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研究生:蕭晏詔
研究生(外文):Gan-Chao Shiao
論文名稱:楊梅樹皮素的降血糖作用之研究
論文名稱(外文):Antihyperglycemic Action of Myricetin
指導教授:鄭瑞棠鄭瑞棠引用關係
指導教授(外文):Juei-Tang Cheng
學位類別:碩士
校院名稱:國立成功大學
系所名稱:藥理學研究所
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:2002
畢業學年度:90
語文別:中文
論文頁數:111
中文關鍵詞:楊梅樹皮色素
外文關鍵詞:myricetin
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在體內(in vivo)試驗方面,使用streptozotocin誘發成胰島素依賴型糖尿病的老鼠,此乃類似人類糖尿病第一型(insulin-dependent diabetes mellitus,IDDM),以此糖尿病的大白鼠作為實驗組,並以Wistar品系的大白鼠作為正常控制組。經由尾靜脈注射Myricetin到糖尿病老鼠可產生濃度遞增性(dose-dependent)的降血糖作用。而且,對於外給葡萄糖所進行的葡萄糖挑戰試驗(glucose challenge test),Myricetin可增加正常老鼠對葡萄糖的利用率。在離體(in vitro)試驗方面,取STZ糖尿病老鼠的骨骼肌,Myricetin會以劑量相關的方式來促進 [14C] 2-deoxy-glucose進入到骨骼肌內。另外,在STZ糖尿病老鼠的肝臟,Myricetin對於肝糖的合成(glycogen synthesis)有顯著的刺激效果。另一方面,以C2C12小鼠骨骼肌細胞株 (mouse myoblast cell line)進行實驗來了解Myricetin的作用方式。結果Myricetin能以劑量相關 的形式增強C2C12小鼠肌母細胞對葡萄糖的吸回 ; 而這項作用可被α1-adrenoceptor(α1-AR)阻斷劑prazosin及α1A-AR阻斷劑RS17053所解消。同時,Myricetin隨著濃度的增加亦可逐漸取代α1-AR的[3H]prazosin在C2C12肌母細胞的結合。而且以phospholipase C (PLC) 的阻斷劑U73122,及protein kinase C (PKC) 的阻斷劑chelerythrine、GF109203X將 α1-AR活化的訊息傳遞路徑阻斷後,亦可解消Myricetin原先可增強C2C12肌母細胞對葡萄糖的吸回作用。另外,α1-AR的阻斷劑prazosin及α1A-AR阻斷劑RS17053會以劑量相關的形式阻斷Myricetin原先在IDDM大白鼠所產生的降血糖效果。使用enzyme-linked immunosorbent assay (ELISA)技術,檢測血中的腦內啡(β-endorphin)時,在IDDM大白鼠發現Myricetin確實會促進血中β-endorphin的含量;這項作用會被α1-AR的阻斷劑prazosin及α1A-AR阻斷劑RS17053所解消。同時,嗎啡m型受體阻斷劑naloxone及naloxonazine會依劑量相關性阻斷Myricetin原先在IDDM大白鼠的降血糖作用。另外,在嗎啡m型受體剔除(opioid m-receptors knockout)的胰島素依賴型糖尿病小鼠,Myricetin也無法再產生降血糖的作用。在去除腎上腺髓質(adrenal medulla)的IDDM大白鼠,Myricetin無法再產生降血糖的現象。另一方面,利用靜脈注射給藥的方式,給予Myricetin 1mg/kg 一天三次,連續處理三天,取其老鼠的肝臟及骨骼肌,利用Northern及Western immunoblotting來看糖尿病老鼠骨骼肌之葡萄糖第四型轉移蛋白(glucose transporter subtype 4 form; GLUT4)及肝臟之解糖酵素 (phosphoenolpyruvate carboxykinase; PEPCK)之mRNA及protein的變化。結果發現,Myricetin可增強IDDM大白鼠骨骼肌GLUT4的基因表現,而且,IDDM大白鼠肝臟亢進的PEPCK基因也會受到抑制;以上兩種作用皆可被naloxone所解消。
. Myricetin produced a dose-dependent hypoglycemic action in streptozotocin-induced diabetic rats after an intravenous injection (i.v.). Myricetin at the effective dose (1mg/kg) significantly attenuated the increase of plasma glucose induced by intravenous glucose challenge test in Wistar rats. In vitro, myrivetin enhanced the uptake of [14C] 2-deoxy-glucose (2-DG) into skeletal muscle in a concentration-dependent manner. In the hepatocytes isolated from diabetic rats, myricetin also increased the synthesis of glycogen.
Myricetin enhanced the uptake of radioactive glucose into mouse myoblast cell line C2C12 cells in a dose-dependent manner, which was abolished by α1-adrenoceptor(α1-AR) blocker prazosin and α1A-AR blocker RS17053 pretreatment. Effect of myricetin on α1-AR was further supported by the displacement of [3H] prazosin binding in C2C12 cells. The plasma glucose lowering effect of myricetin in the STZ-diabetic rats was also abolished by the pretreatment with prazosin and RS17053. Pharmacological inhibition of phospholipase C (PLC) by U73122 resulted in a concentration-dependent decrease in myricetin-stimulated uptake of radioactive glucose into C2C12 cells, although, the inactive congener, U73343, failed to block myricetin-syimulated glucose uptake. Moreover, chelerythrine diminished the action of myricetin at concentration sufficient to inhibit protein kinase C (PKC). The obtained data suggest that an activation of α1A-AR may play an important role in the plasma glucose lowering action of myricetin in the absence of insulin.
Injection of myricetin at the effective dose increased the plasma b-endorphin in STZ-diabetic rats that can be abolished by α1A-AR antagonists. The plasma glucose lowering effect of myricetin was also abolished by pretreatment with naloxone and naloxonazine at doses sufficient to block opioid m-receptors. Plasma glucose lowering action of myricetin disappeared in opioid m-receptors knockout mice, while the plasma glucose lowering response to myricetin was still observed in wild-type mice. Also, myricetin enhanced the β-endorphin release from the isolated adrenal medulla in a concentration-dependent manner. Bilateral adrenalectomy resulted in the loss of plasma glucose lowering effect of myricetin.
The mRNA and protein levels of glucose transporter subtype 4 form (GLUT4) in skeletal muscle was raised by myricetin after repeated treatment for three days in STZ-diabetic rats. Otherwise, similar repeated treatment with myricetin reversed the elevated mRNA and protein level of phosphoenolpyruvate carboxykinase (PEPCK) in liver of STZ-diabetic rats to the normal level.
中文摘要 5
英文摘要 7
縮寫表 9
第一章 緒論
第一節 前言 10
第二節 研究目的 13
第三節 楊梅樹皮素(Myricetin)的特性 14
第二章 實驗方法及材料
第一節 實驗動物 16
第二節 實驗材料 17
第三節 實驗方法 23
第三章 結果 50
第四章 討論 67
第五章 結論 73
附圖 75
引用文獻 103
自述 111
引用文獻
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