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研究生:廖冠晴
研究生(外文):LIAO, KUAN-CHING
論文名稱:利用奈升流速液相層析奈電噴灑游離串聯式質譜儀分析 (1)DNA與尿液中的加成產物5-醛基去氧脲苷 (2)乳癌患者血紅蛋白中的氯化、硝化、亞硝化以及氧化修飾
論文名稱(外文):NanoLC-NSI/MS/MS Analyses of (1) 5-Formyl-2’-deoxyuridine in DNA and Urine and (2) Chlorination, Nitration, Nitrosylation, and Oxidation in Hemoglobin of Breast Cancer Patients
指導教授:陳皓君
指導教授(外文):Chen, Hauh-Jyun Candy
口試委員:陳頌方陳彥伶
口試日期:2020-09-29
學位類別:碩士
校院名稱:國立中正大學
系所名稱:化學暨生物化學研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2020
畢業學年度:109
語文別:中文
論文頁數:88
中文關鍵詞:血紅蛋白轉錄後修飾乳癌DNA加成產物
外文關鍵詞:Hemoglobinpost-translational modificationbreast cancerDNA adduct
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氧化壓力是由於活性氧物種 (Reactive Oxygen Species, ROS) 與抗氧化防禦機制(Antioxidant defenses) 之間的不平衡所產生的,目前已知氧化壓力會導致DNA損傷與導致致癌基因的突變,進而導致癌症的產生。5-醛基去氧尿苷 (5-Formyl-2’-doexyuridine, 5-FodU) 是由ROS攻擊所產生的去氧胸腺嘧啶核苷DNA加成產物。本實驗主要是在合成同位素[13C1,15N2]5-FodU,並且利用奈升流速奈電噴灑游離串聯式質譜儀來進行分析DNA與尿液中的5-FodU的含量,在分析的DNA樣品我們採用小牛胸腺DNA以及人類胎盤DNA來進行分析。另外還比較了兩種DNA水解的方法。利用此分析條件可以在小牛胸腺DNA以及人類胎盤DNA中偵測到每108個核苷酸中有5.7以及9.5個5-FodU。在分析尿液樣品的部分,分析了5位乳癌患者以及5位健康受試者的尿液,5-FodU在乳癌患者以及健康受試者尿液中的平均含量分別為9.4 (pg/ml) 以及10.4 (pg/ml)。
人體內有許多內源性的活性氧物種,在這之中,例如活性氯物種 (Reactive Chlorine Species) 以及活性氮氧物種 (Reactive Nitrogen Oxide Species) 會產生次氯酸 (hypochlorous acid) 以及過氧亞硝酸鹽 (peroxynitrite),這兩種分別為生物體內的氯化試劑以及硝化試劑,分別會在蛋白質上形成3-氯酪胺酸以及3-硝基酪胺酸。在本實驗,從新鮮血液中分離出人類血紅蛋白,再用胰蛋白酶水解,然後使用選擇反應監控模式下利用奈升流速串聯式質譜儀來進行修飾化程度的分析。使用Mann-Whitney U-test來做統計計算,發現乳癌患者之血紅蛋白在α-Tyr-24上的氯化以及亞硝化修飾、α-Tyr-42上的硝化以及α-Tyr-130上的硝化以及氯化修飾高於健康受試者,具有統計學上的差異 ( p < 0.05 )。除此之外還使用Spearman統計分析這些修飾位置與年齡以及BMI的相關性。另外還探討了人類血紅蛋白的保存方式,來比較以溶液的形式保存或者是以粉末的形式保存樣品的差異。排除這些因素,推測在人類血紅蛋白中α-Tyr-42位置上的硝化以及β-Tyr-130位置上的氯化以及硝化修飾程度與乳癌有關聯性,活性氯物種以及活性氮氧物種可能在乳癌的發展中扮演著重要的角色。

