紫外線會對皮膚造成傷害，包括:產生紅斑、DNA斷裂及皮膚癌等。許多研究中證實鳳梨葉萃取物具有降血糖及降血脂之功效；查耳酮其衍生物於藥理活性上具抗發炎、抑制血栓形成、抗氧化及抑制腫瘤細胞生長之活性。
本篇論文中，選用受精後72小時斑馬魚之幼魚為快篩模式物種，評估鳳梨葉萃取物和查耳酮其衍生物對是否具有防護紫外線照射能力。進一步探討是否能夠有效增強UVB於人類表皮癌細胞(A431)所引起之細胞凋亡。
由研究結果得知，鳳梨葉萃取物及查耳酮衍生物皆能夠有效減少UVB照射後所產生之ROS含量及具有防護魚鰭損傷功效。UVB、鳳梨葉萃取物和查耳酮及其衍生物分別作用於A431細胞時，都能夠抑制癌細胞生長。然而，UVB (30 mJ/cm2)與Compound 4 (10 μg/mL)合併與各別作用A431細胞後，發現合併治療之PARP片段(PARP cleavage)表現量增加，即表示合併治療誘導之細胞凋亡情形更加顯著。UVB和Compound 4合併作用於人類表皮膚癌細胞(A431)具有協同作用，因此，Compound 4可能為一種治療皮膚癌之化療藥物。
本研究以斑馬魚之幼魚作為模式物種，添加抗氧化物質評估是否具有防護UVB之效果。此模式的建立，之後可以用於快速檢驗抗氧化物質的光防護能力，並且同時評估抗氧化物質於生物體內之毒性影響。另外，藉由與UVB合併治療A431細胞，探討抗氧化物質是否具有開發為抗癌及化療藥物的潛力。此研究模式之建立，能夠作為日後快速評估防護UVB照射能力與治療皮膚癌之化療藥物開發。

Human exposed to heavy UVR could cause serious health effects such as skin erythema, DNA breakage and skin cancers. It is reported that chalcone have various biological activities such as anti-inflammatory, anti-oxidative, anti-cancer, and anti-coagulant effects. The extract of pineapple leaves has anti-diabetic and anti-dyslipidemic effects. This study is aimed to focus on those antioxidants applied in 3 day-post-fertilization (dpf) zebrafish model system to evaluate whether providing the UV protective effects. 
Here, we investigated whether pineapple leaf extract and chalcone derivatives can sensitize A431 human epidermoid carcinoma cells to UVB induced cell death. We examined the combined effect of UVB and drug on A431 cells. 
Results showed the extract of pineapple leaves and chalcone derivatives can protect zebrafish fin from UVB damage and reduce of reactive oxygen species (ROS) produce. Exposure of A431 carcinoma cells to UVB radiation, pineapple leaves and chalcone derivatives can induced cytotoxicity. However, the combination of Compound 4 (10 μg/mL) and UVB (30 mJ/cm2) exposure was associated with increased cytotoxicity inhibition of A431 cells compared with either agent alone. Moreover, Compound 4 markedly activation the PARP cleavage in protein expression, and finally cell death. In conclusion, our study demonstrates that the combination of Compound 4 and UVB act synergistically against skin cancer cells. Thus, Compound 4 is a potential chemotherapeutic agent against skin carcinogenesis.
In the future, UVB protective effects and speedy antioxidants selection could be applied in these model systems. These screening method are excellent and effective for large-scale organisms toxicity and antioxidants screening. In conclusion, our study demonstrates that the combination of antioxidants and UVB act synergistically against skin cancer cells. Thus, chalcone derivatives and similar antioxidants is a potential chemotherapeutic agent  against  skin carcinogenesis.

