第一章 前言 2
1-1腎臟對生物體之重要性 2
1-2急性腎損傷之概述 2
1-3急性腎損傷之生物指標 5
1-4熊果酸其結構及特性 7
1-5熊果酸之藥理作用 8
1-6白藜蘆醇其結構及特性 9
1-7白藜蘆醇之藥理作用 10
1-8馬兜鈴酸對斑馬魚之毒理機制 11
1-9斑馬魚之優勢 12
1-10斑馬魚之腎臟發育 15
1-11研究動機及目的 18
第二章 研究方法與設計 19
2-1 實驗動物 19
2-2 實驗動物養殖及胚胎收集 19
2-3 基因轉殖魚簡介 20
2-4 斑馬魚發育時期的選擇 20
2-5 藥物及暴露條件 21
2-6體內自由基之偵測 22
2-7腎功能分析-腎絲球過濾率(GLOMERULAR FILTRATION RATE, GFR ) 23
2-8 紅血球染色(WHOLE-MOUNT Ο-DIANISIDINE STAINING) 23
2-9 全胚體免疫染色法(WHOLE-MOUNT IMMUNOSTAINING) 24
2-10冷凍切片 25
2-11 斑馬魚胚胎時期核醣核酸(RNA)之抽取 26
2-12 反轉錄反應 (REVERSE TRANSCRIPTION) 26
2-13即時定量聚合酶鍊鎖反應(REAL-TIME QUANTITATIVE PCR, RT-QPCR) 27
2-14 斑馬魚之萃取及配置NMR 樣品 27
2-14-1 動物實驗 27
2-14-2 NMR 前製作業 27
2-14-3 核磁共振測試 28
2-14-4 數據計算 28
2-15 實驗器材 30
第三章 實驗結果與討論 31
3-1 腎損傷之預防較治療效果顯著 31
3-2白藜蘆醇或熊果酸對存活率並無顯著功效 33
3-3白藜蘆醇或熊果酸能夠提升腎臟功能 33
3-4白藜蘆醇或熊果酸能夠降低體內活性氧之表達 36
3-5白藜蘆醇或熊果酸能夠抑制發炎基因表達 38
3-6 馬兜鈴酸與紅血球生成素之影響 40
3-7白藜蘆醇或熊果酸預防能降低血液堆積及循環功能恢復 41
3-8白藜蘆醇或熊果酸預防能改善心臟發育 44
3-9急性腎損傷的分子標記 46
3-10白藜蘆醇或熊果酸改善腎小管重吸收能力 48
第四章 結論 51
第二部分:TOPIRAMATE對母體卵子形成與子代軟骨發育不良之影響 52
第五章 前言 53
5-1 妥泰膜衣錠(TOPAMAXR)其結構及特性 53
5-2 TOPIRAMATE藥理特性 53
5-3 TOPIRAMATE藥物分級 54
5-4 TOPIRAMATE臨床試驗前之動物實驗 55
5-5斑馬魚之軟骨發育 56
5-6斑馬魚骨骼發育之分子機制 58
5-7 斑馬魚之卵母細胞發育 59
5-8 研究動機及目的 61
第六章 研究方法與設計 62
6-1 實驗動物 62
6-2 實驗動物養殖及胚胎收集 62
6-3 斑馬魚發育時期的選擇 63
6-4 藥物及暴露條件 63
6-5軟骨染色(ALCIAN BLUE STAIN) 66
6-6 硬骨染色(茜素紅染色, ALZARIN RED STAINING) 66
6-7 斑馬魚胚胎時期核醣核酸(RNA)之抽取 67
6-8 反轉錄反應 (REVERSE TRANSCRIPTION) 67
6-9 即時定量聚合酶鍊鎖反應(REAL-TIME QUANTITATIVE PCR, RT-QPCR) 68
6-10 卵巢組織觀察 (HISTOLOGY OF OVARIES) 68
6-10-1 石蠟切片 68
6-10-2 蘇木紫和伊紅染色法 (Hematoxylin and Eosin Stain, H&E Stain) 69
6-11 小量質體萃取 69
6-12 探針(RIBOPROBE)合成 70
6-13 原位雜交法(WHOLE-MOUNT IN SITU HYBRIDIZATION) 71
6-14 實驗器材 74
第七章 實驗結果與討論 75
7-1 TOPIRAMATE對母體體重之影響 75
7-2 TOPIRAMATE影響斑馬魚子代細胞移動(CELL MIGRATION) 76
7-3 TOPIRAMATE降低母體卵母細胞成熟度 78
7-4 TOPIRAMATE會透過母體影響子代頭部軟骨發育 79
7-5斑馬魚安慰劑效應(PLACEBO EFFECT) 之評估 82
7-6 TOPIRAMATE造成頭部軟骨比例短窄 83
7-7 TOPIRAMATE造成礦化作用異常 84
7-8 TOPIRAMATE導致BMP訊號下游基因過度表現 85
7-9 TOPIRAMATE調控RUNX2介導骨骼發育及卵母細胞成熟 87
第八章 結論 89
參考文獻 90
圖表 104
附錄 148
期刊論文 167

圖索引
