臺灣博碩士論文加值系統

慢性發炎是導致自身免疫性系統失調與大多數疾病發生的共同原因之一，有效抑制發炎將能提高疾病的治癒能力。蘭花除觀賞用途外，近年來有研究指出蝴蝶蘭水萃物可以美白，抗 UVA、UVB 所造成的皮膚傷害；而白楊素是一種存在於蘭花中的天然類黃酮類化合物，自古為中國的傳統藥材之一，具有抗發炎特性和神經保護作用。過去文獻指出白楊素可抑制經由脂多醣 (Lipopolysaccharide, LPS) 誘導的發炎反應，阻斷活化神經微膠細胞 (Microglia) NF-κB 和 JNK 的表現量，減少發炎反應。本研究探討使用白楊素 (chrysin, 0.5-10 M) 與蝴蝶蘭水萃物 (water extract of Phalaenopsis orchid flower, WEPF, 25-200 ng/mL) 對 LPS 誘導的小鼠 RAW 264.7 巨噬細胞抗發炎作用與參與機制。利用ELISA、RT-PCR、Western blot 和 Gelatin Zymography 方法測定相關發炎因子水平的變化。結果顯示，白楊素在濃度10 M，蝴蝶蘭水萃物在濃度 200 ng/mL 時對小鼠 RAW264.7 巨噬細胞產生之發炎介質具有顯著抑制作用，藉由減少促炎細胞激素，如:介白素(interleukin, IL)-1, -6、腫瘤壞死因子(tumor necrosis factor, TNF)-的分泌，降低基質金屬蛋白酶 (Matrix metalloproteinase, MMP)-9 的表現，同時抑制 I激酶活性，使 p65 進入細胞核內，進行基因轉錄與調控下游促發炎細胞激素。綜合以上發現，白楊素與蝴蝶蘭水萃物可顯著抑制 LPS 誘導小鼠 RAW 264.7 巨噬細胞的發炎反應，並透過阻斷通過 NF和 MAPK 信號通路，使 MMP-9 表現量減少，以及降低 TNF-、IL-1與IL-6 分泌，達到抗小鼠巨噬細胞發炎的功效。

Inflammation is one of the mechanisms for autoimmune disorders and a common feature of most diseases. Effective suppression of inflammation is a crucial means for disease treatment. Orchids, a group of angiosperms belonging to the Orchidaceae family, are traditionally used as an herbal medicine and many constituents obtained from different parts of orchid with biological activities including anti-inflammation. In the present study, we used water extract of Phalaenopsis aphrodite subsp. Formosana (WEPF) and Chrysin, a flavonoid in Cymbidium, to evaluate and compare their anti-inflammatory properties in a lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophage cell line. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to determine the toxicity of compounds on cells. Nitric oxide (NO) and inducible NO synthase (iNOS) were assayed by commercial kits. The levels of several inflammation-related factors were determined by enzyme-linked immunosorbent assay (ELISA), gelation zymography and RT-PCR. The molecular signaling was analyzed by Western blot. The results showed that the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1 in RAW 264.7 cells were significantly induced by LPS at a concentration of 100 ng/mL; the induced proteins were then depressed by treating chrysin and WEPF at a concentration higher than 10 M, 200 ng/mL, respectively. The gelatinolytic activity and mRNA expression of matrix metalloproteinase (MMP)-9 were inhibited by chrysin and WEPF higher than 10 M and 100 ng/mL, respectively. The levels of NO and iNOS were both increased by the treatment of WEPF or chrysin. Additionally, MAPKs and NF-B signaling were inactivated by chrysin and WEPF. In conclusion, chrysin and WEPF both could inhibit the LPS-stimulated inflammation in RAW264.7 cells by suppressing the levels of NO, iNOS, IL-6, IL-1β, TNF- and MMP-9 through inactivating MAPKs and NF-B. Chrysin and WEPF might use to improve the treatment of inflammation-related diseases.

