臺灣博碩士論文加值系統

乙二醛 (glyoxal, gx)及甲基乙二醛 (methylglyoxal, Mgx)，為高級糖化作用的最終產物 (AGEs)。已有許多研究發現糖尿病患者血漿中gx及Mgx濃度較正常人高。高親電性的gx及Mgx可能會和去氧核醣核酸 (deoxyribosenucleic acid, DNA)反應形成DNA加成產物，進而誘發突變。本實驗是利用穩定同位素稀釋法搭配奈升流速液相層析高解析度軌道阱質譜儀同時分析gx及Mgx所形成的加成產物，N2-carboxymethyl-2’-deoxyguanosine (CMdG)、N2-carboxyethyl-2’-deoxyguanosine (CEdG)及DNA交聯產物，dG-gx-dA和dG-gx-dC。本研究總共分析了十個真實樣品，分別是健康受試者四個血液以及三個唾液DNA，和五個糖尿病患者血液DNA，在所有樣品中皆有偵測到CMdG及CEdG，dG-gx-dC有在四個血液DNA中測到，而dG-gx-dA則只在一個血液樣品中測到。此研究為第一個開發同時分析由gx及Mgx所產生的四個加成產物，CMdG、CEdG、dG-gx-dC、dG-gx-dA，同時也是第一個在人類唾液樣品中分析到這四個加成產物的研究。
雌激素中的雌二醇在人體內會被氧化成雌二醇醌，雌二醇醌會與人體內的DNA及蛋白質反應形成修飾，且有許多文獻提到乳癌患者中雌二醇醌與蛋白質所形成的加成產物大於健康受試者。本實驗使用奈升流速高解析度軌道阱質譜儀分析雌二醇醌在人類血紅蛋白中所形成的修飾，總共鑑定出了16個修飾，分別是α-104Cys+284、α-104Cys+286、α-104Cys+300、α-104Cys+302、α-104Cys+316、α-104Cys+318、β-2His+284、β-93Cys+300、β-93Cys+316、β-93Cys+318、β-112Cys+284、β-112Cys+286、β-112Cys+300、β-112Cys+302、β-112Cys+316、β-112Cys+318。將此實驗應用在真實樣品上，並計算修飾化程度，總共分析了17位乳癌患者與17位與其年紀相仿的女性健康受試者，在樣品上僅分析到β-112Cys的修飾，雖然在所有乳癌患者的β-112Cys上的修飾平均修飾化程度都大於健康受試者，但皆無統計學上顯著差異。

Glyoxal (gx) and methylglyoxal (Mgx) are the end products of advanced glycation (AGEs). Many studies have found that the concentration of gx and Mgx in the plasma of diabetic patients is higher than that of normal people. Highly electrophilic gx and Mgx may react with deoxyribosenucleic acid (DNA) to form DNA addition products, thereby inducing mutations. This experiment uses the stable isotope dilution method with a nanoliter flow liquid chromatography high-resolution orbitrap mass spectrometer to simultaneously analyze the addition products formed by gx and Mgx, N2-carboxymethyl-2'-deoxyguanosine (CMdG), N2-carboxyethyl -2'-deoxyguanosine (CEdG) and DNA cross-linked products, dG-gx-dA and dG-gx-dC. A total of ten real samples were analyzed in this study, including four blood and three saliva DNA from healthy subjects, and five blood DNA from diabetic patients. CMdG and CEdG were detected in all samples, and dG-gx- dC was detected in four blood DNA samples, while dG-gx-dA was detected in only one blood sample. This study is the first to develop the simultaneous analysis of four addition products produced by gx and Mgx, CMdG, CEdG, dG-gx-dC, and dG-gx-dA. It is also the first to analyze it in human saliva samples. Study of these four addition products.
Estradiol in estrogen will be oxidized into estradiol quinone in the human body. Estradiol quinone will react with DNA and proteins in the human body to form modifications. There are many documents mentioning the interaction between estradiol quinone and proteins in breast cancer patients. The addition products formed were greater than in healthy subjects. This experiment used a nanoliter flow rate high-resolution orbital trap mass spectrometer to analyze the modifications formed by estradiol quinone in human hemoglobin. A total of 16 modifications were identified, namely α-104Cys+284, α-104Cys+286, α -104Cys+300, α-104Cys+302, α-104Cys+316, α-104Cys+318, β-2His+284, β-93Cys+300, β-93Cys+316, β-93Cys+318, β-112Cys +284, β-112Cys+286, β-112Cys+300, β-112Cys+302, β-112Cys+316, β-112Cys+318. This experiment was applied to real samples and the degree of modification was calculated. A total of 17 breast cancer patients and 17 healthy female subjects of similar age were analyzed. Only β-112Cys modification was analyzed on the samples, although in all samples The average degree of modification on β-112Cys in breast cancer patients was greater than that in healthy subjects, but there was no statistically significant difference.