第一部分:以斑馬魚模式探討白藜蘆醇和熊果酸對馬兜鈴酸腎病之防護影響
圖 1. RESV和UA分別對馬兜鈴酸腎損傷之治療及防護效果影響 104
圖 2. RESV和UA能預防馬兜鈴酸所導致的腎損傷 105
圖 3. RESV或UA劑量與存活率分析 106
圖 4. RESV 和 UA 10 PPM治療及預防AAN之腎絲球過濾率(GFR) 107
圖 5. RESV 和 UA處理對體內自由基生成之影響 108
圖 6. RESV和UA 對發炎、細胞凋亡及血球基因表達之影響 109
圖 7. 馬兜鈴酸對紅血球生成素受體之影響 110
圖 8. RESV 和 UA對紅血球堆積之影響 111
圖 9. RESV和UA改善循環系統 112
圖 10. RESV 和 UA對心臟之影響 113
圖 11. 腎損傷指標 114
圖 24. 水相1D NMR光譜 115
圖 29. 研究總結示意圖 116

第二部分:Topiramate對母體卵子形成與子代軟骨發育不良之影響
FIGURE 1.餵食七天TOPIRAMATE胚胎發育之影響 117
FIGURE 2. 微量注射TOPIRAMATE胚胎發育之影響 118
FIGURE 3. TOPIRAMATE餵食會導致母體卵母細胞發育異常 119
FIGURE 4. TOPIRAMATE透過母體對子代軟骨發育之影響 120
FIGURE 5. 餵食TOPIRAMATE之不同子代所造成的軟骨型態不盡相同 121
FIGURE 6. 餵食安慰劑並不造成軟骨發育異常 122
FIGURE 7.餵食安慰劑對於卵母細胞形成影響不大 123
FIGURE 8.餵食TOPIRAMATE頭部尺寸之變化 124
FIGURE 9.實驗組與對照組硬骨發育情況 125
FIGURE 10. RUNX2B在卵巢、未分化及分化中卵子間基因表現 126
FIGURE 11. SMAD4在卵巢、未分化及分化中卵子間基因表現 127
FIGURE 12. SMAD1在卵巢、未分化及分化中卵子間基因表現 128
FIGURE13. SMAD5在卵巢、未分化及分化中卵子間基因表現 129
FIGURE 14. 微量注射TOPIRAMATE誘導BMP下游信號基因的表達 130
FIGURE 15. 不同INTERNAL CONTROL之RUNX2B表現 131
FIGURE 16. 原位雜交分析體內RUNX2B表現 132
FIGURE 17. RUNX2蛋白表現誘導軟骨發育不良 133
FIGURE 18. 研究總結示意圖 134

表索引
第一部分:以斑馬魚模式探討白藜蘆醇和熊果酸對馬兜鈴酸腎病之防護影響
表 1. REAL TIME-PCR 所使用之引子序列 135
表 2. 不同物種KIM-1之胺基酸序列比對 136
表 3. REAL TIME-PCR 所使用之引子序列 137
表 4. NMR 水相光譜 ASSIGNMENT 138
表 5. RESV 和UA防護後體內代謝產物之變化 140

第二部分:Topiramate對母體卵子形成與子代軟骨發育不良之影響
TABLE 1. TOPIRAMATE對母體體重之影響 141
TABLE 2. 口服TOPIRAMATE之子代存活率之影響 142
TABLE 3. 口服TOPIRAMATE組胚胎於5.3 HPF之畸形率 143
TABLE 4. 微量注射TOPIRAMATE之胚胎存活率及畸形率 144
TABLE 5. TOPIRAMATE造成子代軟骨發育畸形 145
TABLE 6. TOPIRAMATE會抑制脊椎骨礦化作用 146
TABLE 7. REAL TIME-PCR 所使用之引子序列 147



參考文獻 Adhami VM, Afaq F, and Ahmad N (2001). Involvement of the retinoblastoma (pRb)-E2F/DP pathway during antiproliferative effects of resveratrol in human epidermoid carcinoma (A431) cells. Biochem Biophys Res Commun 288: 579-585.
Aguirre-Crespo F, Vergara-Galicia J, Villalobos-Molina R et al., (2006). Ursolic acid mediates the vasorelaxant activity of Lepechinia caulescens via NO release in isolated rat thoracic aorta. Life Sci 79(11): 1062-1068.
