臺灣博碩士論文加值系統

皮膚為人體第一線保護器官，當遭受創傷時傷口會經歷凝血、發炎、組織增生和重塑四段互相重疊的時期來進行修復。糖尿病 (diabetes mellitus, DM) 患者血糖調控能力的下降除了使身體長期處於慢性發炎狀態，亦造成高糖環境進而促使乳酸大量產生，導致纖維母細胞 (fibroblasts) 增生受阻並減緩膠原蛋白的生成，最終使得糖尿病患者傷口修復不易。本研究旨在探討以胚芽乳酸桿菌 TWK10 (Lactobacillus plantarum stranin TWK10, TWK10) 發酵豆奶乙醇萃取物對經鏈佐黴素 (streptozotocin, STZ) 誘導之第一型糖尿病所引起對傷口不易癒合之促癒功效。第一部份以體外細胞模式探討 TWK10 發酵豆奶乙醇萃取物對經脂多醣 (lipopolysaccharide, LPS) 誘導 RAW 264.7 小鼠巨噬細胞發炎之抗發炎與促進Detroit 551 人類皮膚纖維母細胞增生之功效。實驗結果顯示，以100 µg/mL 之 TWK10 發酵豆奶乙醇萃取物處理可顯著降低經 LPS 誘導發炎的 RAW264.7 小鼠巨噬細胞之一氧化氮生成量至 8.24 ± 2.02 µM (p < 0.05)。且以 600 µg/mL 之 TWK10 發酵豆奶乙醇萃取物處理於高糖環境下培養之 Detroit 551 人類皮膚纖維母細胞，細胞增殖率可上升至 128.44 ± 7.67% (p < 0.05)。第二部分以動物模式探討 TWK10 發酵豆奶乙醇萃取物對經鏈佐酶素 (streptozotocin, STZ) 誘導糖尿病創傷大鼠傷口癒合之影響。結果顯示，塗抹 TWK10 發酵豆奶乙醇萃取物四天後可顯著下降傷口面積至 83.80 – 92.56 %，塗抹後第十四天可顯著下降傷口面積至 8.38 – 10.24 %，與未處理组相比具顯著性差異 (p<0.05); 此外，TWK10 發酵豆奶乙醇萃取物可顯著下降糖尿病創傷大鼠傷口組織與血清中之腫瘤壞死因子 (tumor necrosis factor, TNF-α) 與介白素-6 (interleukin 6, IL-6) 生成量，並提升血清中介白素-10 (interleukin 10, IL-10) 含量。綜合上述結果，塗抹 TWK10 發酵豆奶乙醇萃取物可藉由減緩發炎及促進增生改善經 STZ 誘導第一型糖尿病創傷大鼠之促癒功效。

Skin is an organ, which protects human body from variety injuries. When skin was wounded, it would undergo four overlapping stage: coagulation phase, inflammatory phase, proliferative phase and remodeling phase to repair wounds. Lack of insulin or insufficiency of blood glucose regulation of body were mainly cause of diabetes mellitus (DM) which not only made body under inflammation but lead to high concentration of blood glucose and further cause lactic acid produce numerously, than impede fibroblasts cells proliferation and reduce manufacture of collagen, and, wounds healing is difficult. The objective of this study was to investigate the effects of ethanol extract from Lactobacillus plantarum TWK10 (TWK10)-fermented soy milk on wound healing. First, the anti-inflammatory and proliferation effect of TWK10-fermented soy milk on lipopolysaccharide (LPS)-induced inflammatory in RAW 264.7 cells and effect of proliferation in Detroit 551 fibroblast cells were determined. As the results, LPS-induced inflammation RAW264.7 macrophage cells treated with TWK10-fermented soy milk ethanol extract at a concentration of 100 µg/mL decreased the nitric oxide (NO) content to 8.24 ± 2.02 µM (p < 0.05). In addition, Detroit 551 cells with high glucose medium treated with TWK10-fermented soy milk ethanol extract at a concentration of 600 µg/mL increased proliferation by 128.44 ± 7.67%, compared with the untreated control (p < 0.05). Second, rat with DM induced by streptozotocin (STZ) were treatment with ethanol extracts of TWK10-fermented soy milk to determine the wound healing. The wounded area was significantly decreased to 83.80 – 92.56 % by treating TWK10-fermented soy milk ethanol extract, compared with STZ-induced rats (p < 0.05) for four days post-wounded and 8.38 – 10.24 % fourteen days post-wounded. It also decreased cytokine content of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) on wounded skin and serum by applying topically the TWK10-fermented soy milk ethanol extract and increased interleukin-10 (IL-10) in the serum of wounded STZ -induced diabetic rats. In conclusion, applying topically TWK10-fermented soy milk ethanol extract could improve wound healing of wounded STZ-induced type Ⅰ diabetes mellitus rats by reduce inflammation and improve proliferation.

