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  • 學位論文

體內薯蕷皂苷元Diosgenin對Doxorubicin誘發心毒性之保護作用

In Vivo Protective Effects of Diosgenin against Doxorubicin-Induced Cardiotoxicity

指導教授 : 徐成金

摘要


艾黴素Doxorubicin是臨床上廣泛運用於乳癌化療藥物的成份之一,其常見的副作用是經由促進體內之氧化壓力的上升而導致心毒性。薯蕷皂苷元Diosgenin為山藥中的類固醇皂素 (steroidal saponin),具有抗氧化的效果,在體內能有效地抑制氧化壓力的上升。本研究希望確認Diosgenin抑制小鼠體內氧化壓力的作用可以對Doxorubicin所導致之心毒性產生保護效果。研究結果發現,小鼠投與Doxorubicin後會導致心臟重量與體重之比值顯著地降低,同時對於血清中心毒性之指標,包括乳酸脫氫酶 (lactate dehydrogenase, LDH)、肌酸磷激酶 (creatine phosphokinase, CPK)、肌酸激酶心肌同功酶 (creatine kinase myocardial bound, CK-MB)均有顯著的提升。在心臟組織的部分,投與Doxorubicin小鼠的抗氧化酶活性顯著降低,包括超氧化物歧化酶 (superoxide dismutase, SOD)與麩胱甘肽過氧化酶 (glutathione peroxidase, GPx)。這些數值的降低在給予小鼠Diosgenin後可以恢復正常,同時也可以降低心毒性之指標、巴比妥酸反應物質 (thiobarbituric acid reactive substances, TBARS)、活性氧化物質 (reactive oxygen species, ROS)、活化第三型凋亡蛋白酶 (caspase-3 activation)、粒線體功能障礙 (mitochondria dysfunction),以及發炎因子之一的核轉錄因子κB (nuclear factor kappa B, NF-κB)。此外,Diosgenin可以藉由調控第五型磷酸二酯 (phosphodiesterase-5, PDE5)的活性提升心臟之環鳥糞核苷單磷酸 (cyclic guanosine monophosphate, cGMP),並且對投與Doxorubicin小鼠之心肌纖維化具有改善的作用。分子檢定資料顯示,Diosgenin可能是藉由調節蛋白激脢A (protein kinase A, PKA)與p38裂質素活化蛋白激酶 (p38 mitogen-activated protein kinase, p38 MAPK)產生保護的作用。本研究之數據顯示,Diosgenin對於小鼠心臟因Doxorubicin所引起之心毒性具有保護作用,此與其具有抗氧化作用、抗凋亡活性與調控cGMP有關。

並列摘要


Doxorubicin (DOX) is wildly used as one of the chemotherapy ingredients for breast cancer. Its common adverse effect is inducing oxidative stress leading to cardiotoxicity. Diosgenin, a steroidal saponin of Dioscorea opposita, has been reported to have antioxidant activity and effectively inhibit oxidative stress in vivo. Our study was aimed to find out the protective effect of diosgenin against DOX-induced cardiotoxicity in mice. DOX treatment led to a significant decrease in the ratio of heart weight to body weight, and increases the serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB), markers of cardiotoxicity. In the heart tissue of the DOX-treated mice, DOX reduced activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), were recovered by diosgenin. Diosgenin also decreased the serum levels of cardiotoxicity markers, cardiac levels of thiobarbituric acid relative substances (TBARS) and reactive oxygen species (ROS), caspase-3 activation, and mitochondrial dysfunction, as well as the expression of nuclear factor kappa B (NF-κB), an inflammatory factor. Moreover, diosgenin had the effects of increasing the cardiac levels of cGMP via modulation of phosphodiesterase-5 (PDE5) activity, and in improving myocardial fibrosis in the DOX-treated mice. Molecular data showed that the protective effects of diosgenin might be mediated via regulation of protein kinase A (PKA) and p38. Our data imply that diosgenin possesses antioxidant and anti-apoptotic activities, and cGMP modulation effect, which in turn protects the heart from the DOX-induced cardiotoxicity.

並列關鍵字

Doxorubicin Cadiotoxicity Diosgenin Antioxidant cGMP

參考文獻


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