Ahmad N, Adhami VM, Afaq F et al., (2001). Resveratrol causes WAF-1/p21-mediated G(1)-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells. Clin Cancer Res 7: 1466-1473.
Ali MS, Ibrahim SA, Jalil S et al., (2007). Ursolic acid: a potent inhibitor of superoxides produced in the cellular system. Phytother Res 21(6): 558-561.
Anderson HA, Maylock CA, Williams JA et al., (2003). Serum- derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol 4(1):87-91.
Ali BH, Al Za'abi M, Ramkumar A et al., (2014). Anemia in adenine-induced chronic renal failure and the influence of treatment with gum acacia thereon. Physiol Res 63(3):351-358.
Arnone D (2005). Review of the use of Topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry 4(1): 5.
Baek JH, Lee YS, Kang CM et al., (1997). Intracellular Ca2+ release mediates ursolic acid–induced apoptosis in human leukemic HL‐60 cells. Int J Cancer 73(5): 725-728.
Bagshaw SM, George C, Bellomo R et al., (2008). Early acute kidney injury and sepsis: a multicentre evaluation. Crit Care 12(2): R47.
Bertelli AA, Giovannini L, Giannessi D et al., (1995). Antiplatelet activity of synthetic and natural resveratrol in red wine. Int J Tissue React 17(1): 1-3.
Bollig F, Mehringer R, Perner B et al., (2006). Identification and comparative expression analysis of a second wt1 gene in zebrafish. DevDyn 235: 554-561.
BradamanteS, Barenghi L, and Piccinini F (2003). Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. Eur J Pharmacol 465(1-2): 115-123.
Brandes JL, Saper JR, Diamond M, et al., (2007). Topiramate for migraine prevention. JAMA 291: 965-973.
Briggs GG, Freeman RK, and Yaffe SJ (1986). Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk. 2nd ed, Williams & Wilkins.
Burlacu A (2003). Regulation of apoptosis by Bcl-2 family proteins. J Cell Mol Med 7(3): 249-257.
Castro R, Lamas J, Morais P et al., (2008). Resveratrol modulates innate and inflammatory responses in fish leucocytes. Vet Immunol Immunop 126: 9-19.
