臺灣博碩士論文加值系統

海平面下200公尺深、陽光無法穿透和病原體稀少的海洋深層水含有豐富的礦物質，尤其鎂、鈣和鉀等微量元素均已被認定與心血管疾病預防有關，同時證實可以降低因高膽固醇血症所引起的心肌肥厚和凋亡。已知心臟病是糖尿病患者的嚴重併發症與死因。文獻更指出糖尿病會透過細胞凋亡的方式造成心臟傷害，甚至引發心臟衰竭，顯示糖尿病併發的心臟疾病具有高度的致命性。本實驗採用streptozocin (STZ, 65mg/kg)破壞β細胞，使胰島素無法分泌，造成血糖升高而誘導成糖尿病鼠。並進一步探討海洋深層水防治糖尿病併發心肌肥厚和凋亡的分子訊息機轉。治療的方式則分別管餵STZ糖尿病鼠 1X(37 mg/kg/day）、2X(74 mg/kg/day）、3X(111 mg/kg/day)不同倍數的海洋深層水4週。實驗顯示海洋深層水不但顯著降低糖尿病鼠之血糖更明顯減低死亡提升糖尿病鼠之存活率，並以心肌超音波(ECHO)、組織染色切片、TUNEL assay及西方墨點法(western blotting)分析，探討心肌收縮功能及相關訊息傳遞蛋白質表現。ECHO結果顯示，海洋深層水幾乎完全恢復糖尿病鼠之心臟射出率及收縮率，同時組織染色切片(H&E Stain)，顯示糖尿病鼠心肌細胞紋理雜亂與細胞間隙拉大的狀態，在海洋深層水給輿具有顯著回復的效果，並以2X海洋深層水餵食回復狀態最接近控制組。在TUNEL assay中證實糖尿病會造成細胞凋亡，促使染色體DNA雙股大量斷裂，但給予2X海洋深層水的動物心肌組織中細胞DNA斷裂現象明顯被抑制，降低凋亡的保護效果最為明顯。在以西方墨點法(western blotting)測量生化訊息蛋白中，發現海洋深層水餵食不但抑制TNF-α-NFkB發炎訊息途徑更有效擷抗IL6-MEK5-ERK5及IGFIIR-Gaq-Calcineurin-NFAT3心肌肥大訊息途徑。同時糖尿病的組別中，心肌凋亡包括death-dependent和mitochondria-dependent 路徑，甚至uPA-TIMP-MMPs纖維化途徑。心肌細胞凋亡及纖維化的蛋白質表現量和對照組相比較皆有顯著的上升。而海洋深層水餵食的組別凋亡及纖維化相關路徑蛋白質表現量皆明顯下降。而在survival訊息傳遞路徑中蛋白質的表現量，糖尿病的組別明顯的比對照組低。但在海洋深層水餵食的組別，蛋白質的表現量皆有明顯的回升。實驗結果證明，海洋深層水餵食可有效的抑制心肌細胞凋亡及纖維化相關蛋白表現，並促進survival的相關蛋白表現量，成功的保護了心肌細胞免於走向細胞凋亡的途徑。實驗數據同時顯示海洋深層水主要透過保護粒線體功能蛋白及粒線體完整性來回復糖尿病鼠心肌功能，並提高存活率。因此本篇的實驗建議適當飲用海洋深層水以保護心肌粒線體功能及完整性來預防並治療由糖尿病引起的心臟疾病。

The definition of deep sea water (DSW) is the water exists 200m under the sea level where sun cannot penetrate, and it is rich in minerals and lack of pathogens. Particularly, the consumption of minerals in DSW such as Magnesium, Calcium, and Potassium has been considered to be associated with the prevention of cardiovascular disease and shown to reduce the hypercholesterolemia-induced myocardial hypertrophy and apoptosis. Heart disease is serious complication and lethal to diabetic patients. Many studies revealed diabetes has very highly lethal of cardiac disease and also pointed out hyperglycemia-induced cell apoptosis to causes heart damage in diabetes patients leading to heart failure. In this study, a failed rat model was set up by streptozocin (65mg/kg) injection which destroyed the beta cells to secret insulin failed and cause high blood glucose. Furthermore, experiments were designed to explore the mechanism of DSW further, prevention of diabetes complicated by cardiac