臺灣博碩士論文加值系統

發炎是由於外來物質入侵體內或是體內氧化壓力升高所造成，為生物體對抗外來物質的一種保護方式，但長期的發炎會使得體內氧化壓力的升高，並造成許多疾病的發生，例如癌症與心血管疾病皆與發炎相關。發炎反應發生時，會誘發免疫細胞如巨噬細胞內部NF-κB轉錄因子的活化，並促使下游發炎相關蛋白質如iNOS與COX-2的表現，以及各種促發炎激素如NO、TNF-α、PGE2、IL-1β及IL-6等之生成。根據研究，許多植化素 (phytochemical)如類黃酮等物質，已被證實具有抗發炎的功效，且許多皆是透過抑制NF-κB相關路徑以達到抗發炎的效果。
多甲氧基類黃酮 (polymethoxyflavones, PMFs)為黃酮類化合物中的一群，具有超過兩個以上之甲氧取代基，因極性較低而具有較好的生物可利用率，且已有數種PMFs經實驗證實具有抗發炎效果。5,7,3'',4''-tetramethoxyflavone (TMF)是月橘 (Murraya paniculata) 與黑薑 (Kaempferia parviflora)中主要的PMFs之一，這些植物的萃取物已被證實具有抗發炎、抗腫瘤以及抗氧化等活性，然而TMF以及其代謝物之生理活性仍有待進一步的研究。本研究以LPS誘導RAW264.7巨噬細胞作為發炎反應之細胞模式，並以LPS誘導C57BL/6小鼠產生敗血症作為促發炎動物模式，探討TMF以及其生理代謝物3''-hydroxy-5,7,4''-trimethoxyflavone (M1), 4''-hydroxy-5,7,3''-trimethoxyflavone (M4), 5-hydroxy-7,3'',4''-trimethoxyflavone (M5)之抗發炎功效與其可能機制，同時比較不同生理代謝物之間的抗發炎活性。
研究結果顯示TMF及其生理代謝物對於LPS誘導巨噬細胞產生的促發炎激素NO, TNF-α, IL-6, IL-1β皆具有顯著的抑制效果；TMF、M1、M4以及 M5對於抑制NO生成的IC50分別為26.63、47.39、33.17以及30.24 μM。西方墨點法的結果顯示，TMF及所有生理代謝物皆可顯著抑制iNOS的蛋白質表現，並以TMF及M4的抑制效果較佳；而TMF與M5則具有顯著抑制COX-2蛋白質表現的能力。在上游機制方面，則以生理代謝物M1、M4及M5具有抑制iNOS及COX-2 mRNA之能力。綜合比較後發現TMF對於大部分促發炎指標皆具有顯著的抑制效果，因此以TMF作為探討體內抗發炎功效的樣品。動物實驗的結果顯示，腹腔注射20 mg/kg bw TMF可有效降低血清中以LPS誘導促發炎激素TNF-α以及IL-6的生成，同時可有效降低肺臟中的TNF-α與腎臟中的IL-6生成；而腹腔注射50 mg/kg bw之TMF則可分別顯著降低肝臟、脾臟與腎臟中的TNF-α、脾臟與肺臟中的IL-1β以及肺臟中的IL-6含量；若以腹腔注射100 mg/kg bw之TMF則可顯著降低腎臟中的IL-1β含量以及肝臟與脾臟中的IL-6含量，顯示TMF可抑制C57BL/6小鼠因LPS所誘導之發炎現象。