Chaomei M, Nakamura N, Miyashiro H et al., (1998). Inhibitory effects of ursolic acid derivatives from Cynomorium songaricum, and related triterpenes on human immunodeficiency viral protease. Phytother Res 12(1): 138-142.
Chan CWH and Thompson DR (2006). The use of placebo in clinical nursing research. J Clin Nurs 15: 521-524.
Chen D, Zhao M, and Mundy GR (2004). Bone morphogenetic protein. Growth Factors 22(4): 233-241.
Chen G, Deng C, and Li TP (2012). TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci 8(2): 272-288.
Choudhury D and Ziauddin A (2006). Drug-associated renal dysfunction and injury. Nat Clin Pract Nephrol 2(2): 80-91.
Cipriani A, Barbui C, Salanti G et al., (2011). Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple- treatments meta- analysis. Lancet 378 (9799): 1306-1315.
Cubbage CC and Mabee PM (1996). Development of the cranium and paired fins in the zebrafish, Danio rerio (Ostariophysi, Cyprinidae). J. Morphol 229: 121-160.
Cummings LN, Giudice L, and Morrell MJ (1995).Ovulatory Function in Epilepsy. Epilepsia 36(4): 355-359.
Danielson B (1995). R-HuEPO hyporesponsiveness - who and why?
Nephrol Dial Transplant 1995; 10 (suppl2): 69-73.
Das DK, Prasad MR, Lu D et al., (1992). Preconditioning of heart by repeated stunning. Adaptive modification of antioxidant defense system. Cell Mol Biol 38(7): 739-749.
Das DK, Engelman RM, and Kimura Y (1993). Molecular adaptation of cellular defenses following preconditioning of the heart by repeated ischemia.Cardiovasc Res 27(4): 578-584.
Das DK, Maulik N, Engelman RM et al., (1996). Preconditioning potentiates molecular signaling for myocardial adaptation to ischemia. Ann N Y Acad Sci 793: 191-209.
Das S, Alagappan VK, Bagchi D et al., (2005). Coordinated induction of iNOS-VEGF-KDR-eNOS after resveratrol consumption: a potential mechanism for resveratrol preconditioning of the heart. Vasc Pharmacol 42(5-6): 281-289.
De Beer GR (1937). ‘‘The Development of the Vertebrate Skull.’’ Oxford University Press, Oxford. Reprinted 1985, Chicago University Press, Chicago.
Diep, CQ, Ma D, Deo RC et al., (2011). Identification of adult nephron progenitors capable of kidney regeneration in zebrafish. Nature. 470(7332): 95-101.
Ding YJ and Chen YH (2012). Developmental nephrotoxicity of aristolochic acid in a zebrafish model. Toxicol. Appl Pharmacol 261: 59-65.
Drummond IA, Majumdar A, Hentschel H et al., (1998). Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function. Development 125: 4655-4667.
Drummond IA (2003). Making a zebrafish kidney: a tale of two tubes. Trends Cell Biol 13(7): 357-365.
Drummond IA, and Davidson AJ (2010). Zebrafish kidney development. Methods Cell Biol 100: 233-260.
Du SJ, Frenkel V, Kindschi G, et al., (2001). Visualizing normal and defective bone development in zebrafish embryos using the fluorescent chromophore calcein. Dev Biol 238 (2): 239-246.
FDA (2011). Topamax (topiramate):Label Change – Risk for development of cleft Lip and / or cleft palate in newborns.
FDA (2011). FDA drug safety communication: Risk of oral clefts in children born to mothers taking Topamax (topiramate).
Ferrari A, Tiraferri I, Neri L et al., (2011). Clinical pharmacology of topiramate in migraine prevention. Expert Opin Drug Met 7 (9): 1169-1181.
Fisher S, Jagadeeswaran P, and Halpern ME (2003). Radiographic analysis of zebrafish skeletal defects. Dev. Biol 264: 64-76.
Floreani M, Napoli E, Quintieri L et al., (2003). Oral administration oftrans-resveratrol to guinera pigs increases cardiac DT-diaphorase and catalase activities, and protects isolated atriafrom menadione toxicity. Life Sci 72(24): 2741-2750.
