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| 題名: | Osthole衍生物降血糖活性之分子機轉探討 |
| 作者: | 黎宜寧 |
| 貢獻者: | 醫學科學研究所 |
| 日期: | 2010 |
| 上傳時間: | 2010-08-31 10:58:31 (UTC+8) |
| 摘要: | 腺苷單磷酸活化蛋白激酶 (AMP-activated protein kinase, AMPK) 是一個絲胺酸/酥胺酸激酶，主要功能是會隨著能量的變化而調控細胞及器官的能量代謝，AMPK 的活化已經知道可減少循環中的葡萄糖、降低血漿中脂質和異常的脂肪堆積，進而增加胰島素的敏感性，因此，AMPK 的活化劑可用於預防或治療第二型糖尿病。先前研究指出，p38 是 mitogen-activated protein kinase (MAPK) 家族成員之一，其功能在骨骼肌中的葡萄糖攝取扮演重要的角色。過氧化物酶體增殖物激活受體 (peroxisome proliferator-activatived receptors, PPARs) 在許多生理作用中都扮演很重要的角色，例如：調控脂質、葡萄醣代謝及提高胰島素的敏感性等。在本實驗室先前的研究中發現，在糖尿病小鼠 (db/db mice) 與肥胖小鼠 (ob/ob mice) 中，osthole 可透過活化 PPAR???}???n與 AMPK 的路徑而達到降低血糖的效果。因此，本研究利用 osthole 衍生物探討其在動物體內及體外降血糖的功效。在 STZ (streptozotocin) 所誘導的糖尿病鼠中，osthole 衍生物 Wj1382-2 和 Wj25504-2 具有降低血糖效果。此外，利用 L6 老鼠骨骼肌細胞作為探討分子機轉的模式，在給予 osthole 衍生物 Wj1382-2 和 Wj25504-2 後，利用西方墨點法分析蛋白質的表現及變化，發現Wj1382-2 和 Wj25504-2 具有活化 AMPK 的能力，並抑制下游 Acetyl-CoA carboxylase (ACC) 的活性；另外，也可活化 p38 MAPK。接著利用葡萄糖攝取試驗觀察 Wj1382-2 和 Wj25504-2 是否會增加 L6 細胞對於葡萄糖攝取的能力，發現隨著 Wj1382-2 和 Wj25504-2 濃度的增加，細胞攝取葡萄糖的能力也隨之增加。由上述結果可知， Wj1382-2 和 Wj25504-2 可透過活化 AMPK 或 p38 MAPK 訊息路徑達到降血糖的效果，可能具有開發成為第二型糖尿病藥物的潛力。
AMP-activated protein kinase (AMPK), a serine/threonine kinase, is implicated in the control of energy metabolism at both the cellular and organ levels. Activation of AMPK has been found to decrease circulating glucose, reduced plasma lipid, and ectopic fat accumulation, as well as enhanced insulin sensitivity, therefore AMPK activators may use for prevention or treatment of type 2 diabetes. Recent reports indicated that p38, a member of the mitogen-activated protein kinase (MAPK) family, plays a pivotal role in glucose uptake in skeletal muscles. Peroxisome proliferator-activatived receptors (PPARs) play a important role in control lipid metabolism, glucose metabolism and insulin sensitivity. Our previous studies found that osthole markedly reduced blood glucose level in db/db and ob/ob mice. The hypoglycemic activity might be associated with the activation of PPAR and AMPK. In this study, osthole derivatives were used to examine the hypoglycemic activity in vivo and in vitro. Osthole derivatives Wj1382-2 and Wj25504-2 significantly reduced blood glucose level in STZ-induced DM mice. In vitro study, mouse skeletal muscle cells L6 was used to examine the underlying molecular mechanisms of osthole derivatives Wj1382-2 and Wj25504-2 on hypoglycemic activity. Western blot analysis revealed that Wj1382-2 and Wj25504-2 induced the phosphorylation of AMPK, ACC and p38 MAPK. Next, we examined whether Wj1382-2 and Wj25504-2 could increase glucose uptake by a fluorescent glucose analog in L6 cells. We found that Wj1382-2 and Wj25504-2 significantly increased glucose uptake in a dose-dependent manner. Together, these results suggest that Wj1382-2 and Wj25504-2 may have hypoglycemic activity through AMPK or p38 MAPK signaling pathway, has potential as an antidiabetes agent for the treatment of type 2 diabetes. |
| 關聯: | 61頁 |
| 描述: | 目錄(Contents)
縮寫表 VI
中文摘要 VIII
Abstract IX
第一章 緒論 (Introduction) 1
壹、糖尿病 (Diabetes mellitus) 1
一、糖尿病的定義 1
二、糖尿病的種類 1
三、糖尿病的發病機制 2
四、糖尿病的併發症 4
五、糖尿病診斷標準 4
六、糖尿病的治療 4
貳、胰島素訊息傳遞路徑 (Insulin signaling pathway) 6
一、PI 3-kinase (PI3K) 的活化 7
二、胰島素誘導之磷酸化連鎖反應 (Insulin-stimulated phosphorylation cascades)…………. 8
