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研究生:林怡彣
研究生(外文):I Wen Lin
論文名稱:濱當歸活性成分imperatorin經由cAMP抑制人類嗜中性白血球釋放超氧自由基的探討
論文名稱(外文):Imperatorin, a furocoumarin from Angelica hirsutiflora, inhibits human neutrophil superoxide anion generation via a cAMP-dependent pathway
指導教授:黃聰龍黃聰龍引用關係
指導教授(外文):T. L. Huang
學位類別:碩士
校院名稱:長庚大學
系所名稱:天然藥物研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:79
中文關鍵詞:嗜中性白血球濱當歸
外文關鍵詞:NeutrophilsimperatorinAngelica hirsutiflora
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人類嗜中性白血球在宿主體內扮演著重要的角色來抵抗外物入侵。但是嗜中性白血球過度或不適當的活化會引起一些發炎相關的疾病,例如:氣喘、心肌梗塞、慢性阻塞性肺炎及風濕性關節炎等。在本論文中,我們以人類嗜中性白血球釋放超氧自由基 (O2.-) 和顆粒性蛋白酶的實驗模式來篩選一系列天然物,實驗結果發現,呋喃香豆素類化合物imperatorin具有濃度相關性抑制N-formyl-methionyl-leucyl-phenylalanine (FMLP) 活化人類嗜中性白血球釋放O2.- 的作用,其IC50為0.17±0.02 μM,但不影響elastase的釋放。然而,imperatorin並不會抑制protein kinase (PK)C這條路徑所活化釋出的O2.-。進一步實驗發現,imperatorin抑制O2.-的作用並非經由細胞毒殺、抗氧化或直接清除O2.-、影響細胞中NADPH oxidase活性而來。此外,imperatorin抑制O2.-產生的能力會被PKA抑制劑完全反轉,但不會受PKG抑制劑影響。重要地,cAMP含量的實驗中發現,在FMLP存在下,imperatorin和rolipram一樣都具有提升細胞內cAMP含量以及PKA活性的能力。另外,在FMLP刺激之下,imperatorin和rolipram都無法改變[Ca2+]i上升的最大值,卻會縮短Ca2+的減退時間。Imperatorin減弱了extracellular regulated kinase (ERK),c-Jun N-terminal kinase (JNK) 和protein kinase B (AKT) 的磷酸化,但不影響p38 mitogen-activated protein kinase的活化。Imperatorin 對Ca2+的影響和抑制ERK、JNK及AKT磷酸化的作用都會被PKA抑制劑所逆轉。綜合以上,我們可以推測imperatorin抑制嗜中性白血球釋放O2.- 的作用與增加cAMP濃度及PKA活性這條路徑有相關。本論文的結果將可以提供imperatorin 藥理機轉與藥效作用的新資訊,並瞭解imperatorin具有發展成抗發炎藥物的潛力。
Human neutrophils are known to play important roles in the host to defend against microorganisms. However, the extensive or inappropriate activation of neutrophils may cause inflammatory diseases, such as asthma, myocardial infarction, chronic obstructive pulmonary disease, and rheumatoid arthritis. In a search for new anti-inflammatory agent with high efficacy and low toxicity, the effects of imperatorin, a furocoumarin derivative, on superoxide anion and elastase release in human neutrophils were tested. Imperatorin concentration-dependently inhibited superoxide (O2.-) production with an IC50 value of 0.17±0.02 μM, but not elastase release, in formyl-methionyl-leucyl-phenylalanine (FMLP)-activated human neutrophils. However, imperatorin did not affect protein kinase (PK)C activator-induced O2.- generation. Furthermore, imperatorin displayed no antioxidant or O2.- scavenging ability, and it failed to alter the subcellular NADPH oxidase activity. Significantly, the inhibitory effect of imperatorin on O2.- production was reversed by a PKA inhibitor, but not by a PKG inhibitor. Indeed, imperatorin and rolipram notably increased cAMP levels and PKA activity in FMLP-stimulated human neutrophils. Additionally, the peak [Ca2+]i value was unaltered by imperatorin and rolipram, but the time taken for [Ca2+]i to return to half of the peak values was significantly shorted in FMLP-activated neutrophils. Imperatorin reduced FMLP- induced phosphorylation of extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and protein kinase B (AKT), but not p38 mitogen-activated protein kinase. The inhibitory effects of imperatorin on mobilization of Ca2+ and activation of ERK, JNK and AKT were reversed by PKA inhibitor. In summary, these results demonstrate that inhibition of O2.- release in human neutrophils by imperatorin is associated with an elevation of cellular cAMP levels and PKA activity.
目錄
指導教授推薦書……………………………………………………
口試委員會審定書…………………………………………………
授權書……………………………………………….………….…….…iii
誌謝………………………………………….………………….….……iv
縮寫表……………………………….………………………….….…....v
中文摘要……………………………………………………….………viii
英文摘要………………………………………………………………...ix
目錄……………………………………………………………………....x
研究動機………………………………………………………………....1
第一章 緒論……………………………………………………………3
第二章 材料與方法…………………………………………………..13
第三章 結果…………………………………………………………..19
第四章 討論…………………………………………………………..23
第五張 圖表…………………………………………………………..26
第六張 參考文獻………………………………………..……….……..50
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