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研究生:黃筱庭
研究生(外文):Huang, Hseau-Tyng
論文名稱:腐植酸在高葡萄糖環境下對於小鼠血管內皮細胞 SVEC4-10 中氧化應激反應與訊息傳遞路徑之影響
論文名稱(外文):Effects on Oxidative Adaptive Response andSignal Transduction Pathway in VascularEndothelial Cell (SVEC4-10) Exposed toHumic acid under High Glucose Condition
指導教授:黃登福黃登福引用關係
指導教授(外文):Huang, Deng-Fwu
口試委員:鄭森雄周薰修陳泰源
口試委員(外文):Jeng, Sen-ShyongChou, Shin-ShouChen, Tai-Yuan
口試日期:2016-06-14
學位類別:碩士
校院名稱:國立臺灣海洋大學
系所名稱:食品科學系
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:81
中文關鍵詞:腐植酸糖尿病烏腳病
外文關鍵詞:Humic acidDiabetesBlackfoot disease
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腐植酸 (humic acid; HA)主要存在於土壤及地下飲用水中,被視為是造成烏
腳病 (blackfoot disease) 的主要風險因子之一。烏腳病為地區流行性下肢周邊血
管疾病,早期台灣西南海岸與印度、孟加拉等地區曾有發病案例。地質學及流行
病學報導指出烏腳病盛行地區的自流井水中含高濃度的砷,並大多會和 HA 鍵
結。研究顯示人體攝食腐植酸後,會經腸胃道進入到血液中循環,造成傷害,故
推測烏腳病與腐植酸具密切關係。而統計調查發現烏腳病患者有五成皆患有糖尿
病 (diabetes),流行病學指出糖尿病末期的周邊血管疾病之病理變化與烏腳病之
臨床症狀極為相似,因此推測糖尿病與烏腳病及腐植酸互有關聯。本研究以小鼠
淋巴結血管內皮細胞株 (vascular endothelial cells; SVEC4-10 cells) 作為模擬人
類血管之模型,並以高濃度葡萄糖模擬糖尿病之環境,添加腐植酸共處理後,觀
察兩者是否加劇內皮細胞受到傷害。在高葡萄糖共培養環境下,SVEC4-10 細胞
之死亡對於腐植酸具劑量依賴性。腐植酸會顯著降低粒線體膜電位螢光強度,增
加細胞內活性氧物種 (reactive oxygen species; ROS) 及活性氮分子 (reactive
nitrogen species; RNS) 與胞內氧化指標 1,2-thiobarbituric acid reactive substances
(TBARS) 之含量,增加超氧歧化酶 (superoxide dismutase; SOD) 及降低抗氧化
物 (glutathione; GSH) 表現量。以有絲分裂活化性蛋白激酶 (mitogen-activated
protein kinase; MAPK) 調控酵素 p38 抑制劑 SB202190 與細胞外信號調控激酶
(extracellular signal-regulated kinase; ERK) 抑制劑預處理後,可顯著降低腐植酸
在高濃度葡萄糖共培養環境下對於 SVEC4-10 細胞所誘導之細胞死亡,另外此環
境下造成 MAPK 下游促發炎相關因子介白質 6 (interleukin 1; IL-6),介白質 1β
(interleukin 1β; I IL-1β) 和腫瘤壞死因子 α (tumor necrosis factor ; TNFα ) 之表現
量是透過 ERK 及 JNK 所調控。另以西方墨點法分析同環境下對於 SVEC4-10 細
胞中內質網壓力表現,測得其相關調控蛋白葡萄糖調節蛋白 78 (glucose-regulated
protein78; GRP78) 和同源蛋白 C/EBP (C/EBP homologous protein; CHOP) 表現
量皆顯著上升,另分析出細胞中鈣離子濃度上升;而欲得知鈣離子的增加是否會
調節一氧化氮合成酶 (endothelial nitric oxide synthase; eNOS ),測得結果顯示
eNOS 之基因與蛋白質表現量皆無顯著改變。綜合上述結果,腐植酸在高葡萄糖
環境下可能經由氧化壓力與內質網壓力造成 SVEC4-10 細胞中粒線體損傷、細胞
內氧化壓力指標含量與抗氧化酵素表現量降低而誘導細胞死亡,並經由 p38 與
ERK 途徑誘導細胞內發炎因子表現量上升,以上得知腐植酸與高濃度葡萄糖對
於造成 SVEC4-10 細胞之氧化傷害具有協同作用。
Humic acid (HA) is considered as one of the risk factor causing blackfoot disease that
mainly exists in environmental sources such as soil and underground drinking water.