三、Cbl/CAP 路徑與脂質筏 (Cbl/CAP pathway and lipid rafts) 9
参、腺苷單磷酸活化蛋白激酶 (AMP-activated protein kinase, AMPK) 10
一、AMPK 的結構與調控 10
二、AMPK 與葡萄糖恆定 12
三、AMPK 與糖尿病 13
肆、p38有絲分裂活化蛋白激酶 (p38 mitogen-activated protein kinases, p38 MAPK) 13
伍、過氧化物酶體增殖物激活受體 (Peroxisome proliferator-activatived receptors, PPARs) 14
一、 PPARs 的結構與調控 15
二、 PPAR?? 的介紹 16
三、 PPAR?? 的介紹 16
四、 PPAR ???}???n的介紹 17
陸、研究動機 (Study aim) 18
第二章 材料與方法 19
壹、細胞培養 (Cell culture) 19
一、人類肺癌細胞 (Human lung carcinoma cells) 19
二、老鼠肌纖維母細胞 (Mouse myoblast cells) 19
参、暫時性基因轉殖 (Transient transfection) 20
肆、西方墨點法 (Western blotting) 20
一、細胞蛋白質萃取 (Protein extraction) 20
二、蛋白質定量分析 (Protein quantification) 21
三、西方墨點法 (Western blotting) 21
伍、細胞存活率之分析 (MTT assay) 22
陸、葡萄糖攝取試驗 (Glucose uptake assay) 23
柒、動物實驗 23
一、篩選 Osthole 衍生物在 ICR 小鼠體內降血糖試驗 23
捌、統計方法 ( statistics ) 25
第三章 結果 (Results) 26
一、篩選 osthole 衍生物具有活化 AMPK 的能力 26
二、篩選 osthole 衍生物在動物體內具有降血糖功效 26
三、Osthole 衍生物具有活化 PPAR?? 及 PPAR?? 的能力 27
四、比較 osthole、osthole 衍生物 Wj1382-2 及 Wj25504-2 活化 AMPK、p38 MAPK 及葡萄糖攝取的能力 27
五、Osthole 衍生物 Wj1382-2 及 Wj25504-2 在動物體內具有降血糖功效 28
六、Osthole 衍生物 Wj1382-2 及 Wj25504-2 對於細胞的毒性測試 29
七、Osthole 衍生物 Wj1382-2 及 Wj25504-2 具有促進細胞葡萄糖攝取的能力 29
八、Osthole 衍生物 Wj1382-2 及 Wj25504-2 具有活化 AMPK 的能力 29
九、Compound C 可以抑制由 Wj1382-2 及 Wj25504-2 誘發的 AMPK 磷酸化及葡萄糖攝取的能力 30
十、Osthole 衍生物 Wj1382-2 及 Wj25504-2 具有增加 p38 MAPK 磷酸化的能力 30
十一、SB203580 可以抑制由 Wj1382-2 及 Wj25504-2 誘發的 p38 MAPK 磷酸化及葡萄糖攝取的能力 31
第四章 討論 (Discussion) 32
第五章 參考文獻 (References) 38
第六章 目次圖表 (Figures lists) 46
Figure 1. Chemical structure of osthole and osthole derivatives. 46
Figure 2. Screening osthole derivatives on phosphorylation of AMPK in skeletal muscle cells. 47
Figure 3. Screening osthole derivatives has anti-diabetic effect in vivo experiment. 48
Figure 4. The effects of osthole derivatives on activation of PPAR?? and PPAR?? in A549 cells. 49
Figure 5. The comparison between osthole and osthole derivatives for of AMPK, p38 MAPK phosphorylation and glucose uptake on skeletal muscle cells. 50
Figure 6. The effects of osthole derivatives on blood glucose level in STZ-induced diabetes mellitus mice. 51
Figure 7. The effects of osthole derivatives on cell viability in skeletal muscle cells. 52
Figure 8. The effects of osthole derivatives on glucose uptake in skeletal muscle cells. 53
Figure 9. The effects of osthole derivatives Wj1382-2 on phosphorylation of AMPK and ACC in skeletal muscle cells in a dose- and time-dependent manner. 54
Figure 10. The effects of osthole derivatives Wj25504-2 on phosphorylation of AMPK and ACC in skeletal muscle cells in a dose- and time-dependent manner. 55
Figure 11. The effect of AMPK inhibitor Compound C on phosphorylation of AMPK and glucose uptake after osthole derivatives treatment in skeletal muscle cells. 56
Figure 12. The effect of osthole derivatives Wj1382-2 on phosphorylation of p38 MAPK in skeletal muscle cells. 57
Figure 13. The effect of osthole derivatives Wj25504-2 on p38 MAPK phosphorylation in skeletal muscle cells. 58
Figure 14. The effect of p38 MAPK inhibitor SB203580 on phosphorylation of p38 MAPK and glucose uptake after osthole derivatives treatment in skeletal muscle cells. 59
第七章 附錄 (Appendixes) 60
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