目錄

第一章 前言 1
第二章 文獻回顧 2
2.1 傷口癒合 (wound healing) 2
2.1.1 皮膚的功能與構造 2
2.1.2 皮膚的創傷癒合程序 4
2.2 糖尿病 (diabetes mellitus, DM) 10
2.2.1 糖尿病之判斷標準與分類 10
2.2. 2 糖尿病之創傷傷口 14
2.2.3葡萄糖胺 32
2.2.4四氧嘧啶 32
2.2.5鏈佐黴素 32
2.3 益生菌 39
2.3.1 益生菌之功效 39
2.3.1.1抑制腸道內雜菌生長 39
2.3.1.2改善乳糖不耐症 39
2.3.1.3降低大腸癌機率 40
2.3.1.4降低血液中膽固醇 40
2.3.1.5提升免疫反應 40
2.4益生菌發酵豆奶 40
2.4.1 發酵豆奶 41
2.4.2 發酵豆奶之保健功效 44
第三章 研究目的與試驗架構 50
第四章 材料與方法 53
4.1 試驗材料 53
4.1.1 試驗菌株 53
4.1.2 試驗細胞 53
4.1.3 試驗動物 53
4.1.4 儀器設備 53
4.1.5 塑膠耗材 54
4.1.4 試驗藥品 55
4.2 試驗方法 56
4.2.1 樣品製備 56
4.3 小鼠巨噬細胞模式 56
4.3.1 細胞之冷凍保存 56
4.3.2 活化凍存之細胞 57
4.3.3 細胞培養與繼代 (subculture) 57
4.3.4 細胞存活率試驗 (MTT 染色法) 57
4.3.5 一氧化氮 (nitric oxide) 生成量測定 58
4.4 人類皮膚纖維母細胞模式 59
4.4.1 細胞之冷凍保存 59
4.4.2 活化凍存之細胞 59
4.4.3 細胞繼代 (subculture) 59
4.4.4 細胞增殖試驗 (MTT 染色法) 59
4.4.5 細胞移行測試 (Wound healing migration assay) 59
4.5 動物試驗 59
4.5.1 實驗動物與分组 60
4.5.2 糖尿病動物之誘發與確認 60
4.5.3 動物背部傷口之開創 60
4.5.4 投藥劑量 63
4.5.5 傷口面積測量 63
4.5.6血清中葡萄糖 (glucose) 含量測定 63
4.5.7血清中胰島素 (insulin) 含量測定 64
4.5.8血清中腫瘤壞死因子 (tumor necrosis factor, TNF-α)測定 64
4.5.9血清中介白素-6 (interleukin 6, IL-6) 測定 64
4.5.10血清中介白素-10 (interleukin 10, IL-10) 測定 65
4.5.11創傷皮膚中發炎相關蛋白表現量蛋白質萃取與定量 65
4.5.12創組織病理切片 69
4.6 統計分析 70
第五章 結果 71
5.1 體外細胞模式探討 TWK10 發酵豆奶萃取物之抗發炎功效 71
5.1.1發酵豆奶乙醇萃取物對經 LPS 誘導 RAW 264.7 小鼠巨噬細胞細胞存活率之影響 71
5.1.2發酵豆奶乙醇萃取物對經 LPS 誘導 RAW 264.7 小鼠巨噬細胞一氧化氮產量之影響 71
5.2體外細胞模式探討 TWK10 發酵豆奶萃取物對纖維母細胞增殖情形 78
5.2.1高糖環境對纖維母細胞增殖情形之影響 78
5.2.2 TWK10 發酵豆奶萃取物於不同糖度糖環境下對纖維母細胞增殖情形之影響 78
5.3體外細胞模式探討 TWK10 發酵豆奶萃取物對纖維母細胞遷移情形 85
5.4體內動物模式探討 TWK10 發酵豆奶萃取物對糖尿病傷口癒合之影響 87
5.4.1發酵豆奶乙醇萃取物對經鏈佐酶素誘導糖尿病創傷大鼠體重、飲水及攝食量之影響 87
5.4.2以STZ 誘導大鼠糖尿病試驗期間大鼠血糖與胰島素濃度變化 91
5.4.3以 STZ 誘導糖尿病創傷大鼠臟器重量與體內糖代謝情形 94
5.4.4以 STZ 誘導大鼠糖尿病傷口癒合評估 96
5.4.5經鏈佐黴素誘導糖尿病創傷大鼠血清中發炎相關細胞素含量 103
5.4.6經鏈佐黴素誘導糖尿病創傷大鼠創傷皮膚相關細胞激素蛋白表現量 108
5.4.7經鏈佐黴素誘導糖尿病創傷大鼠創傷皮膚組織學分析 111
第六章 討論 117
第七章 結論與未來展望 121
第八章 參考文獻 122

 

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