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| 題名: | 水飛薊對高濃度葡萄糖促進發炎反應之作用機制 |
| 作者: | 王思璇 |
| 貢獻者: | 藥學研究所 |
| 關鍵詞: | 糖尿病；過量葡萄糖；發炎；一氧化氮；激素；水飛薊；免疫反應 |
| 日期: | 2010 |
| 上傳時間: | 2010-10-21 10:21:35 (UTC+8) |
| 摘要: | 糖尿病為盛行的代謝性疾病，且伴隨多樣性併發症，如：神經病變、粥狀動脈硬化等，又糖尿病的併發症被認為與高血糖所造成的發炎反應有關。然而不論是人類單核球細胞或小鼠巨噬細胞，高血糖對免疫細胞IL-1β、IL-6、TNF-α表現刺激之研究結果尚無定論；又水飛薊萃取物silymarin (SMR) 過去研究顯示其具有降血糖及抑制Lipopolysaccharide (LPS) 所誘發之NO表現。因此，本研究首先利用體外RAW 264.7巨噬細胞培養模式來探討高葡萄糖對於發炎反應及訊息傳遞途徑之作用機制；繼而分析比較SMR對此不同葡萄糖濃度造成之發炎反應的影響。研究方法與結果：在正常濃度 (5.5 mM；正常組) 及15 mM、25 mM高濃度葡萄糖環境下以LPS (1 μg/mL) 刺激巨噬細胞 24小時，以Griess reagents定量NO，其產量在15 mM及25 mM葡萄糖環境下分別為正常組之1.3倍及4.1倍；以ELISA測定IL-1β、IL-6及TNF-α，但其表現沒有差異；而48小時之NO產量分別為正常組的1.87倍及2.40倍；IL-1β為1.22倍及1.27倍；IL-6則減少為正常組的87.8 %及87.4 %；TNF-α之表現減少為正常組的62.4 %及67.1 %。而以西方墨點法測定iNOS、COX-2蛋白質表現及ERK、PKC活化程度，結果顯示，iNOS蛋白質表現與葡萄糖濃度有正向關係，且連續測定5天其表現於25 mM葡萄糖環境下在第2天有最大量；COX-2蛋白質於兩種高濃度葡萄環境下皆表現增加，且其表現於25 mM葡萄糖環境下與時間呈正向關係。在正常及25 mM葡萄糖環境下，NO產量及iNOS蛋白質表現被p38、PKCα及PKCδ抑制劑所拮抗，而COX-2蛋白質表現則被p38、ERK、PKCα及ROS抑制劑限制，但在25 mM葡萄糖環境下COX-2蛋白質表現不受ERK抑制劑影響。25 mM葡萄糖環境會促進LPS活化ERK、PKCα、PKCδ，而以Quanti-BlueTM間接檢測NF-κB活性結果顯示在15 mM及25 mM葡萄糖環境其活性為正常組的1.77倍及2.28倍。SMR之抗發炎機制則分別在正常及25 mM葡萄糖環境下以LPS (1 μg/mL) 刺激48小時為病態模式來分析。正常環境下，SMR對LPS誘發NO、IL-1β、IL-6、TNF-α、及之IC50分別為6.6 ± 0.3 μg/mL、12.3 ± 0.3 μg/mL、11.7 ± 0.5 μg/mL、18.4 ± 1.9 μg/mL，於25 mM葡萄糖環境分別為8.2 ± 0.4 μg/mL、15.0 ± 0.2 μg/mL、13.6 ± 1.5 μg/mL、19.3 ± 1.9 μg/mL，且SMR在兩葡萄糖環境皆可減少iNOS蛋白質表現而不影響COX-2蛋白質表現及NF-κB活性。路徑研究顯示SMR可抑制ERK活化但促進PKCα活化。結論：高濃度葡萄糖環境會促進LPS誘發NO、iNOS、COX-2及IL-1β表現但減少IL-6及TNF-α表現，該發炎反應可能與MAPK、PKC、ROS及NF-κB途徑有關。而SMR於正常及高濃度葡萄糖環境下對抑制LPS所誘發NO、iNOS、IL-1β、TNF-α及IL-6表現之抗發炎作用，可能是透過ERK途徑。未來需要更多研究來證實高濃度葡萄糖對IL-6、TNF-α及SMR 對NF-κB之影響。
Diabetes is a prevalent metabolic disorder. Its complication includes neuropathy and atherosclerosis and is considered to be associated with hyperglycemia-induced inflammation. However, the results of IL-1β, IL-6, TNF-α production changes induced by excess glucose (G) are still controversial. Besides, silymarin (SMR) was shown to possess hypoglycemic actions and inhibitory effects against LPS-induced NO production. Here, we aimed to investigate the effects of excess G on NO or other cytokines productions and the influences of SMR on excess G induced responses. RAW 264.7 macrophages were incubated under various concentrations of G (normal, 15 mM, or 25 mM). Cells were harvested following LPS (1 μg/mL) 24 hr or 48-hr incubations. NO (determined by Griess reagent) increased to 1.3 and 4.1 fold at 24-hr observations in 15 mM and 25 mM G groups, respectively, compared to the normals. However, IL-1β, IL-6 and TNF-α (assayed by ELISA) did not change. Results at 48-hr including NO increased to 1.87 and 2.40 folds and IL-1β increased to 1.22 and 1.27 folds in 15 mM and 25 mM G groups, respectively, were compared to the normals. However, IL-6 decreased 87.8% and 87.4% in 15 mM and 25 mM G groups and TNF-α decreased to 62.4% and 