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。

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.

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

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