臺灣博碩士論文加值系統

馬兜鈴酸 (aristolochic acid, AA) 在中草藥引起的腎病變中扮演重要的角色。本研究的目的藉由投予AA引起之馬兜鈴酸腎病變 (aristolochic acid nephropathy, AAN)，評估人參濃縮劑 (ginseng extrat, GE)、pravastatin sodium (P) 及兩者併用對AAN的改善效果。同時也利用High Performace Liquid Chromatography (HPLC) 針對人參的主要活性物質－人參皂苷Rg1，Rd，Rb1－進行含量分析。
給予純系小鼠C3H/He (6 week-old male) 3.0 μg/mL AA當飲用水連續56天，之後治療組分別經口投予GE 250mg/kg、pravastatin sodium 20mg/kg以及GE 250mg/kg合併pravastatin sodium 20mg/kg (GE+P) 連續14天，對照組則投予等量蒸餾水，Normal組則全程給予蒸餾水。藉由測定尿蛋白、尿中N-acetyl-beta-D-glucosaminidase (NAG) 與血中blood urea nitrogen (BUN) 及creatinine，以評估小鼠腎功能；腎組織使用PAS染色觀察病理組織改變，並進行免疫螢光染色 (TGF-β，MMP-9，HGF)，以辨識損傷部位之特異性抗原。
本實驗選用ODS (Octadecylsilyl；C18) 作為層析管柱，測定波長為203 nm，以乙腈 (acetonitrile) 與水的混合液作為移動相，流速為1 ml/min，GE 在乙腈-水30:70的移動相條件下可分離出人參皂苷Rd及Rb1，乙腈-水20:80則可分離出人參皂苷Rg1。
實驗結果顯示，投予GE 250 mg/kg，P 20mg/kg及GE+P之治療組的尿蛋白、NAG、BUN、Scr值都有降低；組織學及免疫螢光染色觀察發現腎組織損傷的情形皆有緩解。含量分析的結果顯示，GE中皂苷含量之依序為人參皂苷Rb1 > Rg1 > Rd。根據上述結果發現，治療藥物之療效依序為GE+P ≧ GE ≧ P，分析結果也證實人參中確實含有活性成分人參皂苷。總結來說，人參濃縮劑、pravastatin以及兩者合併使用對於馬兜鈴酸所造成的腎臟損傷皆有一定的治療效果。

Aristolochic acid (AA) has been demonstrated to play a crucial role in Chinese herbs nephropathy. The purposes of this study were to evaluate the therapeutic effect of ginseng extrat (GE), pravastatin sodium (P) and GE combined with pravastatin on AA-induced nephropathy and to quantitatively determine the contents of three ginsenosides-Rg1, Rd, Rb1 -in GE using high performance liquid chromatography (HPLC).
AA was dissolved in distilled water (3μg/ml) as drinking water to C3H/He mice (6 week-old male) for 56 days. The treatment groups were administered orally with GE 250 mg/kg, pravastatin sodium 20 mg/kg and GE 250 mg/kg combined with pravastatin sodium 20 mg/kg (GE+P) once daily for 14 days. The control group was administered with distilled water. The normal group was only administered with distilled water throughout the experiment.
Urine protein (UP), urine N-acetyl-beta-D-glucosaminidase (NAG), blood urea nitrogen (BUN) and serum creatinine (Scr) were determined to evaluate renal function. Renal tissues were served to histological examination (PAS stain and immunofluorescence). The antibodies, including TGF-β (transforming growth factor-β), MMP-9 (matrix metalloproteinase-9), and HGF (hepatocyte growth factor), were chosen to recognize the specific antigens in injury sites.
ODS (Octadecylsilyl；C18) column was used for analyzing ginsenosides in GE with detection at 203 nm. Ginsenosides Rd and Rb1 were separated with acetonitrile-water (30:70) as the mobile phase, while ginsenoside Rg1 was separated under acetonitrile-water (20:80). Flow rate was 1 ml/min.
Compared with the control group, urine protein, NAG, BUN, serum creatinine were decreased in the treatment groups. Among all treatment groups, we observed alleviation in the histological examination, decreased staining intensity of TGF-β and increased intensity of MMP-9 and HGF within the injury tissues. The overall therapeutics efficacy of the treatment was as followed: GE+P ≧ GE ≧ P. Based on quantitative analysis, the contents of three ginsenosides in GE was as followed: Rb1 > Rg1 > Rd. In conclusion, our study demonstrates that GE 250 mg/kg alone use, pravastatin 20 mg/kg alone use and GE 250 mg/kg combined with pravastatin 20 mg/kg can beneficially improve the renal outcomes of AAN.

目 錄 I
圖 目 錄 V
表 目 錄 VII
縮 寫 表 i
中 文 摘 要 iii
Abstract v
第一章 緒言 1
第二章 文獻回顧 3
第一節 馬兜鈴酸腎病變的由來 3
第二節 馬兜鈴酸之基本特性 4
2.1 用途 4
2.2 含馬兜鈴酸的生藥及使用現況 4
2.3 結構與特性 5
2.4 馬兜鈴酸的代謝 6
2.5 馬兜鈴酸的致癌機轉 8
第三節 馬兜鈴酸腎病變 (Aristolochic acid nephropathy, AAN) 12
3.1 臨床表徵 12
3.2 病理特徵 13
3.3 鑑別診斷 13
3.4 致病機轉 16
3.5 藥物治療 17
第四節 馬兜鈴酸腎病變的實驗模型 19
4.1 馬兜鈴酸的急性腎毒性 19
4.2 馬兜鈴酸的慢性腎毒性 21
第五節 腎小管間質性纖維化 23
5.1 TGF-β 28
5.2 MMPs 31
5.3 Hepatocyte growth factor (HGF) 34
第六節 人參及其藥效研究 37
第七節 Pravastatin sodium 45
第三章 研究目的 49
第四章 材料與方法 50
第一節 人參濃縮劑與合併藥物在慢性AAN之藥效評估 50
1.1 實驗動物 50
1.2 實驗藥物 50
1.3 實驗設計 50
1.4 尿液收集 52
1.5 動物犧牲法、血液及組織切片製作 52
1.6 尿蛋白、NAG含量測定 53
1.7 血清中BUN及Creatinine的含量測定 53
1.8 Periodoic Acid Schiff’s (PAS) stain組織染色 53
1.9 組織損傷程度的量化 54
1.10 免疫螢光染色 (Immunofluorescence) 54
1.11 統計方法 55
第二節 人參濃縮劑中ginsenoside Rg1、Rb1與Rd之HPLC含量分析 56
2.1 實驗試藥 56
2.2 儀器裝置 56
2.3 HPLC條件 56
2.4 標準品配置與檢量線製作 57
2.5 檢品配置 57
2.6 分析方法之精密度(precision)與準確度(accuracy)試驗 57
第五章 結果 58
第一節 人參濃縮劑與合併藥物對慢性AAN的藥效評估 58
1.1尿蛋白、NAG含量分析 58
1.2血清中BUN分析 61
1.3血清中Creatinine分析 61
1.4組織病理PAS染色 63
1.5組織損傷量化分析 63
1.6免疫螢光染色及量化分析 66
第二節 人參濃縮劑中ginsenoside Rg1、Rb1與Rd之HPLC含量分析 70
2.1人參濃縮劑中ginsenoside Rg1、Rb1與Rd含量之HPLC圖譜 70
2.2線性(linearity) 70
2.3分析方法之精密度與準確度 71
2.4人參濃縮劑之ginsenoside Rg1、Rb1與Rd含量分析 71
第六章 討論 79
第七章 結論 88
參考文獻 89

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