臺灣博碩士論文加值系統

糖尿病造成男性不孕的發生，主因為氧化壓力及生殖內分泌紊亂，導致精子受損及性腺功能異常。本研究以管花肉蓯蓉萃取物及其主要純化物松果菊苷 (echinacoside, ECH) 探討糖尿病造成男性生殖功能損害之保護功效。細胞實驗以 LC-540 leydig 細胞及 TM3 leydig 細胞視其於糖化終產物 (advanced glycation end products, AGEs) 50 µg/ml 刺激下，給予管花肉蓯蓉 (Cistanche tubulosa) 之有效物質 ECH 下改善其抗發炎、抗氧化以及賀爾蒙分泌能力。ECH 濃度10 µM不會造成 LC-540 及 TM3 毒性，且可清除自由基。LC-540 具有糖化終產物受體 (receptor for advanced glycation end products, RAGE)，其發炎反應可能是透過 AGE-RAGE交互作用活化 NF-κB 導致生殖功能受到損傷，ECH 10 µM 的給予可以改善 AGEs 引起的氧化發炎反應，亦可以增加 StAR、CYP11A1、CYP17A1 及 HSD17β3 蛋白質表現量，顯示睪固酮含量可能被提升。動物實驗以 nicotinamide (230 mg/kg) 及 streptozotocin (65 mg/kg) 誘導糖尿病雄性大鼠配合 45 % 高脂飲食，探討氧化壓力，內分泌調節及造精作用。實驗分組：控制組、糖尿病組、糖尿病管餵 rosiglitazone (RSG) 0.571 mg/kg、管花肉蓯蓉萃取物 (含 ECH 25%) 80、160、320 mg/kg，為期 6 週。結果顯示：三個劑量皆可以改善血糖、胰島素阻抗性，160、320 mg/kg 組明顯改善瘦素阻抗，進而調節 KiSS1、GPR54 mRNA 表現量，增加黃體素及睪固酮的分泌，改善內分泌調節及造精作用，且延緩脂質過氧化，增加抗氧化酵素之活性，及超氧陰離子清除能力，減少氧化壓力。

Hypogonadism and oxidative stress occurs commonly in men with diabetes associated male infertility. KiSS1, GPR54, SIRT1 and SOCS-3 gene are related to metabolism of diabetes, that can regulate the reproductive axis by stimulation on GnRH neurons. Additionally, Cistanche tubulosa is the Chinese herbal medicine have traditionally been used for treatment of impotence, female sterility, and cold sensation in the loins and knees. The aim of this study was to investigate the capability of anti-inflammatory, anti-oxidative, and protective effects on male reproduction of Cistanche tubulosa extract against diabetic rats. In vitro, 10 µM echinacoside (major active material of Cistanche tubulosa extract) significantly inhibited reactive oxidative spices production in advanced glycation end products (AGEs) concentration (50 µg/ml) induced LC-540 cell and TM3 cell. The LC-540 cell has receptor for AGEs (RAGE), and 10 µM echinacoside could not only improve NF-κB activity, that is induced by the interaction of AGE and RAGE, but also significantly increase StAR, CYP11A1, CYP17A1 and HSD17β3 protein experission. In vivo, the model diabetic rat was induced by nicotinamide (230 mg/kg), streptozotocin (65 mg/kg) and 45% hight fat diet.Cistanche tubulosa extract was tested in three doses (80, 160 and 320 mg/kg, p.o daily) for 6 weeks. Besides, rosiglitazone (RSG) administration (0.571 mg/kg) as positive control. The results indicate that Cistanche tubulosa extract administration for 6 weeks improve hyperglycemia, insulin resistance, leptin resistance, and lipid peroxidation in diabetic rats. Besides, it has restored KiSS1, GPR54, SOCS-3, and SIRT1 mRNA expression in the hypothalamus, and recover sex hormone level. In conclusion, not only the antioxidant and anti-inflammatory activities but also steroidogenesis effect of Cistanche tubulosa extract might have contributed for its ability to decrease insulin resistance, leptin resistance and protect male reproduction.