中文摘要………………………………………………………………… II
英文摘要………………………………………………………………… IV
目次……………………………………………………………………… VII
圖次……………………………………………………………………… IX
表次……………………………………………………………………… XIV
縮寫表…………………………………………………………………… XV
第一章、前言……………………………………………………………… 1
第二章、文獻探討………………………………………………………… 4
壹、 發炎介紹………………………………………………………… 4
一、 發炎反應…………………………………………………… 4
二、 發炎與巨噬細胞………………………………………… 15
三、 發炎與基質金屬蛋白酶-9………………………………… 31
四、 發炎與癌症關係…………………………………………… 34
貳、 蘭科植物………………………………………………………… 37
一、 蘭科植物特徵……………………………………………… 37
二、 台灣常見蘭花介紹………………………………………… 38
三、 蘭花的生理特性…………………………………………… 40
四、 蘭花的化學成分和藥用性質……………………………… 41
參、 白楊素介紹……………………………………………………… 51
一、 白楊素的來源與特性……………………………………… 51
二、 白楊素傳統保健功效……………………………………… 51
三、 白楊素現代醫學研究 …………………………………… 51
肆、 研究目的………………………………………………………… 58
伍、 研究架構………………………………………………………… 59
第三章、材料與方法……………………………………………… ……… 60
壹、實驗材料與試藥……………………………………………………60
貳、實驗方法……………………………………………………………63
第四章、結果………………………………………………………………72
第一部分:白楊素對以脂多醣誘發小鼠巨噬細胞抗發炎作用研究……72
一、白楊素對小鼠 RAW 264.7 巨噬細胞之毒性測試…………72
二、白楊素對 LPS 誘發小鼠 RAW 264.7 巨噬細胞一氧化氮
生成抑制影響………………………………………………72
三、白楊素對 LPS 誘發小鼠 RAW 264.7 巨噬細胞產生iNOS蛋白的影響………………………………………73
四、白楊素對 LPS 誘發小鼠 RAW 264.7 巨噬細胞產生 MMP-9 酵素活性影響……………………………………73
五、白楊素對 LPS 誘發小鼠 RAW 264.7 巨噬細胞產生促炎
細胞激素 (IL-1, IL-6, TNF-) 的影響…………………73
六、白楊素對 LPS 誘發小鼠 RAW 264.7 巨噬細胞IL-1、
IL-6 與 TNF- mRNA表現之影響………………………74
七、白楊素對 LPS 誘發小鼠 RAW 264.7 巨噬細胞中磷酸化
ERK1/2、JNK 及 p38 蛋白質表現之影響………………75
八、白楊素對 LPS 誘發小鼠 RAW 264.7 巨噬細胞轉錄因子
NF-B 之影響………………………………………………75
九、白楊素對 LPS 誘發小鼠 RAW 264.7 巨噬細胞產生COX-2 與 PGE2 蛋白表現之影響………………………75

第二部分:蝴蝶蘭水萃物對以脂多醣誘發小鼠 RAW267.4 巨噬細胞抗發炎作用研究………………………………………………………………77
一、 蝴蝶蘭水萃物對小鼠 RAW 264.7 巨噬細胞之毒性測試77
二、 蝴蝶蘭水萃物對 LPS 誘發小鼠 RAW 264.7 巨噬細胞產生一氧化氮生成抑制影響………………………………77
三、 蝴蝶蘭水萃物對 LPS 誘發小鼠 RAW 264.7巨噬細胞產生 iNOS 蛋白的影響…………………………………77
四、 蝴蝶蘭水萃物對 LPS 誘發小鼠 RAW 264.7 巨噬細胞產生 MMP-9 酵素活性影響……………………………78
五、 蝴蝶蘭水萃物對 LPS 誘發小鼠 RAW 264.7 巨噬細胞產生促炎細胞激素(IL-1IL-6, TNF-)的影響…………78
六、 蝴蝶蘭水萃物對 LPS 誘發小鼠 RAW 264.7 巨噬細胞 IL-1、IL-6 與 TNF- 之mRNA表現之影響…………79
七、 蝴蝶蘭水萃物對 LPS 誘發小鼠 RAW 264.7 巨噬細胞中磷酸化 ERK1/2、JNK 及 p38 蛋白質表現之影響…80
八、 蝴蝶蘭水萃物對 LPS 誘發小鼠 RAW 264.7 巨噬細胞轉錄因子 NF-B 之影響…………………………………80
九、 蝴蝶蘭水萃物對 LPS 誘發小鼠 RAW 264.7巨噬細胞產生 COX-2 與 PGE2 蛋白表達之影響…………………81
第五章、討論………………………………………………………………82
第六章、結論………………………………………………………………111
參考文獻……………………………………………………………………112