hypertrophy and apoptosis molecules message. Different doses gavages treatment of DSW administration, 1X (37 mg / kg / day), 2X (74 mg / kg / day), 3X (111 mg / kg / day), were applied for four weeks to diabetic rats. The experimental results showed that DSW is not only significantly reduce glucose in diabetic rats, but also significantly reduced death and enhance the survival rate of diabetic rats. Cardiac ultrasound (ECHO), tissue staining, TUNEL assay, and Western blotting assay were used to investigate the myocardial contractile function and related signaling protein expression. As the results shown in ECHO, DSW is almost completely restore the injection rate and shrinkage in the heart of diabetic rats. Tissue H&E Stain shown the DSW has a significant response to public opinion, and 2X DSW feeding can return back to the situation similar to control group. In the measurement of biochemical messages protein in Western blot analysis pointed out the feeding of DSW will inhibit TNF-alpha of NFkB inflammatory signaling pathways and effectively capture the anti-IL6 coding for MEK5-of ERK5 and IGFIIR-Gaq-Calcineurin-NFAT3 cardiac hypertrophy signaling pathway. Group of diabetes, myocardial apoptosis, including death-dependent and mitochondrial-dependent path even fibrosis way of uPA-of TIMP-of MMPs. Cardiac myocyte apoptosis and fibrosis protein expressions are both significant increase compared with control group, and reversed in DSW feeding groups. The protein expression in diabetes group is significantly lower than the control group in the survival pathway and rebound in the DSW feeding group. Experimental results show that the feeding of deep-sea water can be an effective inhibition of cardiomyocyte apoptosis and fibrosis-related protein expression, and to promote the survival-related protein expression and protect myocardial cells from the pathway towards apoptosis. The experimental data also showed that DSW can restore the myocardial function in diabetic rats, and improve survival the protection of mitochondrial function protein and mitochondrial integrity. Above this experimental evidences suggested, the appropriate drinking DSW can protect myocardial mitochondrial function and treat the heart disease caused by diabetes.

