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研究生: 周美佳
Chou, Mei-Jia
論文名稱: 探討種子胜肽Lunasin對於肥胖引起的發炎模式之免疫調節作用
The effect of seed peptide lunasin on immune regulation in obesity-induced inflammatory models
指導教授: 謝佳倩
Hsieh, Chia-Chien
學位類別: 碩士
Master
系所名稱: 人類發展與家庭學系
Department of Human Development and Family Studies
論文出版年: 2016
畢業學年度: 104
語文別: 中文
論文頁數: 123
中文關鍵詞: Lunasin肥胖發炎巨噬細胞細胞激素
英文關鍵詞: Cytokine, Inflammation, Lunasin, Macrophage, Obesity
DOI URL: https://doi.org/10.6345/NTNU202204040
論文種類: 學術論文
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  • 肥胖伴隨著脂肪組織中數種免疫細胞的浸潤及促發炎細胞激素生成,形成低度慢性發炎環境,與許多慢性疾病的發生相關,更是癌症發生的危險因子之ㄧ。Lunasin為一天然種子胜肽已被證實具有抗腫瘤、抗發炎、抗氧化、降低膽固醇及免疫調節等功用,但對於肥胖相關的發炎反應與其可能的作用機制仍不甚清楚。因此,本研究欲探討lunasin是否具有降低肥胖相關的發炎介質生成,並調節其免疫作用。實驗分為兩部分,實驗主題I:探討lunasin對肥胖相關發炎之免疫細胞的調節。此部分建立三個體外肥胖模式,模式一,以瘦體素 (leptin)刺激RAW264.7細胞之發炎模式;模式二,使用脂肪細胞條件培養液(Adipocyte-conditioned medium, Ad-CM)培養RAW264.7細胞;模式三,RAW264.7巨噬細胞與3T3成熟脂肪細胞共同培養環境,分別同時處理Lunasin。結果發現在LPS+leptin以及LPS+Ad-CM組別,lunasin處理分別顯著抑制促發炎細胞激素IL-6、TNF-α及IL-1生成。在動物實驗部分,為探討lunasin對肥胖小鼠免疫細胞分泌的發炎介質之影響,使用C57BL/6J Narl母鼠,分別餵食低脂 (LF)及高脂 (HF)飲食,收集初代免疫細胞同時加入lunasin處理,發現在LPS刺激之HF組腹腔巨噬細胞,lunasin顯著降低IL-6分泌;而脾臟細胞以PHA刺激培養並加入lunasin的處理,其HF組中的IL-4分泌,顯著降低。進一步探討使用lunasin 低劑量 (HF-LL)與高劑量 (HF-LH) 腹腔注射,對於肥胖小鼠免疫細胞的發炎介質的影響。實驗主題II:探討飲食誘導的肥胖對小鼠乳癌生成之影響。給予飲食誘發肥胖小鼠化學致癌劑DMBA (7,12-Dimethylbenz[a]anthracene)以誘發乳腺癌生成,結果發現在高脂飲食組,給予DMBA腫瘤發生率為20% (n=1/5)及而低脂組為14.3% (n=1/7)。由以上結果可知,在體內與體外實驗中,lunasin處理具有降低肥胖相關的促發炎細胞激素的生成。

    Obese progression accompanies chronic inflammation mainly due to infiltrate multiple immune cells in adipose tissue and then produce pro-inflammatory cytokines. This low-grade chronic inflammatorymicro-environment is associated with many chronic diseases, such as type II diabetes mellitus and cancer. Lunasin, is a natural seed peptide, has been shown many bioactivities such as anti-tumoranti-inflammatory, antioxidant, reduce cholesterol, and immune regulation properties. However, there is still a little information described the mechanisms of lunasin acts on obesity-related inflammation, even obesity-related tumor development. Therefore, the present study is to investigate whether lunasin reduced obesity-related inflammatory mediator, and affect immune function. There are two parts of experiments. In the Experiment Ι, to investigate the effects of lunasin on RAW264.7 macrophages in obese physiological model, the RAW264.7 cells were cultured in mediacontaining leptin, adipocye conditioned medium (Ad -CM), or co-culture of adipocyte and macrophage in transwell system, and then treated with lunasin plus LPS stimulation, respectively. The results were showed that the secretions of MCP-1 and IL-1β were decreased by lunasin treatment in leptin and Ad-CM conditions plus LPS stimulation at the same time. Subsequently, in vivo studies were carried on to investigate the effect of lunasin regulate immune cells ofmice fed the experimental diets. The C57BL/ 6J Narl female mice fed the experiment diets containing low-fat (LF) and high-fat (HF) for 10 weeks. The results were showed that the secretion of IL-6 in peritoneal cells stimulated by LPS of HF group was decreased by lunasin treatment. To confirm the effect of lunasin, intraperitoneal injection (IP) of lunasin, at 20 mg/kg and 4 mg/kg body weight was used in dietary induced obese mice (HF) and control mice (LF). In Experiment II, to investigate the effects of breast tumorigenesis in obese mice, a model of oral gavage chemical carcinogen 7,12-Dimethylbenz [a] anthracene (DMBA) induced breast cancer in C57BL/ 6J Narl female mice fed the experiment diet LF and HF for 10 weeks was built. The mice were divided into a LF, HF, LF+DMBA (LFD) and HF+DMBA (HFD), weekly monitoring tumorigenesis situation. The results indicated that incidence of breast tumors is about 20% in HFD group and 14.3% in LFD group.
