- 學位論文
Quercetin對cisplatin誘發體能下降及脂肪流失之影響
The effect of quercetin on cisplatin-induced physical activity decline and body fat loss.
摘要
Quercetin (Q) 是一種在植物中含量豐富的類黃酮，能增強廣泛用於癌症治療的化療藥物cisplatin (CDDP) 抗腫瘤的效果，同時能抑制一些CDDP誘發的副作用。我們先前研究發現，Q可以降低CDDP對BALB/c小鼠所誘發之脂肪流失，然而，Q對CDDP引起脂肪流失的機制及是否能改善CDDP誘發的疲憊尚不清楚。為了探討這個議題，本研究以BALB/c小鼠進行研究，將小鼠隨機分成三組，CDDP組、CDDP+Q組及控制組，分別單獨經腹腔注射7 mg/kg B.W. CDDP (一週一次) ，或CDDP注射合併含1 % Q的飼料，而控制組只給予溶劑及一般飼料處理，分別在CDDP介入一週及兩週後犧牲部份小鼠，秤量體重、副睪脂肪、肌肉、肝臟和睪丸重量，並分析副睪脂肪細胞面積和脂肪、肌肉及肝臟組織之脂質合成與分解相關酵素表現，另外，我們還評估小鼠活動力及前肢抓力作為疲憊程度指標。結果顯示，與控制組相比，CDDP組體重、副睪脂肪、肝臟和睪丸重量顯著降低，且呈現時間依賴關係，此外小鼠活動力及前肢抓力表現亦降低，合併給予Q則會降低CDDP所造成的負面影響，然而，與CDDP單獨處理相比，合併給予quercetin顯著增加體重、前肢抓力表現。除此之外，CDDP也會降低脂肪組織之細胞面積以及肝臟和肌肉中總脂肪、三酸甘油脂含量，當合併給予Q可以顯著抑制CDDP所誘導的臟器脂肪含量改變。進一步關於脂質代謝方面，與控制組相比，CDDP組會降低副睪脂肪組織之脂肪酸合成酶 (FAS) mRNA及蛋白質表現量，並且增加脂質分解相關酵素 (FABP4、AMPKγ2、HSL及HADHA) 表現量，CDDP+Q組則可以回復CDDP所造成的改變，但無論是單獨給予CDDP或合併給予Q對肝臟及肌肉的脂質生成或分解相關酵素影響不大。與控制組相比，CDDP組血漿TNF-α、TBARs及MCP-1表現量顯著增加，特別於CDDP介入第二週， CDDP+Q組則能顯著降低。於肱三頭肌中，CDDP組與控制組相比其肝醣含量無顯著差異，但於CDDP介入第一週，CDDP+Q組肝醣含量顯著高於控制組及CDDP組。綜合上述，本研究結果顯示Q可以透過調控脂質生合成代謝酵素及相關激素，抑制CDDP所誘發之脂肪流失及疲憊現象。
並列摘要
Quercetin (Q), a flavonoid abundantly present in plants, has been shown to increase the antitumor effects of cisplatin (CDDP), a widely used chemotherapy drug, and attenuates some of its side effects. Our previous studies also found that quercetin tended to attenuate cisplatin-induced fat loss in BALB/c mice. However, the mechanisms underlying the suppressed effect of quercetin on fat loss and whether quercetin improves the fatigue induced by cisplatin are unclear. To investigate the issues, the BALB/c mice were randomly treated with CDDP (7 mg/kg B.W., once a week, intraperitoneal injection) alone or in combination with quercetin (a diet containing 1% Q) for 1 or 2 weeks. The control mice were treated with vehicle only. We then determined the body, fat, muscle, liver and testes weight as well as the adipocyte size, fat synthesis and lipolytic associated enzyme expressions in fat, muscle or liver tissues. We also evaluated locomotor activities and grip strength of mice as parameters of fatigue. The results showed that compared to the control group, CDDP significantly decreased body, fat, liver and testes weight, in a dose-dependent manner. CDDP also decreased locomotor activities and maximum grip strength. Q tended to attenuate these effects of CDDP, however, only the differences of body weight and maximum grip strength were significant compared to the CDDP alone group. CDDP also decreased the area of fat in the adipose tissue, total tissue lipid levels and triglyceride in liver and muscle tissues. Q significantly suppressed CDDP-induced total tissue lipid levels changes in liver and muscles. Furthermore regarding fat metabolism, CDDP rather than CDDP+Q decreased the mRNA and protein levels of a fat synthetic enzyme (FAS) and increased the mRNA and protein levels of lypolytic associated enzymes (FABP4, AMPKγ2, HSL and HADHA) in fat tissue but not liver or muscle tissues. In addition, the levels of TNF-α, TBARs and MCP-1 in the plasma increased significantly in the CDDP rather than the CDDP+Q group, especially at week 2. CDDP did not affect the glycogen level in the triceps brachii, but Q significantly increased the level at week 1 compared to the control and CDDP alone groups. Taken together the results of this study demonstrate that CDDP induced fat loss and fatigue. Q attenuated these side effects of cisplatin. The mechanisms were associated with the regulation enzyme levels in fat metabolism and cytokine levels.