臺灣博碩士論文加值系統

乳酸(lactate, LA)與3-羥基丁酸(3-hydroxybutyrate, 3HB)的鏡像異構物具有不同的生理活性，在諸多的研究中指出，LA及3HB鏡像異構物的變化與腎損傷具有關聯性。為探討在免疫性腎損傷進程下LA與3HB的鏡像異構物的變化，本研究採用免疫性腎臟損傷的小鼠加速型腎毒血清(nephrotoxic serum, NTS)腎炎模型，分析NTS注射前正常小鼠(Normal)及IgG小鼠(Control)、注射後七天(Day 7)與注射後十四天(Day 14)三個時間的尿液以及血清。血清及尿液中的LA以二維HPLC分析，D-LA在Normal組血清中濃度為51.23 ± 7.47 μM，尿液中濃度為100.8 ± 37.7 μmole/g creatinine，血清及尿液中D-LA與Control、Day 7、Day 14組均較Normal組顯著上升2倍以上，血清中的L-LA與D-LA趨勢相同，但上升幅度少於1.5倍，尿液中的L-LA則到Day 14組才有顯著上升。血清中的D,L-3HB以二維HPLC分析，其濃度與腎臟損傷無明顯相關，但L-3HB/D-3HB的比值於Control、Day 7、Day 14組均約為Normal組的一半，尿液中3HB無法以二維HPLC分離，故本研究進一步採用以逆相管柱KSAARP、混合作用管柱KSAAMX-001和鏡像管柱Chiralpak AD-H的三維HPLC分析，結果顯示尿液中3HB的變化趨勢與血清相同。由IgG造成細胞發炎損傷之Control組即可觀察到D-LA顯著上升，L-3HB/D-3HB比值則顯著下降，此可能為細胞對能量的需求改變LA與3HB的鏡像異構物表現，因此兩者的鏡像異構物具有潛力做為監測疾病狀態的生物指標。

The enantiomers of lactate (LA) and 3-hydroxybutyrate (3HB) have different bioactivity. From many studies, the relationship between them and kidney damage is found. In order to know the change of LA and 3HB enantiomers in the progression of immune nephritis, the accelerated mice model of nephrotoxic serum (NTS) nephritis was used. The serum and urine at sample were collected three time points, normal mice (Normal) and IgG mice (Control) before NTS injection, 7 days after NTS injection (Day 7) and 14 days after NTS injection (Day 14). LA in the serum and the urine and 3HB in the serum were analyzed by two dimensional HPLC (2D-HPLC). D-LA concentration in normal group were 51.23 ± 7.47 μM in serum and 100.8 ± 37.7 μmole/g creatinine in urine. D-LA concentration in control, day 7 and day 14 groups in the serum and urine were two times higher than those in normal group. The change of L-LA in serum was similar to D-LA in serum, but only increased less than 1.5 times. In the urine, L-LA concentration only in day 14 group significantly increased comparing to that in normal group. D-3HB and L-3HB in serum didn’t show any significant relationship with kidney damage. However, L-3HB/D-3HB ratio in control, day 7 and day 14 groups in the serum and urine were almost half of that in normal group. On the other hand, 3HB in urine cannot be separated by 2D-HPLC. Thus, a 3D-HPLC system which was consisted of a reverse phase column KSAARP, a mix-mode column KSAAMX-001 and a chiral column chiralpak AD-H was used for urinary 3HB determination. The concentration and ratio of 3HB enantiomers in the urine showed similar trend to those in the serum. In the control group with IgG induced cell inflammation, D-LA concentration increased and L-3HB/D-3HB ratio decreased significantly. The alteration of concentration and ratio of the enantiomers are thought to relate to the change of energy demand. In conclusion, the enantiomers of LA and 3HB could be potential biomarkers for some pathological states.