    In summary, the results indicated that lunasin reduced proinflammatory cytokine productions in both in vitro and in vivo models, suggesting lunasin executes potentially anti-inflammatory actions in the obesity-related conditions. More studies are needed to explore the mechanisms of lunasin’s action in the obesity related inflammation and tumorigenesis.

    目錄 第一章 文獻探討 ......................................................................................................... 1 第一節 免疫系統 ...................................................................................................... 1 第二節 肥胖 .............................................................................................................. 4 一、 流行病學調查 .............................................................................................. 4 二、肥胖生理意義 ............................................................................................... 5 三、肥胖與免疫 ................................................................................................... 7 1. 肥胖與免疫細胞.......................................................................................... 7 2. 肥胖與脂肪細胞激素.................................................................................. 9 四、肥胖與癌症 ................................................................................................. 11 1. 慢性發炎.................................................................................................... 11 2. 賀爾蒙之影響............................................................................................ 13 第三節 乳腺癌 ........................................................................................................ 14 一、流行病學 ..................................................................................................... 14 二、乳癌成因與類型 ......................................................................................... 14 三、癌症之化學預防 ......................................................................................... 15 第四節 LUNASIN ..................................................................................................... 17 一、Lunasin簡介 ............................................................................................... 17 二、Lunasin的生理功效 ................................................................................... 18 第五節 研究模式 .................................................................................................... 20 一、肥胖相關之研究模式 ................................................................................. 20 1. 體外研究模式............................................................................................ 20 2. 動物研究模式............................................................................................ 21 二、乳腺癌相關之研究模式 ............................................................................. 22 第二章 研究動機與目的 ........................................................................................... 23 第三章 材料與方法 ................................................................................................... 25 第ㄧ節 實驗材料與設備 ........................................................................................ 25 第二節 實驗材料與方法 ........................................................................................ 28 ㄧ、建立體外肥胖相關之發炎模式,探討Lunasin對RAW264.7細胞其發炎介質生成的影響 ................................................................................................. 28 1. RAW264.7小鼠巨噬細胞培養 ................................................................. 28 2. 3T3-L1小鼠纖維母細胞培養: .................................................................. 29 3. 3T3-L1小鼠纖維母細胞分化為脂肪細胞 ............................................... 30 4. LPS/leptin 誘發RAW264.7巨噬細胞之發炎模式 ................................. 31 5. LPS/Ad-CM誘發RAW264.7巨噬細胞之發炎模式 ............................... 32 6. RAW264.7巨噬細胞與3T3-L1脂肪細胞共培養模式 ........................... 33 二、Lunasin處理對於肥胖小鼠初代免疫細胞其發炎介質生成的影響 ....... 34 三、肥胖小鼠IP注射Lunasin,對於免疫細胞發炎介質生成的影響 ......... 