Fored CM, Ejerblad E, Lindblad P et al., (2001). Acetaminophen, aspirin, and chronic renal failure. N Engl J Med 345(25): 1801-1808.
Garthwaite J and Boulton CL (1995). Nitric oxide signaling in the central nervous system. Annu Rev Physiol 57: 683-706.
Goldsmith P (2004). Zebrafish as a pharmacological tool: the how, why and when. Cur. Opin Pharma 4: 504-512.
Goldberg R and Dennen P (2008). Long-term outcomes of acute kidney injury. Adv Chronic Kidney Dis 15(3): 297-307.
Green CJ, Healing G, Lunec J et al., (1986). Evidence of free-radical-induced damage in rabbit kidneys after simple hypothermic preservation and autotransplantation. Transplantation 41(2):161-165.
Hao Z, Huang B and Wang Y (1989). Hypoglycemic effect of oleanolic acid. Zhongguo Yaoke Daxue Xuebao 22: 210-212.
Hale TW (1999). Medications and mothers' milk: 1999–2000. 8th ed. Amarillo, Tex.: Pharmasoft Medical.
Hattori R, Maulik N, Otani H et al., (2001). Role of Stat3 in ischemic preconditioning. J Mol Cell Cardiol 33(11): 1929-1936.
Hentschel DM, Park KM, Cilenti L et al., (2004). Acute renal failure in zebrafish: a novel system to study a complex disease. AmJ Physiol Renal Physiol 288: 923-929.
Holmes E, Connor SC, Nicholls AW et al., (1998). The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine. Chemometri Intell Lab Sys 44(1): 245-255.
Holthoff JH, Woodling KA, Doerge DR et al., (2010). Resveratrol, a dietary polyphenolic phytoalexin, is a functional scavenger of peroxynitrite. Biochem Pharmacol 80(8): 1260-1265.
Hoste EA and Schurgers M (2008). Epidemiology of acute kidney injury: how big is the problem? Crit Care Med 36: S146-151.
Howitz KT, Bitterman KJ, Cohen HY et al., (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: 191-196.
Hrobjartsson A and Gotzsche PC (2001). Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. New Engl J Med 344: 1594-1602.
Hsu HY, Yang JJ and Lin CC (1997). Effects of olanolic acid and ursolic acid on inhibition tumor growth and enhancing the recovery of hematopoietic system postirradiation in mice. Cancer Lett 111: 7-13.
Hsia N and Zon LI (2005). Transcriptional regulation of hematopoietic stem cell development in zebrafish. Exp Hematol 33(9): 1007-1014.
Huang CC, Chen PC, Huang CW et al., (2007). Aristolochic acid induces heart failure in zebrafish embryos that is mediated by inflammation. Toxicol Sci 100 (2): 486-494.
Huang W, Yang S, Shao J et al., (2007). Signaling and transcrip tional regula 2 tion in osteoblast comm itment and differentiation. Front Biosci 1(12)∶ 3068-3092.
Hsu YL, Kuo PL, and Lin CC (2004). Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells. Life Sci 75(19): 2303-2316.
Hunt S, Russell A, Smithson WH et al., (2008). Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 71(4): 272-276.
Imamura G, Bertelli AA, and Bertelli A (2002). Pharmacologic preconditioning with resveratrol: An insight with iNOS knockout mice. Am J Physiol 282(6): 1996-2003.
Iuchi I and Yamamoto M (1983). Erythropoiesis in the developing rainbow trout, Salmo gairdneri irideus. histochemical and immunochemical detection of erythropoietic organs. J Exp Zool 226: 409-417.
Jang M, Cai L, Udeani GO et al., (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275: 218-220.
Kanduc D, Mittelman A, Serpico R et al., (2002). Cell death: Apoptosis versus necrosis (Review). Internat J Oncol 21(6): 165-170.