圖目錄	v
表目錄	vii
第一章	前言	1
1-1 紫外線 (Ultraviolet, UV)	1
1-2 紫外線 (Ultraviolet, UV) 對皮膚之影響	1
1-3 活性氧化物質(Reactive oxygen species, ROS)與皮膚病變之關係	2
1-4 抗氧化物質	3
1-5抗氧化物質能夠增強UVB所誘導之細胞凋亡	4
1-6 鳳梨	5
1-7 鳳梨葉之應用	6
1-8 查耳酮 (Chalcone) 及其衍生物來源	8
1-9 Chalcone 及其衍生物之應用	9
1-10 模式物種-斑馬魚優勢	10
1-11研究目的	11
第二章 材料與方法	12
2-1 野生型斑馬魚 ( AB strain ) 之飼養及胚胎收集	12
2-2 鳳梨葉萃取物及查耳酮(chalcone)衍生物	12
2-3 浸泡方式及藥物篩選	13
2-4 UVB照射	13
2-5 魚鰭損傷修復觀察記錄	14
2-6 治療損傷之魚鰭修復記錄	14
2-7 偵測活性氧分子 ( Reactive oxygen species ,ROS )	14
2-8 受損魚鰭回復至正常魚鰭面積之統計分析	15
2-9 細胞凋亡分析 (TUNEL assay)	16
2-10 斑馬魚胚胎核酸(Riobonucleotide acid, RNA) 之萃取	17
2-11 反轉錄聚合酶連鎖反應 (Reverse transcription-PCR, RT-PCR )	18
2-12 即時定量聚合酶連鎖反應 (quantitative real-time polymerase chain reaction, qRT-PCR)	18
2-13 人類表皮癌細胞 (A431) 培養	19
2-14 細胞存活率檢測 (MTT assay)	19
2-15 UVB照射處理人類表皮膚癌細胞細胞(A431)	20
2-16 西方墨點法 (Western blot)	21
2-17 統計分析	22
2-18 螢光顯微鏡、顯微照相系統	23
第三章 結果	24
3-1 確立斑馬魚幼魚為模式物種之紫外線暴露劑量	24
3-2人類表皮膚癌細胞(A431)經UVB照射後明顯誘導凋亡	25
PARTⅠ鳳梨葉萃取物	26
3-3鳳梨葉萃取物對斑馬魚幼魚毒性低	26
3-4 鳳梨葉萃取物具顯著防護UVB照射之能力	26
3-5鳳梨葉萃取物具光保護魚鰭損傷能力	27
3-6 鳳梨葉萃取物能減少UVB引起之細胞凋亡	29
3-7 鳳梨葉萃取物為UVB防護劑對細胞凋亡相關基因之影響	31
3-8 長時間浸泡鳳梨葉萃取物會對斑馬魚幼魚造成毒性影響	31
3-9 低濃度鳳梨葉萃取物有效治療及加速魚鰭損傷修復	32
3-10 鳳梨葉萃取物具有抑制人類表皮癌A431細胞生長能力	34
3-11低濃度萃取物無法增加UVB對癌細胞數之影響	35
PARTⅡ查爾酮(chalcone)及其衍生物	37
3-12 低劑量查耳酮衍生物不具生物毒性	37
3-13 低濃度下查耳酮(chalcone)防護UVB能力最佳	38
3-14查耳酮衍生物皆無保護魚鰭損傷	39
3-15斑馬魚對查耳酮衍生物隨浸泡時間增而增強毒性	40
3-16 查耳酮及其衍生物具有抑制人類表皮癌A431細胞生長能力	41
3-17 Compound 4 (Cpd 4)有效增加UV造成之癌細胞數量減少	42
3-18 Compound 4 (Cpd 4)有效增加UVB引起之細胞凋亡	44
第四章 討論	45
4-1 查耳酮衍生物依其結構分析抗癌功效	45
4-2 查耳酮衍生物造成鈣離子失衡，為凋亡過程中之上調因子	46
4-3 鳳梨葉萃取物及查耳酮衍生物為有效之光保護劑	47
4-4 查耳酮衍生物具有良好之滲透性	49
4-5 鳳梨葉萃取物(10 μg/mL)能作為組織修復中抗氧化劑	50
4-5 查爾酮衍生物(Cpd 11)藉由不同路徑對斑馬魚幼魚及癌細胞造成影響	51
4-6 結論與未來研究方向	52
第五章 參考文獻	54

