葉姝蘭Shu-Lan Yeh戴宥安Yu-An Tai營養學系2026-03-242026-08-3120212021-07-16https://handle.ncl.edu.tw/11296/x652mqhttps://scholars.csmu.edu.tw/handle/123456789/7143癌因性疲憊是化療藥物如cisplatin (CDDP) 可能誘發的副作用之一，此一問題降低了患者對治療的耐受度及生活品質。研究顯示造成疲憊的機制可能與monocyte chemoattractant protein 1 (MCP-1，一個趨化劑) 表現增加及下視丘-腦垂體-腎上腺軸 (HPA軸) 功能異常有關。我們先前的研究顯示quercetin可以降低CDDP在正常細胞誘發的氧化傷害、全身性促發炎激素增加、並抑制肌肉及脂肪組織流失的現象，但quercetin能否藉由降低MCP-1/ human CC chemokine receptor R2 (CCR2； MCP-1接受器) 訊號路徑表現，或調節HPA軸相關分子 (corticotropin releasing hormone (CRH) 、pro-opiomelanocortin (POMC) 及cortisol / corticosterone) ，而對抗CDDP誘發的疲憊仍不清楚，另外我們亦想探討quercetin合併leucine對改善癌因性疲憊相關誘發分子的表現是否有相加或加乘的效果，因此本論文分兩部份，分別探討上述問題。第一部分　　本研究將雄性BALB/c小鼠分為Control、CDDP、CDDP+TAK779、CDDP+OQ (飼料含有1% quercetin) 、CDDP+IQ (10 mg/kg B.W. quercetin經注射給予，3次/週) 等五組，探討經口及注射的quercetin緩和CDDP (腹腔注射；5 mg/kg B.W.，1次/週) 誘發之癌因性疲憊的機制是否與調節MCP-1及HPA軸有關，我們並以TAK779 (CCR2之拮抗劑) 作為正控制組進行比較。結果顯示，在給予CDDP後，小鼠抓力及活動力表現降低，反之 OQ、IQ及TAK779均能改善抓力及活動力表現，其中對活動力表現的改善，IQ的效果最好。Quercetin (特別是IQ) 亦降低CDDP誘發的血液MCP-1、cortisol、corticosterone，但TAK779則僅降低cortisol及corticosterone濃度，與CDDP單獨處理組相比，OQ、IQ同時也降低下視丘中的CRH、腦幹及小腦中的MCP-1及CCR2 mRNA表現，以及腦部TNF-α濃度，而TAK779則僅降低腦下垂體中POMC的表現。總結來說，我們的研究顯示quercetin改善CDDP誘發的疲憊，其機制與調節MCP-1、CCR2表現及HPA軸功能有關。第二部分　　CDDP可能因增加氧化壓力或促發炎激素的分泌使體內蛋白質代謝產生改變，亦即增加蛋白質分解與支鏈胺基酸 (branched-chain amino acid, BCAA) 的氧化，惡化肌肉流失及其他問題(如HPA軸及MCP-1路徑的問題)使體能下降，可能亦是造成疲憊的原因之一，因此第二部分我們進一步探討合併quercetin與BCAA中leucine的攝取，是否具相加或加乘效應減緩CDDP誘發的疲憊。我們將雄性BALB/c小鼠分為Control、CDDP、CDDP+Q (飼料中添加0.5% quercetin) 、CDDP+L (飼料中添加1.6% leucine) 、CDDP+QL (Q+L) 等五組處理8周。結果顯示，與第一部分一致的，在給予CDDP後，小鼠抓力表現降低，單獨或合併使用Q或L可以改善抓力表現，且效果相當。L及QL可以降低CDDP誘發的MCP-1，且QL的效果較好，相似的，在小鼠腦幹組織及小腦，Q、L及QL亦能降低MCP-1 mRNA表現，且效果QL>Q、L，並且只有QL顯著降低腦幹中CCR2 mRNA的表現。CDDP亦會增加血液中cortisol濃度，合併Q、L及QL均有降低cortisol的趨勢。不過不論是CDDP單獨活合併各種補充劑對下視丘中CRH及腦下垂體中POMC mRNA的表現量都沒有影響。各種補充劑均能抑制血液及腦部促發炎激素 TNF-α、IL-1β、IL-6的增加，整體而言QL效果最佳。綜合上述，我們發現合併Q及L，能透過相加性調節MCP-1/CCR2路徑、 cortisol 濃度以及抗發炎激素的產生的作用而減緩CDDP所誘發之疲憊。Cancer-related fatigue (CRF) is a common symptom found in cancer patients treated with cisplatin (CDDP) . This side effect decreases the tolerance to chemotherapy and quality of life. Research shows that the mechanisms contributing to CRF are associated with the increase of monocyte chemoattractant protein 1 (MCP-1) signaling and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Our previous study demonstrated that quercetin attenuated CDDP-induced oxidative damage in normal cells, the increase of systemic pro-inflammation cytokines, as well as the loss of muscle and body fat. However, whether quercetin attenuates CDDP-induced CRF through down-regulation of MCP-1/ human CC chemokine receptor R2 (CCR2; a MCP-1 receptor) signaling or HPA axis associated compounds (corticotropin releasing hormone (CRH) , pro-opiomelanocortin (POMC) and cortisol/corticosterone) is unclear. In addition, whether quercetin and leucine additively or synergistically suppress CDDP-induced CRF is another topic of interest. Therefore, we performed two animal studies to investigate these issues.Part I Male BALB/c mice were randomly assigned to the following five groups for 15 weeks: Control, CDDP