Kapcala LP (2011). Clinical Review, Topamax / topiramate. NDA 20505/20844.
Kimmel CB, Miller CT, and Moens CB (2001). Specification and morphogenesis of the zebrafish larval head skeleton. Dev Biol 233(2): 239-257.
Kim AL, Zhu Y, Zhu H et al., (2006). Resveratrol inhibits proliferation of human epidermoid carcinoma A431 cells by modulating MEK1 and AP-1 signalling pathways. Exp Dermatol 15(7): 538-546.
Kinsey GR, Li L, and Okusa MD (2008). Inflammation in acute kidney injury. Nephron Exp Nephrol 109(4): 102-107.
Kinsey GR and Okusa MD (2012). Role of leukocytes in the pathogenesis of acute kidney injury. Critical Care 16(2): 214.
Klinge CM, Risinger KE, Watts MB et al., (2003). Estrogenic activity in white and red wine extracts. J Agri Food Chem 51(7): 1850-1857.
Kreidberg JA, Hagiwara MK, and Mirandola RM (1993). Experimental citrinin nephrotoxicosis in dogs: renal function evaluation. Vet Hum Toxicol 35(2): 136-140.
Li N, Felber K, Elks P et al., (2009). Tracking gene exp ression during zebrafish osteoblast differentiation. Dev Dyn 238(2): 459-466.
Liang YC, Tsai SH, Chen L et al., (2003). Resveratrol-induced G2 arrest through the inhibition of CDK7 and p34CDC2 kinases in colon carcinoma HT29 cells. Biochem Pharmacol 65(7): 1053-1060.
Liang Q, Ni C, Xie M et al., (2009). Nephrotoxicity study of Aristolochia fangchi in rats by metabonomics. J Integr Med 8(7): 746-752.
Lieschke GJ and Currie PD (2007). Animal models of human disease: zebrafish swim into view. Nat Rev Genet 8(5): 353-367.
Liu J (1995). Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol 49(2): 57-68.
Lyseng-Williamson KA and Yang LP (2007). Topiramate: A review of its use in the treatment of epilepsy. Drugs 67(15): 2231-2256.
Martini FH and Bartholomew EF (2000). Essentials of anatomy and physiology (2e). Prentice-Hall 530-540.
Maryanoff BE, Nortey SO, Gardocki JF et al., (1987). Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D- fructopyranose sulfamate and related compounds. J Med Chem 30(5): 880.
McCampbell, KK, Springer, KN, and Wingert RA (2014). Analysis of nephron composition and function in the adult zebrafish kidney. J Vis Exp 90: e51644.
McCampbell KK and Wingert RA (2014). New tides: using zebrafish to study renal regeneration. Transl Res 163(2): 109-122.
Meldrum BS and Rogawski MA (2007). Molecular targets for antiepileptic drug development. Neurotherapeutics 4 (1): 18-61.
Mehta RL, Kellum JA, Shah SV et al., (2007). Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11(2): R31.
Moran SM, and Myers BD (1985). Course of acute renal failure studied by a model of creatinine kinetics. Kidney Int 27(6): 928-937.
Murry CE, Jennings RB, and Reimer KA (1986). Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74(5):1124-1136.
Murugan R and Kellum JA (2011). Acute kidney injury: what’s the prognosis? Nat Rev Nephrol 7(4): 209-217.
Nihei T, Miura Y, and Yagasaki K (2001). Inhibitory effect of resveratrol on proteinuria, hypoalbuminemia and hyperlipidemia in nephritic rats. Life Sci 68(25): 2845-2852.
Ning G, Liu X, Dai M et al, (2013). MicroRNA-92a upholds Bmp signaling by targeting noggin3 during pharyngeal cartilage formation. Dev Cell 24(3): 283-295.
Nissenson AR (1998). Acute renal failure: definition and pathogenesis. Kidney Int Suppl 66: 7-10.