圖目錄
Fig. 1UVB 照射次數不同對斑馬魚幼魚存活率有顯著差異 .............. 61
Fig. 2 UVB 不同照射劑量處理A431 細胞皆有顯著影響 .................. 61
Fig. 3 UVB 對A431 細胞之影響程度隨時間增加而更顯著 .............. 62
Fig. 4 斑馬魚幼魚浸泡不同濃度鳳梨葉萃取物1.5 小時之存活率 .... 62
Fig. 5 鳳梨葉萃取物相對應UVB 控制組所產生ROS 表現量 .......... 63
Fig. 6 UVB 照射24 小時後對魚鰭造成之損傷程度分類 ................... 63
Fig. 7 UVB 照射後顯著對魚鰭造成傷害並造成大量細胞凋亡訊號
產生 ................................................................................................. 64
Fig. 8 高濃度鳳梨葉萃取物有效減少UVB 造成之細胞凋亡訊號產
生 ..................................................................................................... 64
Fig. 9 隨著鳳梨葉萃取物濃度增加，細胞凋亡之相關基因表現越不
顯著 ................................................................................................. 65
Fig. 10 長時間浸泡鳳梨葉萃取物對斑馬魚幼魚之毒性影響 ............ 65
Fig. 11 高濃度之鳳梨葉萃取物具有效抑制A431 細胞生長能力 ..... 66
Fig. 12 低濃度鳳梨葉萃取物無法增強抑制A431 細胞生長能力 ..... 66
Fig. 13 斑馬魚幼魚經Compound 11 (Cpd 11)浸泡1.5 小時後，造成
幼魚出現心包腔腫大及積血之情形 ............................................. 67
Fig. 14 查耳酮相對應UVB 控制組能夠減少產生ROS 表現量 ........ 67
Fig. 15 Compound 4 不同濃度作用於A431 細胞12 小時後之細胞存
活率分析 ......................................................................................... 68
Fig. 16 Compound 4 與UVB (50mJ/cm2)合併治療A431 細胞 ........... 68
Fig. 17 Compound 4(10 μg/mL)與UVB (30mJ/cm2)合併治療A431 細
胞，顯著減少細胞存活率 ............................................................. 69
Fig. 18 Compound 4(10 μg/mL)與UVB (30mJ/cm2)合併治療後增加
A431 細胞凋亡 ............................................................................... 70

表目錄
Table 1 Chalcone 衍生物主要之結構式、名稱及化學式 .................... 71
Table 2 反轉錄聚合酶連鎖反應(qRT-PCR) 所用之引子 ................... 72
Table 3 Kaplan-Meier 法分析鳳梨葉萃取物作為防護時各實驗組受
損魚鰭(未回復正常魚鰭面積)，估計各組恢復正常魚鰭面積平
均時間 ............................................................................................. 73
Table 4 Cox proportional hazards regression method 分析鳳梨葉萃取
物防護UVB 照射後臀鰭恢復率 ................................................... 74
Table 5 Kaplan-Meier 法分析鳳梨葉萃取物作為治療時各實驗組受
損魚鰭(未回復正常魚鰭面積)，估計各組恢復正常魚鰭面積平
均時間 ............................................................................................. 75
Table 6 Cox proportional hazards regression method 分析鳳梨葉萃取
物治療UVB 照射後臀鰭恢復率 ................................................... 76
Table 7 斑馬魚幼魚浸泡查耳酮衍生物1.5 小時之存活率 ................ 77
Table 8 Kaplan-Meier 法分析查耳酮及其衍生物作為防護時各實驗
組受損魚鰭(未回復正常魚鰭面積)，估計各組恢復正常魚鰭面
積平均時間 ..................................................................................... 78
Table 9 Cox proportional hazards regression method 分析查耳酮及其
衍生物防護UVB 照射後臀鰭恢復率 ........................................... 79
Table 10 斑馬魚幼魚浸泡查耳酮衍生物24 小時之存活率 ................ 80
Table 11 查耳酮及其衍生物具有效抑制A431 細胞生長能力 ........... 81

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