中文摘要 Ι
Abstract II
縮寫表 III
目錄 1
前言 7
第一章、 文獻回顧 9
一、 男性不孕症 9
1. 不孕症現狀 9
2. 男性不孕症診斷 9
3. 男性不孕症分類 9
4. 男性不孕症成因 10
二、 糖尿病 11
1. 糖尿病現況 11
2. 糖尿病分類 11
2.1 糖尿病前期 (prediabetes) 11
2.2 第一型糖尿病 (Type 1 diabetes) 12
2.3 第二型糖尿病 (Type 2 diabetes) 12
2.4 妊娠型糖尿病 (gestational diabetes mellitus, GDM) 12
2.5 其他特異型糖尿病 (other type) 13
3. 糖尿病的診斷標準 13
三、 糖尿病與男性生殖 13
1. 流行病學與動物模式研究 13
2. 糖尿病與氧化壓力 13
3. 糖尿病與生殖內分泌異常 14
3.1 男性生殖內分泌調控：下視丘-腦下垂體-性腺調控軸 (hypothalamic-pituitary-gland, HPG axis) 14
3.2 糖尿病對 KiSS1/ GPR54 系統與生殖內分泌之影響 15
四、 管花肉蓯蓉 16
第二章、 實驗流程 19
細胞實驗 19
動物實驗 20
犧牲後分析項目 21
第三章、 實驗材料 23
一、 材料來源 23
二、 細胞株 23
三、 實驗動物 23
四、 動物飼料 23
五、 藥品 23
六、 儀器設備 26
第四章、 實驗方法 27
一、 細胞實驗 27
1. 細胞培養 27
2. 細胞存活率測定 27
3. 吞噬球呼吸爆 NBT 還原分析法 27
4. 細胞內 ROS 含量 28
5. 蛋白質表現量分析 28
二、 動物實驗 30
1. 第二型糖尿病之誘導與分組 30
2. 實驗動物飼養 31
3. 血液樣品分析 31
3.1 葡萄糖 (glucose) 含量測定 31
3.2 總三酸甘油酯 (total triglyceride) 濃度測定 31
3.3 總膽固醇 (total cholesterol) 濃度測定 32
3.4 胰島素 (insulin) 含量測定 32
3.5 瘦素 (leptin) 含量測定 32
3.6 HOMA-IR 值計算 32
3.7 血漿之脂質過氧化影響 32
3.8 血漿之睪固酮測定 33
3.9 血漿之 LH 濃度 33
3.10 TNF-α、IL-6 濃度測定 33
4. 精子樣品分析 34
4.1 精子樣品收集 34
4.2 精子數目之計算 34
4.3 具活動力精子之計算 34
4.4 異常精子之計算 34
4.5 精子之脂質過氧化程度 35
4.6 NBT 還原法分析 35
5. 睪丸分析 35
5.1 睪丸之脂質過氧化影響 35
5.2 睪丸中抗氧化酵素測定 35
5.3 睪丸型態之組織冷凍切片及染色 36
6. 下視丘分析 36
下視丘之 Kiss1、Gpr54、Socs-3、Sirt1 mRNA 表現量 36
7. 蛋白表現量分析 38
第五章、 統計分析 38
第六章、 結果與討論 41
一、 以體外實驗探討 ECH 對於 LC-540 大鼠 leydig 細胞及 TM3 小鼠 leydig 細胞之生殖功能 41
1. ECH、CTE、Resveratrol (RES)、Trolox 抗氧化能力比較 41
2. ECH 對 LC-540 leydig 細胞及 TM3 leydig 細胞存活率探討 41
3. AGEs 對 LC-540 leydig 細胞及 TM3 leydig 細胞存活率探討 41
4. ECH 對 AGEs 誘發超氧陰離子之 NBT 還原能力試驗 42
5. ECH 抑制 AGEs 誘發胞內 ROS 產生之探討 42
6. ECH 抑制 AGEs 誘發 LC-540 leydig 細胞的 RAGE 活化 NF-κB 反應 42
7. ECH 抑制 AGEs 誘發 LC-540 leydig 細胞睪固酮生成路徑異常 42
二、 以體內實驗探討 CTE 對於 STZ-NA誘導糖尿病雄性大白鼠合併高脂飲食之生殖功能 44
1. CTE 對於高脂飲食誘導之糖尿病大鼠體重變化、攝食量、臟器重量及腹部脂肪之變化量 44
2. CTE 對於高脂飲食誘導之糖尿病大鼠葡萄糖耐受性之探討 44
3. CTE 對於高脂飲食誘導之糖尿病大鼠血漿生化指標濃度之影響 44
4. CTE 對於高脂飲食誘導之糖尿病大鼠睪丸與精子之探討 45
5. CTE 對於高脂飲食誘導之糖尿病大鼠生精小管形態之影響 45
6. CTE 對高脂飲食誘導之血漿中 LH 及睪固酮之影響 46
7. CTE 對於高脂飲食誘導之糖尿病大鼠下視丘 KiSS1、GPR54、SOCS-3 及 SIRT1 mRNA 表現量之影響 46
8. CTE 對於高脂飲食誘導之糖尿病大鼠血漿及睪丸中抗氧化酵素的影響 47
9. CTE 對於高脂飲食誘導之糖尿病大鼠血漿及睪丸中氧化壓力及發炎的改善 47
10. CTE 對於高脂飲食誘導之糖尿病大鼠精子中氧化壓力及發炎的改善 48
11. CTE 對於高脂飲食誘導之糖尿病大鼠精子中脂質過氧化的改善 48
第七章、 結論 49
第八章、 參考文獻 51
圖表 61
附錄 91