Ostermann M, Philips BJ, and Forni LG (2012). Clinical review: Biomarkers of acute kidney injury: where are we now? Crit Care 16(5): 233.
Othman M, Salem AH, Sequeira R et al., (2014). Effects of the therapeutic doses of topiramate on the placenta of rats: A histological and morphometric study (LB62). Faseb J 28: LB62.
Paller MS, Hoidal JR, and Ferris TF (1984). Oxygen free radicals in ischemic acute renal failure in the rat. J Clin Invest 74(4): 1156-1164.
Perner B, Englert C, and Bollig F (2007). The Wilms tumor genes wt1a and wt1b control different steps during formation of the zebrafish pronephros. Dev Biol 309(1): 87-96.
Peterson RT, Shaw SY, Peterson TA et al., (2004). Chemical suppression of a genetic mutation in a zebrefish model of aortic coarctation. Nat Biotechnol 22(5): 595-599.
Piotrowski T, Schilling TF, Brand M et al., (1996). Jaw and branchial arch mutants in zebrafish II: anterior arches and cartilage differentiation. Development 123: 345-356.
Pippin JW, Brinkkoetter PT, Cormack-Aboud FC et al., (2009). Inducible rodent models of acquired podocyte diseases. Am J Physiol Renal Physiol 296(2): 213-229.
Porter RJ, Dhir A, Macdonald RL et al., (2012). Mechanisms of action of antiseizure drugs. Handb Clin Neurol 108: 663-681.
Pozo M, Castilla V, Gutierrez C et al., (2006). Ursolic acid inhibits neointima formation in the rat carotid artery injury model. Atherosclerosis 184(1): 53-62.
Ramprasath VR and Jones PJH (2010). Anti-atherogenic effects of resveratrol. Eur J Clin Nutr 64(7): 660-668.
Recio MC, Giner RM, Manez S et al., (1995). Investigations on the steroidal anti-inflammatory activity of triterpenoids from diospyros leucomelas. Planta Med 61(1): 9-12.
Renshaw SA, Loynes CA, Trushell DMI et al., (2006). A transgenic zebrafish model of neutrophilic inflammation. Blood 108(3): 3976-3978.
Retting KN, Song B, Yoon BS et al., (2009). BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development 136(7): 1093-1104.
Salminen A and Kaarniranta K (2012). AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11(2): 230-241.
Santoriello C and Zon LI (2012). Hooked! Modeling human disease in zebrafish. J Clin Invest 122(7): 2337-2343.
Saravanan R and Pugalendi V (2006). Impact of ursolic acid on chronic ethanol-induced oxidative stress in the rat heart. Pharmacol Rep 58(1):41-47.
Schmidt-Nielsen K (1997). Animal physiology: adapation and environment, 5th edition. The press syndicate of the University of Cambridge, New York, USA. pp. 96-97.
Schilling TF (1997). Genetic analysis of craniofacial development in the vertebrate embryo. BioEssays 19(6): 459-468.
Schilling TF and Kimmel CB (1997). Musculoskeletal patterning in the pharyngeal segments of the zebrafish embryo. Development 124(15): 2945-2960.
Schrier RW, Wang W, Poole B et al., (2004). Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 114(1): 5-14.
Shah N, Al-Khoury S, Afzali B et al., (2006). Posttransplantation anemia in adult renal allograft recipients: prevalence and predictors. Transplantation 81(8): 1112-1118.
Shoskes DA. (1998). Effect of bioflavonoids quercetin and curcumin on ischemic renal injury: a new class of renoprotective agents. Transplantation 66(2):147-152.
Singh GB, Singh S, Bani S et al., (1992). Anti-inflammatory activity of oleanolic acid in rats and mice. J Pharm Pharmacol 44(5): 456-458.
Steinkamp-Fenske K, Bollinger L, Voller N et al., (2007)Ursolic acid from the Chinese herb danshen (Salvia miltiorrhiza L.) upregulates eNOS and downregulates Nox4 expression in human endothelial cells. Atherosclerosis 195(1): e104-111.
