大蒜精油及其組成份對糖尿病引起心臟病之療效評估及分子機轉訊息途徑探討

CMUR > College of Life Sciences > Department of Biological Science and Technology > Research reports > Item 310903500/25435

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Title:	大蒜精油及其組成份對糖尿病引起心臟病之療效評估及分子機轉訊息途徑探討 Investigating the Effects and Mechanisms of Garlic Oil and Its Constituents on Diabetic Cardiac Cardiomyopathy
Authors:	郭薇雯;黃志揚
Contributors:	中國醫藥大學生物科技學系
Date:	2009-07
Issue Date:	2010-09-01 18:05:07 (UTC+8)
Abstract:	先前的文獻顯示，高血糖透過增加活性氧化物的生成造成糖尿病引發的心臟病，而此活性氧化物即為引起心肌損害的主因。這些有害的因子會活化許多訊息路徑，導致心臟肥大及凋亡，以及心臟細胞內的離子通道蛋白活性的改變而影響心臟收縮的功能。先前的研究也顯示大蒜及其組成份具有抗氧化功能，且大蒜具有抗糖尿病及保護心血管的作用。然而目前的研究文獻，有關大蒜改善糖尿病引發的心臟病的療效及機轉仍然很有限。在本計劃中，第一年以Streptozotocin誘導糖尿病大鼠及Goto- kakizak大鼠兩種動物模式，餵食大蒜精油(0, 10, 50, 100 mg/Kg 體重)，藉TBARS實驗及ROS測量和氧化生物指標，來觀察氧化壓力變化，並以Na＋/K＋ ATPase活性及心臟超音波來偵測心臟功能的改變，並測定凋亡相關之訊息活性來評估大蒜精油的療效。路徑包括：death-dependent和 mitochondria-dependent路徑，及心臟抗凋亡之存活途徑：PI3K-Akt/PKB 和 Ras-Raf-MEK-ERK。第二年以相同之模式，餵食大蒜的組成份diallyl sulfide(DAS), diallyl disulfide(DADS), diallyl trisulfide(DATS)，以類似之測定來評估大蒜精油之療效是來自於何種大蒜組成份。第三年，利用Streptozotocin誘導的糖尿病大鼠的心肌細胞初代培養及經高濃度葡萄糖(33mmole/L)處理的H9C2細胞，來確認第二年活體實驗的結果。接下來，在大蒜有效成份的理想劑量確認後，處理不同葡萄糖濃度(0, 11, 22, 33 mmole/L)之H9C2細胞，分別加入或不加入有效單一成份，再者，高濃度葡萄糖(33mmole/L)處理之H9C2細胞在加入或不加入有效單一成份，在0, 0.5, 1.0, 3.0, 6.0小時收細胞，此二實驗進行後，將測定H9C2細胞中，MAPK MEK,JNK,和P38及NFκB的表現量，來評估何種訊息路徑參與在大蒜對糖尿病引發的心臟病療效的過程中。這些結果將提供大蒜或其組成物，在分子層次上調控慢性糖尿病引發的心臟病之機轉。 The pathogenesis of diabetic cardiomyopathy has been reported to be initiated by hyperglycemia, which induces the production of reactive oxygen species (ROS), the major cause of myocardial injury. These harmful effects activate a number of secondary messenger pathways, leading to cardiac hypertrophy and apoptosis. Alteration in intracellular ion channel protein activity also causes cardiac contractile failure. Garlic (Allium sativum), and its constituents have shown an antioxidant property. Antidiabetic and cardiovascular-protective effects of garlic have been reported in a number of studies. However, the information of the effect and mechanism of garlic on improving diabetic cardiomyopathy is very limited. In the project, the 1st year, streptozotocin (STZ)-induced diabetic rats and Goto-Kakizaki (GK) rats will be administered with garlic oil at dose 0, 10, 50, 100 mg/Kg body weight. The effect of garlic oil will be evaluated by the alterations of oxidative stress by thiobarbiturin acid-reactive substances (TBARS), ROS measurement and several oxidative biomarkers, and changes of cardiac functions by measurements of Na+/K+-ATPase activity and echocardiography. The measurements of cardiac hypotrophy, apoptosis, as well as apoptosis-related signaling pathways will be also examined. The pathways include death receptor-dependent and mitochondrial-dependent signalings, and cardiac antiapoptotic pathways for survival: PI3K-Akt/PKB and Ras-Raf-MEK-ERK. The 2nd year, the STZ-induced diabetic and GK-rats will be administered with garlic and its constituents, diallyl sulfide (DAS), diallyl disulfide (DADS) and diallyl trisulfide (DATS). We will use the same endpoints to evaluate which compound (s) of garlic contributes to the effects. The 3rd year, we will use STZ-induced diabetic rat cardiomyocyte (primary cell culture) and high concentration (33 m mole/L) glucose-treated H9C2 cells, mimicking the diabetic cardiomyocytes, to confirm the in vivo results of the 2nd year. Then, after the optima dose of effective compound is selected, H9C2 cells treated by different levels of glucose (0, 11, 22 and 33 m mole/L) will be added with or without the effective pure compound. Then, high concentration glucose (33 m mole/L)-treated H9C2 cells will be added with or without effective pure compound for 0, 0.5, 1.0, 3.0 and 6.0 hours. MAPK (MEK, JNK and p38) and NFkB will be examined in both experiments to evaluate the possible signaling pathways involved in the effect of garlic on diabetic cardiomyopathy. These results will provide a molecular approach of managing chronic diabetic cardiomyopathy with garlic oil or its constituents.
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