臺灣博碩士論文加值系統

　　麵包樹 (Artocarpus communis Moraceae)為桑科麵包樹屬植物，又稱麵包果樹 (breadfruit tree)，多分佈於台灣南、東部以及東南亞地區，具有抗氧化、抗血小板凝集、抗發炎及抗癌等功效，由於麵包樹植物萃取物於臨床活體中之功效性未明，因此本研究利用已建立之動物試驗探討麵包樹植物萃取物之生物活性評估。內容主要分成兩部分：(一)麵包樹植物萃取物於活體抗發炎之功效評估與 (二)麵包樹植物之果實主要類黃酮成分3’-geranyl-2’,3,4,4’-tetrahydroxychalcone及葉部之xanthoangelol於活體抗發炎之功效評估。
　　首先，探討麵包樹植物：果實及葉部甲醇萃取物 (methanol extracts of the fruit and the leaf of Artocarpus communis, MEFA and MELA)於活體抗發炎功效。由總多酚及總類黃酮之分析結果證實，MEFA及MELA中富含具抗發炎活性之多酚類化合物。12-O-tetradecanoylphorbol-13-acetate (TPA)誘導皮膚，於發炎試驗指出， MEFA及MEFA皆可減少耳部組織中TPA誘發之發炎指標蛋白PGE2、促發炎細胞激素TNF-α、IL-1β、發炎基因 (IL-1β、IL-6、TNF-α)表現及改善皮膚水腫、耳部皮膚增厚與皮下嗜中性白血球浸潤等發炎現象。綜合以上，麵包樹植物萃取物於TPA誘導發炎之動物模式中具有良好之抗發炎作用，其中MEFA之抑制效果較MELA顯著。進一步評估MEFA及MELA於化學誘導皮膚癌模式中抑制腫瘤生成之功效，結果發現以MEFA及MELA皆可抑制TPA誘發之腫瘤生成、腫瘤惡化及腫瘤周邊血管新生，推測MEFA及MELA可減緩TPA持續誘發之發炎反應，進而使腫瘤生成減少。
　　HPLC分析結果顯示，MEFA中主要類黃酮成分為3’-geranyl-2’,3,4,4’-tetrahydroxychalcone (AC-F)而MELA則為xanthoangelol (AC-L)，推測其個別為MEFA及MELA中主要之抗發炎活性成分。基於上述假設，進一步各別評估AC-F及AC-L於活體之抗發炎功效。於TPA誘導皮膚發炎實驗結果發現，AC-F及AC-L可減少耳部組織中TPA誘發之發炎因子 (PGE2、TNF-α、IL-1β)表現，以及背部皮膚水腫、耳部皮膚發炎紅腫與皮下嗜中性白血球浸潤等發炎現象。另外，利用化學誘導皮膚癌模式評估AC-F及AC-L於抑制腫瘤生成之功效發現，塗抹AC-F及AC-L於小鼠皮膚上皆可減少7,12-dimethylbenz[α]anthracene (DMBA)/TPA兩階段誘發之腫瘤生成，推測其可能藉由調控MAPK途徑並抑制NF-κB活化、抑制DMBA/TPA誘發之iNOS及COX-2表現，達到減緩皮膚癌化之效果。綜合以上，3’-geranyl-2’,3,4,4’-tetrahydroxychalcone及xanthoangelol為麵包樹植物萃取物中兩種含量最高之黃酮類抗發炎成分。

Artocarpus communis has been identified as a rich source of flavonoids, which have been highly gaining attention for their potential chemopreventive abilities. In this study, methanol extract of the fruit of A. communis (MEFA) and methanol extract of the leaf of A. communis (MELA) were prepared and their effects on inflammation-associated skin tumorigenesis were assessed using mouse models including 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cutaneous inflammation as well as 7,12-dimethylbenz[α]anthracene (DMBA)-initiated and TPA-promoted skin tumorigenesis. There are two topics included in this study: (1) Effects of methanol extracts of fruit and leaf of Artocarpus communis on inflammation-associated skin tumorigenesis in ICR mice; (2) Effects of 3’-geranyl-2’,3,4,4’-tetrahydroxychalcone and xanthoangelol of Artocarpus communis on inflammation-associated skin tumorigenesis in ICR mice.
According to the results, both of MEFA and MELA produced a significant decrease in intensity of neutrophil infiltration in mouse skin caused by TPA, which appeared to be mediated by inhibition of NF-κB/AP-1-regulated pro-inflammatory genes (iNOS, COX-2, TNF-α, IL-1β and IL-6) and production of pro-inflammatory factors (TNF-α, IL-1β and PGE2). In addition, topical application with MEFA or MELA significantly reduced cutaneous edema in dorsal skin and ear of TPA-induced mice. Topical application with MEFA or MELA effectively attenuated tumor incidence, hyperplasia (evaluated by multiplicity and volume of tumors), malignancy and angiogenesis of TPA-caused skin tumor promotion in DMBA-initiated mice. These findings first demonstrate that flavonoid-rich MEFA and MELA may inhibit the promotion of skin tumorigenesis in vivo by directly potent anti-inflammatory actions.
Moreover, an HPLC analysis revealed that MEFA contained flavonoids compounds such as 3’-geranyl-2’,3,4,4’-tetrahydroxychalcone and xanthoangelol. Furthermore, we investigate the anti-inflammatory abilities of 3’-geranyl-2’,3,4,4’-tetrahydroxychalcone and xanthoangelol on TPA-induced cutaneous inflammation as well as DMBA-initiated and TPA-promoted skin tumorigenesis in ICR mice. As the results showed, topical application with 3’-geranyl-2’,3,4,4’-tetrahydroxychalcone and xanthoangelol significantly decreased the production of pro-inflammatory mediators (TNF-α, IL-1β and PGE2) and reduced cutaneous edema in dorsal skin and ear of TPA-induced mice. In addition, topical application with 3’-geranyl-2’,3,4,4’-tetrahydroxychalcone or xanthoangelol effectively attenuated tumor incidence, hyperplasia of TPA-caused skin tumor promotion in DMBA-initiated mice.
In conclusion, these results indicate that MEFA and MELA are rich in flavonoids, which possess great anti-inflammatory potential. Also, it suggests that 3’-geranyl-2’,3,4,4’-tetrahydroxychalcone and xanthoangelol are the bioactive compounds of MEFA and MELA from Artocarpus communis.