35 四、飲食誘發肥胖小鼠給予化學致癌劑DMBA以誘發乳腺癌生成 ........... 36 五、動物犧牲、樣品收集與分析: .................................................................... 37 1. 腹腔細胞之取得與培養............................................................................ 37 2. 脾臟細胞之取得與培養............................................................................ 38 3. 腸繫膜淋巴結細胞之取得與培養............................................................ 39 4. 皮耶氏體細胞之取得與培養.................................................................... 39 5. 細胞激素測定............................................................................................ 40 6. TBA反應物含量 (thiobarbituric acid reactive substances, TBARS)的測定......................................................................................................................... 41 7. 血清中生化指標分析................................................................................ 42 8. 組織切片.................................................................................................... 43 第三節 統計分析 .................................................................................................... 44 第四章 實驗結果 ....................................................................................................... 45 第一節 以RAW264.7巨噬細胞,建立肥胖相關之體外發炎模式 ................... 45 ㄧ、Lunasin處理對Leptin刺激之RAW264.7細胞其發炎介質生成的影響45 二、Lunasin處理對Ad-CM刺激之RAW264.7細胞其發炎介質生成的影 51 三、Lunasin處理RAW264.7細胞與3T3-L1細胞共培養模式之細胞激素分泌之影響 ............................................................................................................. 57 第二節 LUNASIN處理對於肥胖小鼠初代免疫細胞其發炎介質生成的影響 .... 61 一、餵食高脂及低脂飲食對小鼠體重變化、攝食量及攝食效率的影響 ..... 61 二、餵食高脂及低脂實驗飲食後小鼠組織重量的變化 ................................. 63 三、餵食高脂及低脂飲食,小鼠初代免疫細胞數 ......................................... 65 四、小鼠血清之脂肪細胞激素之含量 ............................................................. 66 五、Lunasin處理對小鼠初代腹腔細胞之細胞激素分泌的影響 ................... 67 六、Lunasin處理對小鼠初代脾臟細胞之細胞激素分泌的影響 ................... 70 七、Lunasin處理小鼠腸繫膜淋巴結細胞與皮耶氏體之細胞激素分泌含量75 第三節 腹腔注射LUNASIN對餵食高脂飲食之肥胖鼠其免疫細胞的調節 ....... 76 一、Lunasin IP對餵食高脂飲食小鼠體重變化及攝食效率的影響 .............. 76 二、Lunasin IP對餵食高脂飲食小鼠組織重量的變化 .................................. 78 三、Lunasin IP餵食高脂飲食,小鼠初代免疫細胞數 .................................. 80 四、Lunasin IP對飲食誘導肥胖小鼠其血清生化值之影響 .......................... 81 五、Lunasin IP飲食誘導肥胖小鼠血清中脂肪細胞激素分泌之影響 .......... 83 六、Lunasin IP對小鼠初代腹腔細胞之細胞激素分泌的影響 ...................... 83 七、Lunasin IP對飲食誘導肥胖小鼠其肝臟、脂肪組織TBARS之影響 ... 87 八、Lunasin IP對飲食誘導肥胖小鼠其脂肪組織H & E染色之影響 .......... 88 第四節 LUNASIN對肥胖小鼠以DMBA誘發乳癌症模式之影響 ...................... 89 VII 一、以DMBA誘發肥胖小鼠乳癌生成之體重變化、攝食量及攝食效率的影響……………………………………………………………………………….89 二、以DMBA誘發肥胖小鼠乳癌生成之存活率及腫瘤生成率的影響 ....... 93 三、以DMBA誘發肥胖小鼠乳癌生成之組織重量的變化 ........................... 93 四、以DMBA誘發肥胖小鼠生成乳癌其組織之H&E、ki-67染色分析 .... 97 第五章 討論 ............................................................................................................. 100 第一節 探討LUNASIN對肥胖相關發炎之免疫細胞的調節 ............................. 100 一、建立體外肥胖相關之發炎模式,探討Lunasin對RAW264.7細胞其發炎介質生成的影響 ............................................................................................... 100 1. Lunasin處理對Leptin刺激之RAW264.7細胞其發炎介質生成的影響....................................................................................................................... 101 2. Lunasin對Ad-CM刺激之RAW264.7細胞其發炎介質生成的影響....................................................................................................................... 101 二、 Lunasin處理探討對於肥胖小鼠初代免疫細胞其發炎介質生成的影響……………………………………………………………………………...105 三、探討肥胖小鼠IP注射Lunasin對於免疫細胞發炎介質生成的影響 .. 107 第二節 探討肥胖對小鼠乳癌生成之影響 .......................................................... 109 一、給予飲食誘發肥胖小鼠化學致癌劑DMBA以誘發乳腺癌生成 ......... 109 第三節 綜合討論與未來研究方向 ...................................................................... 110 第六章 結論 ............................................................................................................. 111 第七章 參考文獻 ..................................................................................................... 113

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