圖表
圖一、ECH 對 DPPH 自由基清除能力 61
圖二、ECH 對 LC-540 leydig 細胞及 TM3 leydig 細胞存活率之影響 62
圖三、不同濃度之糖化終產物誘發傷害下對 LC-540 leydig 細胞及 TM3 leydig 細胞存活率之影響 63
圖四、ECH 和 RES 對 AGEs 誘導 LC-540 leydig 細胞及 TM3 leydig 細胞超氧陰離子產生量之抑制能力 64
圖五、以流式細胞儀測定ECH 和 RES 對 AGEs 誘導 LC-540 leydig 細胞產生 H2O2 之影響 65
圖六、不同濃度之 RAGE antagonist 對 LC-540 leydig 細胞存活率之影響 66
圖七、ECH 對AGEs 誘導 LC-540 leydig 細胞活化 RAGE 及 NF-κB 之蛋白質表現量 67
圖八、ECH 活化 AGEs 抑制 LC-540 Leydig 細胞睪固酮生成路徑相關蛋白質之表現量 68
圖九、餵食管花肉蓯蓉六週後，大白鼠體重變化及高脂飲食每周平均攝食熱量變化趨勢圖 69
圖十、餵食管花肉蓯蓉六週後，大白鼠葡萄糖耐受性測量血漿葡萄糖變化趨勢圖及血漿葡萄糖變化量曲線下面積 70
圖十一、餵食管花肉蓯蓉六週後，糖尿病大鼠曲精小管形態 71
圖十二、餵食管花肉蓯蓉六週後，糖尿病大鼠睪丸內睪固酮生路徑酵素之蛋白質表現量 72
圖十三、餵食管花肉蓯蓉六週後，糖尿病大鼠下視丘中 KiSS1、GPR54 mRNA 表現量之影響 73
圖十四、餵食管花肉蓯蓉六週後，糖尿病大鼠下視丘中 SIRT1、SOCS-3 mRNA 表現量之影響 74
圖十五、 餵食不同濃度管花肉蓯蓉後，糖尿病大鼠血漿、睪丸中 NO 產生量之變化 75
圖十六、餵食不同濃度管花肉蓯蓉六週後，糖尿病大鼠血漿及睪丸中 TNF-α 含量之影響 76
圖十七、餵食不同濃度管花肉蓯蓉六週後，糖尿病大鼠血漿及睪丸中 IL-6 含量之影響 77
圖十八、餵食管花肉蓯蓉六週後，糖尿病大鼠睪丸內 RAGE 及 NF-κB 之蛋白質表現量 78
圖十九、餵食管花肉蓯蓉六週後，糖尿病大鼠精子中超氧陰離子產生量之影響 79
表一、餵食不同濃度管花肉蓯蓉六週後，對於糖尿病大鼠之肝、腎、心、及腹部脂肪重量之影響 80
表二、餵食不同濃度管花肉蓯蓉後，糖尿病大鼠之禁食血糖、血漿總膽固醇、三酸甘油酯之含量變化 81
表三、餵食不同濃度管花肉蓯蓉六週，糖尿病大鼠之血漿胰島素、瘦素含量及胰島素阻抗指標 (HOMA-IR) 變化 82
表四、餵食不同濃度管花肉蓯蓉後，糖尿病大鼠之尿素、肌酸酐、丙氨酸基轉移酶 （ALT）和天冬氨酸氨基轉移酶（AST）之含量變化 83
表五、餵食不同濃度管花肉蓯蓉六週後，對於高脂飲食糖尿病大鼠之睪丸、附睪、附睪脂肪重量之影響 84
表六、餵食不同濃度管花肉蓯蓉六週後，糖尿病大鼠精子參數之影響 85
表七、餵食不同濃度管花肉蓯蓉六週後，糖尿病大鼠血漿中荷爾蒙之影響 86
表八、餵食不同濃度管花肉蓯蓉六週後，糖尿病大鼠血漿中抗氧化酵素之變化 87
表九、餵食不同濃度管花肉蓯蓉六週後，糖尿病大鼠睪丸中抗氧化酵素之變化 88
表十、餵食不同濃度管花肉蓯蓉六週後，糖尿病大鼠血漿、睪丸、精子 TBARS 89

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