全文摘要(中)........................................... i
全文摘要(英)........................................... iii
目次 ................................................. v
圖次.................................................. ix
表次.................................................. xiii
縮寫表................................................ xiv

前言.................................................. 1
第一章、文獻整理........................................ 3
壹、發炎反應與疾病..................................... 4
一、發炎反應與其相關轉錄因子............................ 4
二、發炎相關酵素與促發炎激素............................ 7
三、發炎反應與癌症.................................... 12
四、發炎與血管新生.................................... 15
貳、皮膚組織............................................17
一、皮膚簡介.......................................... 17
二、皮膚構造及功能............................. 17
三、皮膚發炎與皮膚癌生成........................ 20
參、小鼠皮膚處理TPA模式..................... 23
肆、化學致癌過程....................................... 23
伍、小鼠皮膚兩階段致癌模式............................... 24
陸、麵包樹介紹.......................................... 26
柒、研究目的.......................................... 30
捌、研究架構............................................ 31
第二章、麵包樹植物萃取物於活體抗發炎之功效評估................. 32
中文摘要................................................ 33
英文摘要................................................. 34
前言................................................... 35
實驗架構................................................ 37
材料與方法.............................................. 38
實驗結果................................................ 49
一、MEFA與MELA之多酚與類黃酮含量分析....................... 49
二、MEFA與MELA對TPA誘導耳朵之發炎指標蛋白
PGE2與促發炎激素TNF-α及IL-1β表現之影響..................... 49
三、MEFA與MELA對TPA誘導小鼠背部皮膚之發炎指標
iNOS與COX-2及促發炎激素TNT-α、IL-6、IL-1β mRNA
表現之影響............................................ 50
四、MEFA與MELA預處理於小鼠皮膚對於TPA誘
發小鼠皮膚表皮水腫現象之影響............................. 50
五、MEFA與MELA預處理於小鼠耳朵對於TPA誘
發小鼠耳朵表皮增厚程度之影響............................. 51
六、MEFA與MELA對於小鼠體重之影響........................ 52
七、MEFA與MELA於小鼠兩階段致癌實驗中對小鼠平
均腫瘤數及腫瘤發生率之影響............................... 52
八、MEFA與MELA於小鼠兩階段致癌實驗中對小鼠腫
瘤癌化程度之影響...................................... 53
九、MEFA與MELA於小鼠兩階段致癌實驗中對小鼠皮
膚下血管分布情形的影響................................. 53
十、HPLC分析MEFA及MELA中之活性成分.................... 54
討論............................................ 55
第三章、麵包樹植物之果實主要類黃酮成分
3’-geranyl-2’,3,4,4’-tetrahydroxychalcone及葉部之
xanthoangelol於活體抗發炎之功效評估..................... 75
中文摘要............................................ 76
英文摘要............................................. 77
前言.............................................. 78
實驗架構............................................ 80
材料與方法.......................................... 81
實驗結果............................................. 88
一、3’-geranyl-2’,3,4,4’-tetrahydroxychalcone與xanthoangelol
對TPA誘導耳朵之發炎指標蛋白PGE2與促發炎激素
TNF-α及IL-1β表現之影響....................................88
二、3’-geranyl-2’,3,4,4’-tetrahydroxychalcone與xanthoangelol
預處理於小鼠皮膚對於TPA誘發小鼠皮膚表皮水腫現象
之影響.............................................. 88
三、3’-geranyl-2’,3,4,4’-tetrahydroxychalcone與xanthoangelol
對預處理於小鼠耳朵均可顯著減少TPA誘發小鼠耳朵表
皮增厚程度........................................... 89
四、3’-geranyl-2’,3,4,4’-tetrahydroxychalcone與xanthoangelol
對於小鼠體重之影響..........................................89
五、3’-geranyl-2’,3,4,4’-tetrahydroxychalcone與xanthoangelol
於小鼠兩階段致癌實驗中對小鼠平均腫瘤數及腫瘤發生
率之影響................................................ 90
六、3’-geranyl-2’,3,4,4’-tetrahydroxychalcone與xanthoangelol
於小鼠兩階段致癌實驗中對小鼠腫瘤癌化程度之影響.................. 90
七、3’-geranyl-2’,3,4,4’-tetrahydroxychalcone與xanthoangelol
對小鼠皮膚腫瘤中iNOS及COX-2蛋白質表現之影響................... 91
八、3’-geranyl-2’,3,4,4’-tetrahydroxychalcone與xanthoangelol對小鼠皮膚腫瘤中核內磷酸化p65蛋白質表現之影響................ 91
九、3’-geranyl-2’,3,4,4’-tetrahydroxychalcone與xanthoangelol
對小鼠皮膚腫瘤中磷酸化p38、ERK1/2、JNK蛋白質表現之影響............................................... 92
討論............................................. 93
總結論............................................ 111
參考文獻.......................................... 112

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