alone, CDDP+TAK779, CDDP+OQ (quercetin given by a diet containing 1% quercetin) and CDDP+IQ (quercetin given by i.p., 10 mg/kg, 3 times per week). We determined whether quercetin given orally or intraperitoneally exerts its effect on CDDP-induced CRF through the mechanisms associated with regulation of MCP-1 signaling and HPA axis activation. We also compared the effects of quercetin with those of TAK-779, an antagonist of CCR2. The results showed that CDDP decreased the grip strength and locomotor activity. In contrast, OQ, IQ and TAK-779 attenuated the effects of CDDP. The efficiency of IQ was the best in increasing the locomotor activity. Quercetin, especially IQ, also suppressed the increase in the plasma MCP-1 level, cortisol and corticosterone induced by CDDP; while TAK779 only decreased the plasma level of cortisol and corticosterone. OQ and IQ also decreased the mRNA level of CRH in the hypothalamus, MCP-1 and CCR2 in the brain stem or the cerebellum, and TNF-α in the cerebrum in mice exposed to CDDP. TAK779 only significantly decreased the mRNA level of POMC in the pituitary gland. Taken together, our study demonstrates that OQ and IQ attenuate CDDP-induced CRF through the mechanisms associated with downregulation of MCP-1/ CCR2 signaling and HPA axis activity. Part II It has been shown that CDDP increases muscle wasting by increasing protein degradation and branched-chain amino acid oxidation, which may also contribute to CRF in cancer patients. Thus, in this part of the study we performed the second animal study to investigate whether the combined supplementation of quercetin and leucine, a branched-chain amino acid, additively or synergistically attenuated CDDP-induced CRF. The male BALB/c mice were randomly assigned to the following five groups for 8 weeks: Control, CDDP alone, CDDP+Q (quercetin given by a diet containing 0.5% quercetin), CDDP+L (leucine given by a diet containing 1.6% leucine) and CDDP+QL (Q+L). In agreement with part I, CDDP decreased the grip strength. Q and L alone or combined, similarly restored the parameter. Q, L and QL also decreased the plasma MCP-1 level in mice exposed to CDDP in the order of QL>L, Q. A similar trend was observed in the MCP-1 mRNA level in the brain stem and cerebellum. However, only QL significantly decreased the CDDP-increased CCR2 mRNA level in the brain stem but not the cerebellum. CDDP also increased the plasma level of cortisol; while Q, L and QL tended to decrease it. However, CDDP alone or in combination with various supplements did not affect the CRH mRNA level in the hypothalamus as well as the POMC mRNA level in the pituitary gland. All supplements tended to decrease CDDP-induced TNF-α, IL-1β and IL-6 in the plasma or the brain tissue, but only the effects of L and QL were significant. Taken together, this part of the study suggests that the combination of Q and L may attenuate CDDP-induced CRF by additively regulating the MCP-1/CCR2 pathway, cortisol level and proinflammatory cytokines.槲皮素順鉑白胺酸癌因性疲憊下視丘-腦垂體-腎上腺軸單核球趨化蛋白-1quercetincisplatinleucinecancer-related fatigueHPA axisMCP-1thesis