Inflammation is caused by pathogen or elevation of oxidative stress in our body; therefore it is a protective mechanism against external invasions. Inflammation also plays an important role in many degenerative diseases such as cancer and cardiovascular diseases. During inflammation, activation of NF-κB pathway would induce expression of downstream protein such as iNOS and COX-2. Also it would cause the secretion of pro-inflammatory chemokines and cytokines like NO、TNF-α、PGE2、IL-1β and IL-6. Several plant flavonoids have been shown to exhibit anti-inflammatory activities through inhibition of NF-κB pathway.
Polymethoxyflavones (PMFs) are flavonoids that bear two or more methoxy groups on their basic skeleton and therefore have greater bioavailability due to their lower polarity. 5,7,3'',4''-Tetramethoxyflavone (TMF) is one of the major PMFs occurred in Murraya paniculata and Kaempferia parviflora and has been reported to have various bioactivities such as anti-inflammatory, anti-carcinogenic, anti-viral, and antioxidative properties. However, the metabolism of TMF has been scarcely performed. Previous studies in our lab have identified several metabolites of TMF in vivo and developed related methods to synthesize these metabolites, but their bioactivities are still unknown. In this study, TMF and its 3 major metabolites, including 3''-hydroxy-5,7,4''-trime
-thoxyflavone, 4''-hydroxy-5,7,3''-trimethoxyflavone, and 5-hydroxy-7,3'',4''-trime-
thoxyflavone were investigated for their anti-inflammatory effects in lipopolysaccharide (LPS)-induced inflammation in murine macrophage RAW264.7 cells and lipopolysaccharide-induced sepsis in C57BL/6 mice.
Results of western blot analysis revealed that the inhibition of iNOS and COX-2 expressions by TMF and its metabolites in LPS-induced macrophage were different. Our results also showed that induction of NO by LPS in RAW 264.7 cell was suppressed by TMF and its metabolites, with TMF having the lowest IC50. The levels of TNF-α、IL-1β and IL-6 were also decreased differently among the 3 metabolites and TMF. In vivo study revealed that TMF showed anti-inflammatory effects in septic shock mice and exhibited inhibitory effects on serum TNF-α and IL-6 level induced by LPS. The levels of organ pro-inflammatory cytokines, such as TNF-α、IL-1β and IL-6 were also suppressed by TMF. In conclusion, our results suggested that the anti-inflammatory properties of TMF and its metabolites exert through the suppression of NF-κB pathway, and the activities are structure-dependent. We also conclude that TMF has in vivo anti-inflammatory activity in septic shock mice. The detailed mechanism of anti-inflammatory properties of TMF and its metabolites remains to be explored.

中文摘要 i
英文摘要 iii
目錄 v
圖次 viii
表次 x
附錄次 xi
縮寫對照表 xii
壹、 前言 1
貳、 文獻整理 2
第一節、 黃酮類與多甲氧基類黃酮類 2
一、 黃酮類簡介 2
二、 多甲氧基類黃酮簡介 4
三、 5,7,3’,4’-tetramethoxyflavone簡介 4
四、 5,7,3’,4’-tetramethoxyflavone的代謝與吸收 7
五、 5,7,3’,4’-tetramethoxyflavone的代謝產物與途徑 8
第二節、 發炎反應 13
一、 發炎 13
二、 巨噬細胞 (Macrophage) 15
三、 脂多醣體Lipopolysaccharide (LPS) 16
四、 Nuclear factor-κ B (NF-κB) 17
五、 一氧化氮 (NO) 19
六、 環氧化酵素Cyclooxygenase (COX) 21
七、 腫瘤壞死因子α(Tumor necrosis factor α, TNF-α) 22
八、 細胞介白素6 (Interleukin-6, IL-6) 23
九、 細胞介白素1β (Interleukin-1β, IL-1β) 24
第三節、 敗血症與發炎 25
一、 敗血症的定義： 25
二、 敗血症之相關併發症： 26
參、 研究目的與實驗架構 28
第一節、 研究目的 28
第二節、 實驗架構 29
肆、 材料與方法 30
第一節、 實驗材料與儀器設備 30
一、 實驗材料 30
二、 實驗細胞株 30
三、 實驗動物 30
四、 實驗藥品與溶劑 31
五、 細胞培養液 32
六、 西方墨點法材料 33
七、 儀器設備 34
八、 實驗溶液配方 36
第二節、 實驗方法 40
一、 合成樣品之結構鑑定 40
二、 以RAW 264.7細胞株評估樣品之抗發炎功效 40
三、 以螢光素酶報告基因檢測法(Luciferase Assay)評估樣品抗發炎功效 48
四、 以動物敗血症模式探討樣品抗發炎功效 49
五、 統計分析 52
伍、 結果 53
第一節、 以RAW 264.7細胞株評估樣品之抗發炎功效 53
一、 樣品對RAW 264.7巨噬細胞存活能力影響 53
二、 樣品影響LPS誘導RAW 264.7巨噬細胞一氧化氮生成能力 55
三、 樣品影響LPS誘導RAW 264.7巨噬細胞生成促發炎細胞激素之能力 59
四、 樣品影響發炎相關蛋白質之表現能力 70
五、 螢光素酶報告基因檢測法 (Luciferase Assay)評估發炎相關蛋白質之mRNA表現量 75
第二節、 以動物敗血症模式探討樣品抗發炎功效 81
六、 TMF對敗血症模式小鼠血清中促發炎激素濃度的影響 81
七、 TMF對敗血症模式小鼠臟器中促發炎激素濃度的影響 84
陸、 討論 93
第一節、 以RAW 264.7細胞評估樣品抑制一氧化氮功效 93
第二節、 樣品抑制促發炎激素生成之功效 96
第三節、 樣品於細胞模式中抗發炎機制的探討 99
第四節、 以敗血症動物評估TMF之體內抗發炎效果 101
柒、 結論 104
捌、 參考文獻 105
玖、 附錄 117

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