目錄 I
摘要 IX
Abstract XI
表目錄 XIII
圖目錄 XIV
縮寫表 XVII
第一章 前言 1
1.1 海洋深層水(Deep sea water , DSW) 1
1.1.1 海洋深層水的定義 1
1.1.2 海洋深層水的特性 2
1.1.3 海洋深層水所含的礦物質 3
1.2 硫酸鎂(Magnesium sulfate , MgSO4) 5
1.2.1 鎂在人體含量與分佈 5
1.2.2 鎂的生理與生化功能 5
1.2.3 鎂與輔基 5
1.2.4 鎂與骨骼 5
1.2.5 鎂與能量 6
1.2.6 離子恆定與肌肉收縮 6
1.2.6.1 在心肌細胞中: 6
1.2.6.2 在肌肉組織中: 6
1.2.6.3 血管壁肌肉中: 6
1.2.7 鎂與心臟 7
1.2.8 鎂與糖尿病 7
1.2.9 鎂的缺乏與過量 7
1.3 心血管疾病(Cardiovascular Disease；CVD) 8
1.4 糖尿病(Diabetes Mellitus ，DM) 10
1.5 心肌細胞的特性與訊息路徑 13
1.6 發炎(Inflammation) 14
1.7 心肌肥大(Hypertrophy) 15
1.7.1 心肌細胞肥大型態 15
1.7.1.1 向心性心臟肥大(Concentric hypertrophy)：心肌細胞寬度會擴大，而導致左心室壁增厚。 16
1.7.1.2 離心性肥大(Eccentric hypertrophy)：心肌細胞長度會拉長，而導致心室壁擴張。 16
1.7.2 肥大與MAPKs pathway 17
1.8 心肌細胞程序性凋亡(Cardiomyocyte apoptosis) 18
1.8.1 Fas 依賴凋亡路徑(Fas depend death pathway) 19
1.8.2 粒線體凋亡路徑(Mitochondrial apoptosis pathway) 19
1.8.3 存活(Survival) 21
1.9 纖維化(Fibrosis) 22
1.9.1 心肌(臟)功能衰竭 (Cardiac Dysfunction) 與基質金屬蛋白酵素(Matrix metalloproteinases; MMPs) 22
1.9.2 MMPs的調控： 22
第二章 研究動機與實驗架構 25
2.1.1 研究動機 25
2.1.2 實驗設計 27
第三章 研究材料與方法 29
3.1 研究材料Table 3 29
3.1.1 實驗材料 29
3.1.2 實驗儀器 32
3.2 實驗方法 33
3.2.1 海洋深層水來源 33
3.2.2 樣品組織來源之第一型糖尿病動物模型的建立 33
3.2.3 大白鼠 34
3.2.4 血糖檢測 34
3.2.5 基質金屬蛋白質脢活性測試 (Gelatin Zymography) 35
3.2.6 採集心臟 35
3.2.7 組織研磨萃取-分離細胞質（cytosol）與粒腺體（mitochondria） 35
3.2.8 蛋白質濃度測定( Lowry protein assay ) 35
3.2.9 心臟組織切片（Histological analysis） 36
3.2.10 H＆E（hematoxylin and eosin）染色 37
3.2.11 心臟凋亡組織染色TUNEL assay (Terminal deoxynucleotidyl Transferase (TdT)-mediated dUTP-biotin nick endlabeling) 37
3.2.12 心臟纖維化組織染色(Masson Trichrome stain) 38
3.2.13 西方墨點法(Western blotting) 39
3.2.14 心臟及肝臟蛋白質萃取及各訊息路徑偵測 40
3.2.15 統計方法 40
第四章 結果 41
4.1 巨觀變化 41
4.1.1 存活率與死亡率 41
4.1.2 毛髮外觀 42
4.2 生化指標(Biochemical indicators) 43
4.2.1 血糖(Blood sugar) 43
4.2.2 體重(Body weight) 43
4.3 心臟功能(Cardiac function) 45
4.4 缺氧指標蛋白(Hypoxia protein) 47
4.5 分子生物機制 48
4.5.1 發炎路徑 48
4.5.1.1 IHC 48
4.5.1.2 IF 48
4.5.1.3 發炎路徑之發炎指標蛋白(TNF-α、i-NOS) 49
4.5.1.4 發炎路徑之MAPK family上游發炎指標蛋白(p-ERK1/2、p-JNK、p-P38) 49
4.5.1.5 發炎路徑之下游NFκB發炎指標蛋白(p-IKKα/β、p-IκBα、p-NFκB) 50
4.5.2 肥大路徑 51
4.5.2.1 心臟重量 51
4.5.2.2 心臟橫切片 53
4.5.2.3 H＆E stain 53
4.5.2.4 肥大路徑之指標蛋白(BNP) 54