67.1% in 15 mM and 25 mM excess-G groups, respectively. Expressions of proteins such as iNOS, COX-2, ERK, PKC were all determined by western blot. Results showed that iNOS increased with increasing concentrations of G. Following 5-day excess G incubations, peak of iNOS were observed at 48 hr. COX-2 increased in both excess-G cultures, and increased with increasing culture times under excess-G. NO and iNOS were suppressed by inhibitors of p38, PKCα and PKCδ. In excess-G groups, COX-2 was suppressed by inhibitors of p38, ERK, PKCα and ROS, but not ERK. Activation of ERK, PKCα and PKCδ were enhanced in excess-G groups. Regarding the NF-κB activity, Quanti-BlueTM was used and their activities increased to 1.77 and 2.28 folds at 48-hr in 15 mM and 25 mM G, respectively, vs normals. Influences of SMR was investigated by using a LPS (1 μg/mL) induced inflammatory responses under normal or excess G (25 mM) for 48 hrs. IC50 of SMR on LPS-induced NO, IL-6, IL-1β and TNF-α productions were 6.6±0.3 μg/mL, 12.3±0.3 μg/mL, 11.7±0.5 μg/mL, 18.4±1.9 μg/mL under normal conditions and they were 8.2±0.4 μg/mL, 15.0±0.2 μg/mL, 13.6±1.5 μg/mL, 19.3±1.9 μg/mL under excess G challenge respectively. iNOS was suppressed by SMR, but not COX-2 and NF-κB activity either in normal or excess G groups. SMR inhibited activated ERK but enhanced PKCα activation. In conclusions, Excess G enhanced LPS-induced NO, iNOS, COX-2 and IL-1β productions; however, IL-6 and TNF-α were reduced. Such responses maybe performed via MAPK, PKC, ROS and NF-κB pathways. Here, we first observed suppressions of NO, iNOS, IL-1β, IL-6 and TNF-α under normal and excess glucose condition by SMR may be via the ERK pathway. Further studies are needed to confirm the effects of excess G on IL-6, TNF-α productions and effects of SMR on NF-κB. |
| 關聯: | 110頁 |
| 描述: | (一)論文目次
目錄 I
中文摘要 IV
Abstract V
表目錄 VI
圖目錄 VII
縮寫簡表 (Abbreviation) IX
第一章 緒論 1
第一節 水飛薊 (Silymarin) 2
第一項、 來源與產地 2
第二項、 藥理作用與臨床用途 2
第二節 糖尿病之相關研究 5
第一項、 糖尿病之流行病學 5
第二項、 糖尿病的定義與診斷 6
第三項、 糖尿病之併發症 7
第四項、 糖尿病併發症之病理機轉 8
第三節 免疫與發炎反應相關因子 12
第一項、 巨噬細胞及其功能 12
第二項、 發炎機制相關之調控物質 13
第四節 研究目的 21
第二章 研究材料與方法 22
第一節 藥品試劑與試驗儀器 23
第一項、 實驗細胞 23
第二項、 藥品試劑 23
第三項、 實驗儀器 25
第二節 細胞培養與保存 26
第一項、 Mouse Macrophage RAW 264.7培養 26
第二項、 Mouse Macrophage RAW Blue培養 27
第三項、 細胞計數 28
第三節 試驗分析 29
第一項、 細胞存活率分析 29
第二項、 一氧化氮 (Nitric Oxide) 濃度測定 29
第三項、 NF-κB活性測定 29
第四項、 西方墨點法 (Western Blot) 30
第五項、 IL-1β、IL-6、TNF-α濃度測定 31
第六項、 統計分析 32
第三章 研究結果 33
第一節 高濃度葡萄糖對發炎反應之影響 34
第一項、 巨噬細胞RAW 264.7之細胞存活率 34
第二項、 一氧化氮產量及誘導型一氧化氮合成酶之表現 34
第三項、 環氧化酶-Ⅱ (COX-2) 表現 36
第四項、 細胞激素IL-1β、IL-6及TNF-α產量 37
第五項、 細胞核因子κB配位體 (NF-κB) 活性 38
第六項、 細胞內訊息傳導表現 38
第二節 Silymarin於正常或高濃度葡萄糖環境對發炎反應之影響差異 39
第一項、 巨噬細胞RAW 264.7之細胞存活率 39
第二項、 一氧化氮產量及誘導型一氧化氮合成酶表現 39
第三項、 環氧化酶-Ⅱ (COX-2) 表現 40
第四項、 細胞激素IL-1β、IL-6及TNF-α產量 40
第五項、 細胞核因子κB配位體 (NF-κB)活性 41
第六項、 細胞內訊息傳導表現 42
第四章 討論 43
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