Snyckers FQ and Fourle TG (1984). Ulcer prevention and treatment with oleanoic acid. Chem Abs 100: 39613k.
Stainier DY, Lee RK, Fishman MC (1993). Cardiovascular development in the zebrafish. I. Myocardial fate map and heart tube formation. Development 119(1): 31-40.
Stainier DY (2001). Zebrafish genetics and vertebrate heart formation. Nat Rev Genet 2(1): 39-48.
Subbaramaiah K, Michaluart P, Sporn MB et al., (2000). Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer Res 60(9): 2399-2404.
Suzuki N, Hayakawa K, Kameda T et al., (2009) Monohydroxylated polycyclic aromatic hydrocarbons inhibit both osteoclastic and osteoblastic activities in teleost scales. Life Sci 84(13-14): 482-488.
Thadhani R, Pascual M, and Bonventre JV (1996). Acute renal failure. N Engl J.Med 334(20): 1448-1460.
Thomson/Micromedex (2007). Drug information for the health care professional. Volume 1, Greenwood Village, CO. 2785-2786.
Uchino S, Kellum JA, Bellomo R et al., (2005). Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294(7): 813-818.
Vaidya VS, Ferguson MA, and Bonventre JV (2009). Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol 48: 463-493.
Vila Ceren C, Demestre Guasch X, Raspall Torrent F (2005). Topiramate and pregnancy. Neonate with bone anomalies. An Pediatr (Barc) 63(4):363-365.
Vize PD, Woolf AS, and Bard JB (2003). The kidney: From normal development to congenital diseases. N Engl J Med 349: 2176-2177.
Waikar SS, Curhan GC, Wald R et al., (2006). Declining mortality in patients with acute renal failure, 1988 to 2002. J Am Soc Nephrol 17(4): 1143-1150.
Walker MB and Kimmel CB (2007). A two-color acid-free cartilage and bone stain for zebrafish larvae. Biotech Histochem 82 (1): 23-28.
Wang M, Jin H, Tang D et al., (2011). Smad1 plays an essential role in bone development and postnatal bone formation. Osteoarthritis Cartilage 19 (6): 751-762.
Wang Y and Ge W (2003). Spatial expression patterns of activin and its signaling system in the zebrafish ovarian follicle: evidence for paracrine action of activin on the oocytes. Biol Reprod 69(6): 1998-2006.
Wingert RA, Selleck R, Yu J et al., (2007). The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet 3(10): 1922-1938.
Wrzeciono U, Malecki I, Budzianowski J et al., (1985). Nitrogenous triterpene derivatives. 10. Hemisuccunates of some derivatives of oleanolic acid ad their antiulcer effects. Pharm 40(8): 542-544.
Yaqoob N, Holotta M, Prem C et al., (2009). Ontogenetic development of erythropoiesis can be studied non-invasively in GATA-1: DsRed ransgenic zebrafish. Comp Biochem Physiol A Mol Integr Physiol 154(2): 270-278.
Zaletova NI, Shchavlinskii AN, and Tolkachev ON. (1986). Preparation of certain derivatives of ursolic acid and their antimicrobial activity. Chem Abs 106(20): 18867e.
Zhang YY, Deng T, Hu ZF et al., (2006). Mechanisms of inhibiting proliferation and inducing apoptosis of human gastric cancer cell line SGC7901 by ursolic acid. Chin J Cancer 25(4):432-437.
Zhou Y, Li JS, Zhang X et al., (2010). Ursolic acid inhibits early lesions of diabetic nephropathy. Int J Mol Med 26(4): 565-570.
Zhou W and Hildebrandt F (2012). Inducible podocyte injury and proteinuria in transgenic zebrafish. J Am Soc Nephrol 23(6):1039-1047.
Zylberberg L, Bereiter-Hahn J, and Sire JY (1988). Cytoskeletal organization and collagen orientation in the fish scales. Cell Tissue Res. 253(3): 597-607.
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