圖目錄
圖1、發炎反應……………………………………………………………4
圖2、MAPK 訊息傳遞路徑………………………………………………7
圖 3、細胞核轉錄因子傳遞訊息路徑……………………………………11
圖 4、NF-B 在腫瘤發展進程的角色……………………………………14
圖 5、巨噬細胞吞噬凋亡細胞過程………………………………………16
圖 6、細胞內毒素 LPS 構造……………………………………………17
圖 7、腫瘤壞死因子在免疫調節與腫瘤的雙重作用……………………20
圖 8、IL-6 與 發炎作用機制……………………………………………22
圖 9、中性粒細胞趨化因子 IL-8 訊息傳遞路徑………………………24
圖 10、L-精胺酸的吸收代謝與合成一氧化氮的關係…………………27
圖 11、PGE2 生成路徑……………………………………………………30
圖 12、MMP-9 與發炎……………………………………………………33
圖 13、癌症與慢性發炎之相關訊息調控路徑…………………………36
圖 14、旭東威士忌 品種權字第 A00595 號……………………………39
圖 15、類黃酮類基本架構…………………………………………………49
圖 16、白楊素結構式 ……………………………………………………52
圖 17、慢性發炎與癌症……………………………………………………55
圖 18、皮膚微發炎模型……………………………………………………56
圖 19、白楊素對小鼠 RAW 264.7巨噬細胞之毒性測試………………89
圖 20、白楊素對 LPS誘發小鼠RAW 264.7 巨噬細胞一氧化氮生成
量影響……………………………………………………………90
圖 21、白楊素對 LPS 誘導小鼠 RAW 264.7 巨噬細胞產生 iNOS 蛋白表現之影響……………………………………………………91
圖 22、白楊素對 LPS 誘導小鼠 RAW 264.7 巨噬細胞產生 MMP-9 活性之影響………………………………………………………92
圖 23、白楊素對 LPS 誘導小鼠 RAW 264.7 巨噬細胞產生細胞激素 TNF-之影響……………………………………………………93
圖 24、白楊素對 LPS 誘導小鼠 RAW 264.7 巨噬細胞產生細胞激素 IL-6 之影響………………………………………………………94
圖 25、白楊素對 LPS 誘導小鼠 RAW 264.7 巨噬細胞產生細胞激素
IL-1之影響………………………………………………………95
圖 26、白楊素對 LPS 誘發小鼠 RAW 264.7 巨噬細胞 IL-1、IL-6
與 TNF-mRNA表現之影響…………………………………96
圖27、白楊素對LPS 誘導小鼠 RAW 264.7 巨噬細胞中磷酸化 ERK1/2、JNK 及 p38 蛋白質表現之影響 ……………………97
圖 28、白楊素對LPS 誘導小鼠 RAW 264.7 巨噬細胞分泌 NF-B 轉錄因子蛋白表現之影響…………………………………………98
圖 29、白楊素對LPS 誘導小鼠 RAW 264.7 巨噬細胞分泌 COX-2 與 PGE2蛋白表現之影響……………………………………………99
圖 30、蝴蝶蘭水萃物對小鼠 RAW 264.7 巨噬細胞之毒性測定………100
圖 31、蝴蝶蘭水萃物對 LPS 誘發小鼠RAW 264.7 巨噬細胞一氧化氮生成量影響……………………………………………………101
圖 32、蝴蝶蘭水萃物對 LPS 誘導小鼠 RAW 264.7 巨噬細胞分泌
iNOS蛋白表現之影響……………………………………………102
圖 33、蝴蝶蘭水萃物對 LPS 誘導小鼠 RAW 264.7 巨噬細胞分
MMP-9 活性之影響……………………………………………103
圖34、蝴蝶蘭水萃物對 LPS 誘導小鼠 RAW 264.7 巨噬細胞分泌
細胞激素 IL-1之影響…………………………………………104
圖 35、蝴蝶蘭水萃物對 LPS 誘導小鼠 RAW 264.7 巨噬細胞分泌
細胞激素 IL-6之影響……………………………………………105
圖 36、蝴蝶蘭萃取物對 LPS 誘導小鼠 RAW 264.7 巨噬細胞分泌
細胞激素 TNF-之影響…………………………………………106
圖37、蝴蝶蘭水萃物對 LPS 誘發小鼠 RAW 264.7 巨噬細胞IL-1、IL-6與 TNF-之mRNA表現之影響…………………………107
圖 38、蝴蝶蘭水萃物對 LPS 誘導小鼠 RAW 264.7 巨噬細胞中
磷酸化 ERK1/2、JNK 及 p38 蛋白質表現之影響……………108
圖 39、蝴蝶蘭水萃物對LPS 誘導小鼠 RAW 264.7 巨噬細胞產生
NF-B 轉錄因子蛋白表現之影響………………………………109
圖 40、蝴蝶蘭水萃物對LPS 誘導小鼠 RAW 264.7 巨噬細胞產生
COX-2 與 PGE2蛋白表現之影響………………………………110


表目錄

表 一、蘭花成分-二級代謝產物種類與藥理作用………………………42
表 二、蘭花成分-多環芳香烴類與藥理作用……………………………44

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