4.5.2.5 離心性肥大(Eccentric Hypertrophy)路徑之指標蛋白(IL-6、p-MEK-5、STAT3) 54
4.5.2.6 向心性肥大(Concentric Hypertrophy )路徑之上游指標蛋白(IGF-2、p-PKCα、CaMK-Ⅱ) 55
4.5.2.7 向心性肥大(Concentric Hypertrophy )路徑之下游指標蛋白(p-ERK、p-JNK、p-P38、NFATc-3、GATA-4) 56
4.5.3 凋亡 57
4.5.3.1 TUNEL( Terminal transferase dUTP Nick End Labeling) 57
4.5.3.2 Fas依賴凋亡路徑(Fas dependent apoptosis Pathway)之指標蛋白 (Fas、FADD、Caspase-8、Cleaved caspase-3) 57
4.5.3.3 粒線體凋亡路徑(Mitochondrial apoptosis pathway)之指標蛋白 (Bid、Bad、Bak、Cytochrome C 、Caspase-3) 58
4.5.4 存活 60
4.5.5 纖維化反應(Fibrosis) 61
4.5.5.1 膠質纖維染色（Masson’s trichrome staining） 61
4.5.5.2 纖維化TGFβ-1路徑之指標蛋白(TGFβ-1、MEK-1、CTGF) 61
4.5.5.3 纖維化TGF-2路徑之指標蛋白(t-PA、MMP-2、MMP-9、TGF-2) 62
第五章 討論與結論 63
5.1 討論 63
5.1.1 大鼠生理觀察 63
5.1.1.1 巨觀變化 63
5.1.1.2 生化指標 63
5.1.1.3 心臟功能(Cardiac function) 63
5.1.1.4 缺氧指標蛋白(Hypoxia protein) 64
5.1.2 分子生物機制 66
5.1.2.1 發炎反應 (Inflammation)透過影饗發炎路徑的一些蛋白質如：TNF-α、p-ERK、p-JNK、p-P38、p-IKKα/β、p-IκBα、p-NFκB p65探討 66
5.1.2.2 透過影饗發炎下游路徑的一些蛋白質如p-ERK、p-JNK、p-P38、p-IKKα/β、p-IκBα、p-NF-K?? p65進一步做探討 66
5.1.3 肥大反應（Hypertrophy） 68
5.1.3.1 在心臟整體功能之觀察與比較 68
5.1.3.2 糖尿病鼠與餵食硫酸鎂及不同倍數的海洋深層水之心臟橫切面圖之心肌變化 69
5.1.3.3 心臟縱切面圖之心肌變化 69
5.1.3.4 心臟組織中心肌細胞走向病理性肥大的指標ANP、BNP 70
5.1.3.5 IL-6、p-MEK-5、STAT3途徑會誘導DM Rat的心肌細胞走向肥大 71
5.1.3.6 IGF-2、p-PKCα、CaMKⅡ途徑會誘導DM Rat的心肌細胞走向肥大 71
5.1.3.7 NFATc3、GATA-4途徑誘導Obese Zucker Rat心肌細胞肥大 72
5.1.4 凋亡反應(Apoptosis)與存活反應(Surivial) 74
5.1.4.1 TUNEL/DAPI 染色分析 74
5.1.4.2 糖尿病SD Rat亦會透過Fas-death receptor-dependent誘導心肌細胞走向凋亡 74
5.1.4.3 糖尿病SD Rat亦會透過Mitochondrial apoptosis pathway誘導心肌細胞走向凋亡 75
5.1.4.4 觀察Caspases蛋白質的表現情形 75
5.1.4.5 糖尿病的SD Rat會促使心肌對於存活(救援)路徑(Survival)蛋白的影響 76
5.1.5 纖維化反應(Fbrosis) 78
5.1.5.1 Trichron 染色 78
5.1.5.2 觀察TGF-?牷BMEK1、CTGF蛋白質的表現情形 78
5.1.5.3 觀察FGF-2、t-PA、PAI-I蛋白質的表現情形 78
5.1.5.4 觀察MMP、TIMP蛋白質的表現情形 79
5.2 結論 81
5.2.1 糖尿病大鼠餵食硫酸鎂與不同倍數海洋深層水，其各路徑之各蛋白表現量比較 81
5.2.1.1 關於發炎路徑蛋白表現比較 81
5.2.1.2 關於肥大路徑蛋白表現比較 81
5.2.1.3 關於凋亡路徑蛋白表現比較 82
5.2.1.4 關於存活路徑蛋白表現比較 83
5.2.1.5 關於纖維化路徑蛋白表現比較 83
5.2.2 糖尿病大鼠餵食硫酸鎂與不同倍數海洋深層水，其各路徑之蛋白表現量比較 85
5.2.3 總結本實驗相關路徑與總結論 89
5.2.4 研究未來之發展前景與方向 92
第六章 實驗結果圖 93
6.1 巨觀變化 93
6.2 生化指標(Biochemical indicators) 95
6.3 心臟功能(Cardiac function) 97
6.4 分子生物機制 99
第七章 參考文獻 118

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