臺灣博碩士論文加值系統

隨著生活型態改變，糖尿病的盛行率逐年升高。長期血糖的控制不良，促使體內產生大量的自由基，造成氧化壓力上升，並且伴隨生殖內分泌系統紊亂，導致性腺功能異常及精子損傷。Toll-like receptor 4 (TLR4) 為一先天性免疫反應，當糖尿病患者體內游離脂肪酸濃度上升時，可將其活化，產生訊號傳遞，使細胞內 NF-κB 被啟動，分泌促發炎細胞激素。紫錐花 (Echinacea) 原生於北美地區，屬於多年生菊科植物，已被證實具有免疫調節、抗氧化、抗發炎、抗菌、抗病毒、抗癌及預防和治療感冒的功效，但對於糖尿病與男性生殖功能尚未被研究。因此，本研究欲利用紫錐花之抗氧化及抗發炎的生理活性，探討紫錐花乙醇萃取物 (Echinacea purpurea ethanol extract, EPE) 對於糖尿病雄性大鼠生殖功能之影響，並且是否透過調控 TLR4 達到抗發炎的效果。動物實驗以 streptozotocin (65 mg/kg) 及 nicotiamide (230 mg/kg) 誘導糖尿病雄性大鼠，再利用管餵方式給予不同劑量 (93、279、465 mg/kg) 的 EPE，觀察其內分泌調節、抗氧化、抗發炎等作用，並以糖尿病用藥 metformin (100 mg/kg) 作為正控制組。結果顯示，餵食 EPE 四週後，可有效改善糖尿病大鼠之高血糖及胰島素阻抗；雄性大鼠生殖系統方面，EPE 也能有效改善生精小管結構、精子形態、精子參數、粒線體膜電位以及維持 DNA 完整性，並且增加睪固酮合成酵素之蛋白質表現量、提高血漿中睪固酮濃度；此外，EPE 可以提升抗氧化酵素超氧歧化酶 (superoxide dismutase, SOD)、過氧化氫酶 (catalase) 的活性及還原態麩胱甘肽 glutathione (GSH) 的生成，同時降低 TLR4 及 phosphor-NF-κB p65 之蛋白質表現量，進一步減少促發炎細胞激素 interleukin-1 beta (IL-1β)、tumor necrosis factor-alpha (TNF-α) 及 nitric oxide (NO) 的濃度。綜合以上結果，因糖尿病所引起之氧化壓力上升，可藉由餵食 EPE 增加抗氧化酵素活性，並且透過 TLR4 降低發炎的產生，達到保護雄性大鼠生殖功能之目的。

As lifestyle changes, the prevalence of diabetes increases every year. Diabetes-induced male reproductive dysfunction is predominantly due to increased oxidative stress, and then result in sperm damage and infertility. Echinacea purpurea, the North America herbal medicine, have traditionally been used for immune-modulatory, anti-oxidative, anti-inflammatory, anti-cancer, anti-viral function and prevention from common cold. The toll-like receptor 4 (TLR4) plays a critical role in innate immune responses leading to NF-κB phosphorylation and release of pro-inflammatory cytokines including nitric oxide (NO), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). However, relation between Echinacea purpurea and TLR4 remains unclear. The aim of this study was to investigate the protective effects on male reproduction of Echinacea purpurea ethanol extract (EPE) against diabetic rats, and whether the anti-inflammatory effects were through TLR4 pathway. Diabetic male Sprague-Dawley (SD) rats were induced by nicotinamide (230 mg/kg) and streptozotocin (65 mg/kg). EPE was tested in three doses (93, 279 and 465 mg/kg p.o. daily) for 4 weeks. Besides, metformin administration (100 mg/kg/day) was treated as the positive control. Results indicated that EPE administration about 4 weeks improved hyperglycemia and insulin resistance. In addition, EPE ameliorated sperm motility, morphology, DNA integrity and keeping mitochondrial membrane potential as well as plasma testosterone level and protein for testosterone synthesis enzyme. In plasma or testis anti-oxidant superoxide dismutase (SOD), catalase and glutathione (GSH) were increased whereas pro-inflammatory cytokines NO, IL-1β and TNF-α were decreased. Beside, testis protein content of TLR4 and downstream phospho-NF-κB p65 were reduced. The EPE might reduce production of pro-inflammatory cytokine via TLR4 pathways and improve diabetes-induced male infertility.

摘要 I
Abstract II
目錄 III
圖目錄 V
表目錄 VII
附錄目錄 VIII
名詞縮寫表 IX
壹、緒論 1
貳、文獻回顧 3
一、糖尿病 3
1.1 糖尿病之流行病學 3
1.2 糖尿病之分類 3
1.3 糖尿病前期 4
1.4 糖尿病之診斷標準 4
1.5 糖尿病與氧化壓力 5
1.6 糖尿病之併發症 6
1.7 Streptozotocin (STZ)-nicotinamide (NA) 誘導糖尿病模式 6
二、男性生殖與不孕症 7
2.1 男性生殖系統 7
2.2 男性不孕症 8
三、糖尿病與男性生殖 11
3.1 動物模式研究 11
3.2 糖尿病與氧化壓力 11
3.3 糖尿病與生殖內分泌異常 11
四、發炎反應的調節機制 12
五、紫錐花 (Echinacea spp.) 13
5.1 紫錐花之簡介 13
5.2 紫錐花之傳統功效 13
5.3 紫錐花之生理活性 13
5.4 安全性及毒性研究 15
參、實驗流程 17
一、動物實驗 17
二、犧牲後分析項目 18
肆、實驗材料與方法 19
一、材料與樣品 19
1.1 紫錐花樣品 19
1.2 實驗動物 19
1.3 動物飼料 19
1.4 藥品 19
1.5 儀器設備 21
二、實驗方法 21
2.1 糖尿病大鼠之誘導與分組 21
2.2 實驗動物飼養 22
2.3 血漿生化數值分析 22
2.4 雄性生殖功能分析 24
2.5 抗氧化能力分析 26
2.6 抗發炎能力分析 27
2.7 蛋白質表現量分析 29
三、統計分析 32
陸、實驗結果 33
一、EPE 對於糖尿病雄性大鼠體重之變化 33
二、EPE 對於糖尿病大鼠臟器及腹部脂肪重量之分析 33
三、EPE 對於糖尿病大鼠血漿生化指標之影響 33
3.1 口服葡萄糖耐受試驗 (oral glucose tolerance test, OGTT) 33
3.2 空腹血糖、胰島素及胰島素阻抗評估 33
3.3 血漿總膽固醇及三酸甘油酯含量 34
3.4 血漿天門冬胺酸轉胺酶、丙胺酸轉胺酶、尿素及肌酸酐含量 34
四、EPE 對於糖尿病雄性大鼠生殖功能之探討 34
4.1 睪丸、副睪、副睪脂肪重量及睪丸重 / 長度比值之變化 34
4.2 睪丸組織形態之影響 34
4.3 精子形態及參數之影響 35
4.4 睪固酮合成路徑之影響 35
4.5 精子粒線體膜電位之分析 35
4.6 精子 DNA 損傷程度之分析 35
五、EPE 對於糖尿病大鼠氧化壓力之改善 35
六、EPE 對於糖尿病大鼠抗發炎能力之分析 36
七、各組實驗結果比較 36
柒、討論 38
捌、結論 40
玖、參考文獻 41
圖表 51

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