目錄
目錄 I
圖表目錄 IV
表格目錄 VI
縮寫表 VII
摘 要 IX
Abstract X
第一章 緒論 1
第二章 背景 2
第一節 乳酸 2
2.1.1 乳酸的結構與特性 2
2.1.2 乳酸之生成與代謝 2
2.1.3 D-乳酸之相關疾病 4
第二節 3-羥基丁酸 6
2.2.1 酮體簡介 6
2.2.2 3-羥基丁酸之結構與特性 8
2.2.3 3-羥基丁酸之生理作用與相關疾病 9
第三節 甲基乙二醛 10
2.3.1 甲基乙二醛的結構與特性 10
2.3.2 甲基乙二醛的來源與代謝 10
第四節 腎毒血清腎炎模型 12
2.4.1 腎毒血清腎炎模型 12
2.4.2 「加速型」腎毒血清腎炎模型 12
第三章 研究目的 14
第四章 實驗材料、儀器與方法 15
第一節 實驗試藥、耗材及儀器 15
4.1.1 實驗試藥 15
4.1.2 耗材 16
4.1.3 儀器 16
第二節 動物實驗 17
4.2.1 兔子Immunoglobulin G與Nephrotoxic serum nephritis備製 17
4.2.2 加速型NTS腎炎小鼠模型實驗流程 18
4.2.2.1 尿液收集 19
4.2.2.2 動物犧牲方法 19
4.2.2.3 血清備製 19
4.2.2.4 組織包埋切片與Hematoxylin-Eosin染色 19
第三節 實驗方法 20
4.3.1 D,L-lactate與D,L-3-hdroxybutyrate之分析方法概要 20
4.3.2 血清及尿液中D,L-lactate之分析方法 22
4.3.2.1 生物檢品前處理 22
4.3.2.2 螢光衍生化條件 22
4.3.2.3 Column-switching HPLC 系統 22
4.3.3 血清中D,L-3-hydroxybutyrate之分析方法 24
4.3.2.1 生物檢品前處理 24
4.3.2.2 螢光衍生化條件 24
4.3.2.3 二維Column-switching HPLC 系統 24
4.3.4 尿液中D,L-3-hydroxybutyrate之分析方法 26
4.3.4.1生物檢品前處理 26
4.3.4.2螢光衍生化條件 26
4.3.4.3 三維HPLC系統 26
4.3.5 血清及尿液中甲基乙二醛之分析方法 28
4.3.5.1 螢光衍生化條件 28
4.3.5.2 HPLC系統條件 29
4.3.6 蛋白質定量 29
4.3.7 血清及尿液中Creatinine分析方法 30
4.3.7.1生物檢品前處理 30
4.3.7.2 HPLC系統條件 30
4.3.8 組織損傷程度的量化指標 31
第四節 統計方法 31
第五章 實驗結果 32
第一節 三維HPLC對小鼠尿液分析條件優化 32
5.1.1 第三維移動相調整 32
5.1.2 三維HPLC乳酸與3-羥基丁酸精確度測試 36
5.1.3 三維HPLC小鼠尿液乳酸與3-羥基丁酸回收率測試 37
第二節 病理切片與基礎生化數值檢驗 38
5.2.1 小鼠腎臟組織切片Hematoxylin-Eosin染色 38
5.2.2 小鼠尿液蛋白質定量分析結果 41
5.2.3 尿液Creatinine定量分析結果 42
5.2.4小鼠血清Creatinine定量分析結果 43
第三節 3-羥基丁酸 44
5.3.1 標準品與NTS小鼠3-羥基丁酸二維HPLC層析圖 44
5.3.2 標準品與NTS小鼠3-羥基丁酸三維HPLC層析圖 47
5.3.3 NTS小鼠尿液中3-羥基丁酸鏡像異構物定量分析結果 50
5.3.4 NTS小鼠血清中3-羥基丁酸鏡像異構物定量分析結果 52
第四節 乳酸 54
5.4.1標準品與NTS小鼠乳酸二維HPLC圖譜 54
5.4.2 NTS小鼠尿液中乳酸鏡像異構物定量分析結果 59
5.4.3 NTS小鼠血清中乳酸鏡像異構物定量分析結果 61
第五節 甲基乙二醛 63
5.5.1標準品與NTS小鼠甲基乙二醛HPLC圖譜 63
5.5.2 NTS小鼠尿液中甲基乙二醛定量分析結果 66
5.5.3 NTS小鼠血清中甲基乙二醛定量分析結果 67
第六章 討論 68
6.1 加速型NTS模型進程的誘導狀況 68
6.2 NTS小鼠模型血清與尿液中3-羥基丁酸定量分析結果 68
6.3 NTS小鼠模型血清與尿液中乳酸定量分析結果 70
6.3 NTS小鼠模型血清與尿液中甲基乙二醛定量分析結果 71
6.4 NTS小鼠模型中D-乳酸與甲基乙二醛關聯 72
6.5 NTS小鼠模型中乳酸與3-羥基丁酸的關聯 72
第七章 結論 74
參考文獻 75