Blackfoot disease is the peripheral vascular epidemic disease which occurred early
days in areas of the southwest coast of Taiwan, India and Bengal. The reports of
geology and epidemiology indicate that artesian wells of blackfoot disease in hyper
endemic area contain high level of arsenic, which is mostly bonded with HA. HA may
highly relate to blackfoot disease since researches have shown HA enters blood
circulation system through gastrointestinal tract after human body exposed to HA and
causes disease. Statistics show that there are 50% of people who have blackfoot
disease that are diabetes, epidemiology notes that pathologic changes of peripheral
vascular disease in end stage of diabetes are similar to clinical symptoms of blackfoot
disease, therefore presumed diabetes may relate to blackfoot disease and HA. In this
research, it is vascular endothelial cells (SVEC4-10 cells) are used to simulate blood
vessels of human being and high glucose condition simulates the environment of
blood vessels in diabetes. In high glucose cocultivation condition, the death of
SVEC4-10 cells is dose-dependent to HA. HA significantly decreases the the
fluorescence intensity of mitochondrial membrane potential, increases reactive
oxygen species (ROS), reactive nitrogen species (RNS) and content of
1,2-thiobarbituric acid reactive substances (TBARS) in cells, and varies amount of
performance of superoxide dismutase (SOD) and glutathione (GSH). The
preprocessing with depressor U-0126 to control of enzyme p38 and depressor
SB202190 to control extracellular signal-regulated kinase (ERK) by
mitogen-activated protein kinase (MAPK) markedly decrease the death of SVEC4-10
induced by HA in high glucose cocultivation condition, and revert amount of
performance of downstream promoting inflammation related factors interleukin 1
(IL-6), interleukin 1β (I IL-1β) and tumor necrosis factor (TNFα) which are controlled
by MAPK in the condition. Useing western blot to analyze endoplasmic reticulum
stress performance in the same condition and find amount of performance of related
regulatory protein glucose-regulated protein78 (GRP78) and C/EBP homologous
protein (CHOP) are dramatically increased, and the concentration of calcium ions in
the cell is increased as well; the amount of endothelial nitric oxide synthase (eNOS)
protein and gene having no significant change indicates that the increase of calcium
ions is irrelevant to regulation of eNOS. In conclusion, HA may make apoptosis of
SVEC4-10 by damaging mitochondria and decreasing the amount of performance of
indicators of oxidative stress contents and SOD in the cells via varying oxidant stress
and ER stress and increase the amount of performance of cellular inflammation factor
through p38 and ERK pathway. The results suggest that HA and high glucose may
have synergistic effect on making SVEC4-10 oxidative damage.
壹、 文獻整理 2
一、糖尿病 3
二、血管疾病 7
三、腐植酸 11
四、自由基與氧化壓力 13
貳、研究內容 16
第一章、 腐植酸對於SVEC4-10細胞在高葡萄糖環境下所誘導之氧化傷害 17
一、前言 17
二、材料與方法 18
三、結果 25
四、討論 28
五、圖表 33
第二章、腐植酸對於SVEC4-10細胞在高葡萄糖環境下,內質網壓力途徑與相關基因之影響 41
一、前言 41
二、材料與方法 42
三、結果 49
四、討論 51
五、圖表 55
結論 62
參考文獻 63
謝辭 74
附錄 75


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