利用奈升流速液相層析電噴灑串聯質譜儀分析 (一)乙二醛及甲基乙二醛所誘導的去氧核醣核酸加成產物 (二)分析人類血紅蛋白中雌二醇所形成的修飾 1
謝誌 i
總摘要 ii
目錄 iii
表目錄 vi
圖目錄 vii
附圖 ix
(一) 利用奈升流速液相層析電噴灑串聯質譜儀分析乙二醛及甲基乙二醛所誘導的去氧核醣核酸加成產物 1
摘要 2
一、 緒論 3
1-1 去氧核醣核酸 (deoxyribonucleic acid, DNA) 3
1-2 DNA加成產物 (DNA adducts) 5
1-3 脂質過氧化 (lipid peroxidation) 7
1-4 梅納反應 (Maillard reaction) 8
1-5 乙二醛 (glyoxal)與甲基乙二醛 (methylglyoxal) 10
1-6 乙二醛與甲基乙二醛形成的DNA加成產物 11
1-7 dG-gx-dC, dG-gx-dA, CMdG, CEdG之相關文獻 13
1-8 研究動機 19
二、 實驗流程 20
2-1 藥品 20
2-2 儀器 20
2-3 材料 21
2-4 標準品製備 21
2-5 實驗設計 22
2-6 酶水解DNA 23
2-7 從人類血液中萃取DNA48 24
2-8 從人類唾液中萃取DNA49 24
2-9 計算水解效率 25
2-10 利用液相層析儀 (HPLC)對分析物進行濃縮淨化 25
2-11 利用固相萃取管柱 (SPE)對分析物進行濃縮淨化 26
2-12 偵測極限 26
2-13 nanoLC-NSI/MS/MS之分析條件 26
2-14 改善萃取後DNA純度之方法 28
三、 結果與討論 30
3-1 SPE進行濃縮淨化之回收率 30
3-2 LC進行純化濃縮淨化之回收率 30
3-3 TSQ比較使用SPE+LC及LC純化之回收率 31
3-4 找尋OE 120最佳碰撞能量 31
3-5 純化收集步驟有機相對CMdG之影響 33
3-6 四個加成產物在OE120偵測極限 34
3-7 使用不同水解方法水解小牛胸腺DNA及人類胎盤DNA 35
3-8 使用方法A水解測試再現性 38
3-9 分析唾液及血液DNA真實樣品 42
3-10 進一步純化DNA結果 45
四、 結論 47
(二) 利用奈升流速液相層析電噴灑串聯質譜儀分析人類血紅蛋白中雌二醇所形成的修飾 48
摘要 49
五、 緒論 50
5-1 人類血紅蛋白介紹 (human hemoglobin, hHb) 50
5-2 轉譯後修飾 (post translational modification, PTM) 52
5-3 雌激素 (estrogen) 52
5-4 雌二醇醌在胺基酸上形成的修飾 54
5-5 乳癌 (breast cancer) 55
5-6 雌二醇醌在胺基酸上形成修飾相關文獻 56
5-7 甲基乙二醛 (Methylglyoxal, Mgx) 60
5-8 丙二醛 (malondialdehyde, MDA) 61
5-9 甲基乙二醛與丙二醛 61
5-10 研究動機 62
六、 實驗流程 63
6-1 藥品 63
6-2 儀器 63
6-3 藉由雌二醇 (E2)合成雌二醇醌 (E2Q) 63
6-4 藉由雌二醇醌 (E2Q)對血紅蛋白進行反應 64
6-5 水解血紅蛋白 64
6-6 奈升流速液相層析質譜儀分析E2Q treated Hb條件 65
6-7 胜肽斷裂形式 66
6-8 數據依賴擷取 (Data-dependent acquisition, DDA)分析 66
6-9 相對修飾化程度 (relative extent of modification, EoM) 66
6-10 劑量相關性 (dose-dependency) 67
6-11 血液樣品資訊 67
6-12 從人類血液樣品中萃取血紅蛋白 68
6-13 使用螢光定量萃取出的血紅蛋白 68
6-14 水解真實樣品之血紅蛋白 68
6-15 統計分析 69
6-16 藉由Mgx對血紅蛋白進行反應 69
6-17 藉由MDA對血紅蛋白進行反應 69
6-18 奈升流速液相層析質譜儀分析MDA及Mgx treated Hb條件 69
七、 結果與討論 71
7-1 調整分析梯度 71
7-2 鑑定雌二醇醌在人類血紅蛋白所形成的修飾 72
7-3 定性修飾胜肽及計算胜肽修飾化程度 (EoM) 75
7-4 劑量相關性 (dose dependency) 80
7-5 乳癌患者與健康受試者樣品資訊 83
7-6 乳癌患者與健康受試者血紅蛋白修飾與統計分析結果 83
7-7 丙二醛和離胺酸的反應81 88
7-8 甲基乙二醛和離胺酸的反應81 89
7-9 人類血紅蛋白與Mgx及MDA反應所得K+72修飾 89
7-10 人類血紅蛋白與MDA反應所得11K+72修飾之peak位置 91
7-11 人類血紅蛋白水解 92
7-12 人類血紅蛋白與MDA進行劑量反應 (dose-dependency) 93
八、 結論 95
九、 參考文獻 96
十、 附圖 103

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