圖目錄
Figure 1 乳酸的鏡像異構物結構 2
Figure 2 Glyoxalase system 3
Figure 3 酮體的生成路徑 7
Figure 4 3-羥基丁酸的鏡像異構物結構 8
Figure 5 甲基乙二醛之化學結構 10
Figure 6 甲基乙二醛的來源與代謝 11
Figure 7 加速型NTS腎炎小鼠模型進程動物實驗設計時間軸 18
Figure 8 乳酸與3-羥基丁酸藉由NBD-PZ螢光衍生化機轉 21
Figure 9 二維Column-switching HPLC系統 23
Figure 10 以DDP衍生化甲基乙二醛 28
Figure 11. 標準品與小鼠尿液檢品在三維HPLC的第三維層析圖 32
Figure 12. 不同移動相下第三維中小鼠尿液LA的層析圖 33
Figure 13 EtOH/MeCN混合移動相下D-LA跟L-LA與中間未知物的Resolution 34
Figure 14 NTS模型小鼠腎臟組織切片Hematoxylin-Eosin染色 39
Figure 15 組織切片損傷量化 40
Figure 16 分析3-羥基丁酸標準品鏡像異構物的二維HPLC層析圖 44
Figure 17 分析Normal小鼠血清中3-羥基丁酸的二維HPLC層析圖 45
Figure 18分析損傷組小鼠血清中3-羥基丁酸的二維HPLC層析圖 46
Figure 19 3-羥基丁酸標準品的三維HPLC層析圖 47
Figure 20 三圍HPLC分析NTS模型Normal小鼠尿液3-羥基丁酸之層析圖 48
Figure 21三圍HPLC分析NTS模型損傷組小鼠尿液3-羥基丁酸之層析圖 49
Figure 22 NTS小鼠尿液中3-羥基丁酸鏡像異構物分析結果 51
Figure 23 NTS小鼠血清中3-羥基丁酸鏡像異構物定量分析結果 53
Figure 24分析乳酸標準品鏡像異構物的二維HPLC層析圖 54
Figure 25分析Normal小鼠尿液中乳酸的二維HPLC層析圖 55
Figure 26分析損傷組小鼠尿液中乳酸的二維HPLC層析圖 56
Figure 27分析Normal小鼠血清中乳酸的二維HPLC層析圖 57
Figure 28分析損傷組小鼠血清中乳酸的二維HPLC層析圖 58
Figure 29 NTS小鼠尿液中乳酸鏡像異構物定量分析結果 60
Figure 30 NTS小鼠血清中乳酸鏡像異構物定量分析結果 62
Figure 31 甲基乙二醛標準品的HPLC層析圖 63
Figure 32 NTS小鼠模型尿液中甲基乙二醛的HPLC層析圖 64
Figure 33 NTS小鼠模型血清中甲基乙二醛的HPLC層析圖 65
Figure 34 NTS小鼠尿液中甲基乙二醛定量分析結果 66
Figure 35 NTS小鼠血清中甲基乙二醛定量分析結果 67
Figure 36 細胞激素對3-羥基丁酸生成的影響 69
Figure 37 L-3-羥基丁酸的可能來源 70
Figure 38 乳酸與3-羥基丁酸關聯代謝路徑 73
Figure 39假設NTS小鼠模型中乳酸與3-羥基丁酸關聯影響 73

表格目錄
Table 1組織損傷程度量化表 31
Table 2. 精確度測試兩次進樣的D,L-LA和DL-3HB螢光強度及兩次的誤差 36
Table 3. 三維HPLC小鼠尿液乳酸與3-羥基丁酸回收率測試 37
Table 4 NTS小鼠尿液中的蛋白質含量 41
Table 5 NTS小鼠尿液中的Creatinine含量 42
Table 6 NTS小鼠血清中Creatinine定量分析結果 43
Table 7 NTS小鼠尿液中3-羥基丁酸鏡像異構物分析結果 50
Table 8 NTS小鼠血清中3-羥基丁酸鏡像異構物分析結果 52
Table 9 NTS小鼠尿液中乳酸鏡像異構物定量分析結果 59
Table 10 NTS小鼠血清中乳酸鏡像異構物定量分析結果 61
Table 11 NTS小鼠尿液中甲基乙二醛定量分析結果 66
Table 12 NTS小鼠血清中甲基乙二醛定量分析結果 67

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