- 學位論文
探討補充鱸魚精對改善癌症惡病質肌肉耗損功效及相關機制
To explore the effect and the relative mechanism of perch essence supplementation on modulating cancer cachexia induced muscle wasting
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摘要
癌症惡病質是一種全身性的代謝綜合症，是因腫瘤與寄主產生物質使體內氧化壓力與、促發炎細胞激素上升等因素，導致癌症惡病質病人食慾不振、持續體重下降、脂肪組織流失與骨骼肌肉耗損。癌症惡病質主要通過活化增加蛋白質異化作用，泛素-蛋白酶體途徑(Ubiquitin-proteasome pathway, UPP)和自噬-溶酶體途徑(Autophagy-lysosome pathway, ALP)相關分子表現是癌症惡病質骨骼肌肉耗損的主因。骨骼肌耗損會影響生活品質及對治療耐受性降低和感染風險增加，降低癌症病人存活率。安永鱸魚精(Perch essence, PE)是將鱸魚以細胞活存技術(Cells Alive System)保鮮並使用整隻去鱗鱸魚經恆溫高壓烹煮萃取所得。本研究利用C26大腸癌細胞誘導小鼠惡病質之實驗模式，將雄性BALB/c小鼠隨機分成control組、Tumor組、Tumor＋PE組(飲水添加一倍劑量PE和灌食兩倍劑量PE濃縮粉末)和Tumor＋Tryptone組(飲水和灌食同PE克數之Tryptone)，評估補充PE對改善癌症惡病質肌肉耗損的效果。研究結果顯示，補充PE能夠顯著改善C26腫瘤細胞誘發惡病質小鼠的攝食與飲水減少和體重減輕，也顯著回復肌肉功能、股四頭肌橫切面積大小和肌肉質量，並增加了骨骼肌蛋白質含量指標MyHC(Myosin heavy chain)表現量，且功效優於Tryptone補充。補充PE可以顯著抑制蛋白質分解途徑UPP和ALP相關因子MuRF-1、Atrogin-1/MAFbx、Beclin-1和LC3-II，以及減少促凋亡蛋白Bax表現量，與減少癌症惡病質肌肉耗損相關症狀。此外，補充PE可顯著降低癌症惡病質小鼠紅血球和脾臟中MDA含量、血漿和三頭肌中促發炎細胞激素IL-6含量和脾臟和腓腸肌中IL-6和IL-1β mRNA表現量，改善全身性與肌肉微環境氧化損傷和發炎反應。在肌肉微環境中，使用西方墨點法分析發現，補充PE可顯著提升癌症惡病質小鼠腓腸肌中抗氧化酵素Superoxide dismutase2 (SOD2)和Heme oxygenase-1(HO-1)表現。值得注意的是，與蛋白質異化相關訊號蛋白Myostatin、 p-Akt和轉錄因子p-FoxO1、p-NF-κB p65表現量，補充PE後除了p-Akt和p-FoxO1上升其餘的表現量均下降。綜合上述可知，補充PE能減少全身性發炎反應及氧化壓力，有助於改善癌症惡病質小鼠攝食和飲水量下降、體重減輕、與肌肉耗損等癌症惡病質症狀。此外，補充PE亦可經由提升腫瘤小鼠肌肉中抗氧化能力、抑制發炎反應、和透過調控蛋白質分解相關訊號蛋白Myostatin、p-Akt和轉錄因子p-FoxO1、p-NF-κB p65表現，下調UPP和ALP路徑，減緩癌症惡病質相關肌肉耗損和功能下降。
並列摘要
Cancer cachexia is a systemic metabolic syndrome caused by substances produced by tumors and the host, leading to increased oxidative stress and pro-inflammatory cytokines in the body. This condition results in anorexia, continuous weight loss, loss of adipose tissue, and skeletal muscle wasting in cancer cachexia patients. The main mechanisms underlying muscle wasting in cancer cachexia are the increased protein catabolism, particularly through the ubiquitin-proteasome pathway (UPP) and autophagy-lysosome pathway (ALP). Skeletal muscle wasting affects quality of life, reduces tolerance to treatment, increases the risk of infection, and lowers the survival rate of cancer patients. Anyong perch essence (PE) is obtained by preserving perch using the Cells Alive System (CAS) and then extracting the essence from whole, scaled perch through constant temperature and high-pressure cooking. This study utilized a mouse model of cachexia induced by C26 colon cancer cells to assess the effects of PE on muscle wasting in cancer cachexia. Male BALB/c mice were randomly assigned to four groups: control, Tumor, Tumor + PE (with PE added to drinking water and concentrated PE powder administered via gavage), and Tumor + Tryptone (with Tryptone added to drinking water and gavage in the same amount as PE).Results indicated that PE supplementation significantly improved food and water intake, body weight, muscle function, quadriceps cross-sectional area, and muscle mass in cachectic mice. It also increased the muscle protein marker MyHC (Myosin heavy chain) expression. Furthermore, its efficacy is superior to Tryptone supplementation.PE supplementation significantly inhibited the protein degradation pathways UPP and ALP, reducing the expression of related factors MuRF-1, Atrogin-1/MAFbx, Beclin-1, LC3-II, and pro-apoptotic protein Bax, thereby mitigating muscle wasting associated with cancer cachexia. Additionally, PE supplementation significantly decreased MDA levels in red blood cells and spleen, IL-6 levels in plasma and triceps, and IL-6 and IL-1β mRNA expression in spleen and gastrocnemius muscle. This improvement mitigates oxidative damage and inflammatory responses in both systemic and muscle microenvironments. In the muscle microenvironment, Western blot analysis showed that PE supplementation significantly increased antioxidant enzymes SOD2 and HO-1 expression in the gastrocnemius muscle of cachectic mice. PE also modulated the expression of protein catabolism-related signaling proteins Myostatin, p-Akt, and transcription factors p-FoxO1, p-NF-κB p65, with increased p-Akt and p-FoxO1 and decreased levels of the others. In summary, supplementation with PE can reduce systemic inflammatory responses and oxidative stress, thereby helping to alleviate cancer cachexia symptoms such as decreased food and water intake, weight loss, and muscle wasting in cancer cachexia mice. Additionally, PE supplementation enhances antioxidant capacity in the muscles of tumor-bearing mice, inhibits inflammatory responses, and regulates the expression of protein degradation-related signaling proteins such as Myostatin, p-Akt, and transcription factors p-FoxO1 and p-NF-κB p65. This downregulates the UPP and ALP pathways, mitigating cancer cachexia-associated muscle wasting and functional decline.
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