Oxidative stress is a disturbance in the balance between the production of reactive oxygen species (ROS) and antioxidant defenses. Oxidative stress is known to cause DNA damage and mutations of tumor suppressor genes that are critical initial events in carcinogenesis. 5-formyl-2’-deoxyuridine (5-FodU) is a major thymidine lesion generated by ROS, in addition, in vitro and in vivo replication studies showed that 5-FodU is mutagenic. the goal of this experiment is synthesized the isotope [13C1,15N2]5-FodU, and analyze the content of 5-FodU in DNA sample by using nanoLC-NSI/MS/MS. We chose the calf thymus DNA and human placental DNA for analysis. In addition, also compare the two different DNA enzyme hydrolysis method. Using this analysis condition, 5.7 and 9.5 of 5-FodU per 108 nucleotides can be detected in calf thymus DNA and human placantal DNA. Analyzed the urine samples of 5 breast cancer patients and 5 healthy subjects. the average content of 5-FodU in the urine of breast cancer patients and healthy subjects was 9.4 (pg/ml) and 10.4 (pg/ml), respectively.
Human are exposed to endogenous reactive oxygen species. Among them, reactive halogen species and reactive nitrogen oxide species, such as hypochlorous acid and peroxynitrite, are biological chlorinating and nitrating agent of biomolecules, leading to form 3-chlorotyrosine and 3-nitrotyrosine, respectively, formation on proteins. 3-Nitrotyrosine has been detected in vivo under several pathophysiological conditions, including breast cancer. Studies show that the concentrations of 3-Nitrotyrosine in plasma proteins and platelets were significantly elevated in breast cancer patients. In this study, human hemoglobin was isolated from fresh blood, digested with trypsin, and the modified peptides were measured by nanoflow liquid chromatography nanospray ionization tandem mass spectrometry (nanoLC-NSI//MS/MS) under the selected reaction monitoring (SRM) mode. The relative extents of chlorination at α-Tyr-24 and α-Tyr-130, nitrosylation at α-Tyr-24, and nitration at α-Tyr-42 and α-Tyr-130 are significantly higher in globin of breast cancer patients (n = 25) than in healthy subjects (n = 25) (p <0.05). Additionally, the extents of these modifications are not correlated with the body-mass index (BMI). In addition, we also discussed the storage types of human hemoglobin, like solvent or powder. Excluding these factors, the extent of nitration at the α-Tyr-42 and the chlorination and nitration at the β-Tyr-130 in human hemoglobin may related to breast cancer. The results indicated that the reactive nitrogen oxide species and reactive chlorine species might play an important role in the pathology of breast cancer.

目錄
圖目錄 V
表目錄 VIII
總摘要 1
Abstract 2
Part 1. 4
摘要 5
第一章、緒論 6
1-1. 去氧核醣核酸(DNA)介紹 6
1-2. DNA加成產物介紹 8
1-3. 氧化壓力 9
1-4. 活性氧化物質 10
1-5. 去氧胸腺嘧啶的氧化產物相關文獻介紹 11
1-6. 研究動機 14
第二章、藥品、儀器與實驗方法 15
2-1. 藥品 15
2-2. 儀器 15
2-3. 材料 15
2-4. 合成5-HMdU標準品 16
2-5. 利用Strata-X固相萃取管柱收集5-HMdU標準品 16
2-6. 合成5-FodU標準品 17
2-7. 利用Strata-X固相萃取管柱收集5-FodU標準品 17
2-8. 5-FodU之衍生化 18
2-9. 合成[13C1,15N2]5-FodU標準品 18
2-10. HPLC分析條件 19
2-11. nanoLC-NSI/MS/MS 分析條件 20
2-12. 萃取人類血液DNA 21
2-13. DNA 酵素水解方法 22
2-14. 利用Strata-X以及HPLC收集尿液中的5-FodU 23
2-15. SCX-HPLC/UV定量肌酸酐之方法 23
2-16. 分析尿液之準確度 24
第三章、實驗結果與討論 25
3-1. 合成與純化5-HMdU 25
3-2. 合成與純化5-FodU 28
3-3. 5-FodU衍生化及純化之結果探討 31
3-4. 合成與純化[13C1,15N2]5-FodU標準品 34
3-5. 5-FodU與[13C1,15N2]5-FodU碰撞能量最佳化條件 36
3-6. 利用nanoLC-NSI/MS/MS分析[13C1,15N2]5-FodU 37
3-7. [13C1,15N2]5-FodU標準曲線 38
3-8. 分析小牛胸腺DNA與人類胎盤DNA中的5-FodU 39
3-9. SCX-HPLC/UV定量人類尿液中肌酸酐的含量 44
3-10. 分析尿液中的5-FodU 46
3-11. 分析尿液之準確度 50
第四章、結論 51
Part 2 52
摘要 53
第五章、緒論 54
5-1. 血紅蛋白之介紹 54
5-2. 轉譯後修飾 ( Post-translational modifications, PTM ) 55
5-3. 氧化壓力 55
5-4. 蛋白質的氯化以及硝化 56
5-5. 乳癌介紹及相關文獻 58
5-6. 研究動機 59
第六章、藥品、儀器與實驗方法 60
6-1. 藥品 60
6-2. 儀器 60
6-3. 實驗方法 61
6-4. 奈升流速液相層析質譜儀之分析條件 62
6-5. 血液樣品資料 64
6-6. 比較血紅蛋白保存方式之樣品資訊 66
第七章、實驗結果與討論 67
7-1. 鑑定胜肽上的修飾 67
7-2. 相對定量血紅蛋白之氯化、硝化、亞硝化及氧化修飾 68
7-3. 分析乳癌患者與健康受試者血液中血紅蛋白之氯化、硝化、亞硝化以及氧化之修飾程度 69
7-4. 統計分析之結果 73
7-5. 探討人類血紅蛋白之保存形式 78
第八章、結論 81
參考文獻 82


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