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。本研究為藉由投予AA引起馬兜鈴酸腎病變 (aristolochic acid nephropathy, AAN) 後評估人參濃縮劑 (ginseng extrat, GE) 及其成分人參皂苷Rg1 (ginsenoside, GS) ，並分別與去氫羥化腎上腺皮質素 (Prednisolone, P) 合併對AAN的改善效果。純系小鼠C3H/He (6 week-old male) 給予3.0 μg/mL AA作為飲用水連續56天，之後治療組連續14天經口分別投予GE 250 mg/kg、GS 5 mg/kg、prednisolone 2 mg/kg 及prednisolone合併GE或GS；對照組在前56天同樣予以AA作為飲用水，在投予治療藥物期間則給予等量蒸餾水；Normal組則是在整個實驗過程皆給予蒸餾水。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。實驗結果顯示，以GE，P，GE+P及GS+P對尿蛋白、NAG、BUN及SCr值皆能有效降低；組織學觀察各組腎組織損傷的情形皆有緩解現象；免疫螢光染色觀察發現TGF-β沈積情形降低，MMP-9及HGF的沈積增加。根據上述結果得知以合併治療組在各實驗中皆有較佳療效，推測應是GE及GS結構類似prednisolone具有抗發炎效果，可以減少基質堆積並延緩纖維化過程以降低腎臟損傷程度，且與prednisolone合併使用可有加成療效。

Aristolochic acid (AA) has been demonstrated to play an important
role in aristolochic acid nephropathy (AAN). The purpose of this study was to evaluate the therapeutic effect of ginseng extract (GE) or its active component ginsenoside Rg1 (GS), combined with prednisolone on AAN.
AA was dissolved in distilled water as drinking water to C3H/HE mice (6 week-old male) for 56 days. The treatment groups in phase one were administered with GE 250mg/kg, prednisolone 2mg/kg, and both GE and prednisolone orally for 14 days. In phase two, under the same process, GE was replaced by GS. The control group was administered with distilled water and the normal group was only administered with distilled water throughout the experiment. Urine protein, urine N-acetyl-beta-D-glucosaminidase (NAG), blood urea nitrogen (BUN) and serum creatinine 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), HGF (hepatocyte growth factor), were chosen to recognize the specific antigens in injury sites.Compared with the control group, urine protein, NAG, BUN and serum creatinine were decreased at different level in all treatment groups. In the histological examination, we observed the alleviation in all treatment groups. The fluorescence dots of TGF-β were significantly decreased and MMP-9, HGF were significantly increased in experimental groups. Based on our result, both GE and GS combined with prednisolone has the superior effect among the concomitance groups. Our findings demonstrated that GE and GS are structure analogs of prednisolone and they have anti-inflammatory properties to slow down the fibrosis process and repair the renal injury.

目 錄
目 錄 I
圖 目 錄 VI
表 目 錄 VIII
縮 寫 表 i
中 文 摘 要 ii
Abstract iv
第一章 緒言 1
第二章 文獻回顧 2
第一節 馬兜鈴酸腎病變的由來 2
第二節 馬兜鈴酸之基本特性 3
2.1 用途 3
2.2 含馬兜鈴酸的生藥及使用現況 3
2.3 結構與特性 4
2.4 馬兜鈴酸的代謝 5
2.5 馬兜鈴酸的致癌機轉 7
第三節 馬兜鈴酸腎病變 (Aristolochic acid nephropathy, AAN) 11
3.1 臨床表徵 11
3.2 病理特徵 12
3.3 鑑別診斷 12
3.4 致病機轉 15
3.5 藥物治療 16
第四節 馬兜鈴酸腎病變的實驗模型 18
4.1 馬兜鈴酸的急性腎毒性 18
4.2 馬兜鈴酸的慢性腎毒性 19
第五節 腎小管間質性纖維化 22
5.1 TGF-β 27
5.2 MMPs 30
5.3 Hepatocyte growth factor (HGF) 33
第六節 人參及其藥效研究 37
第七節 人參皂苷 (Ginsenoside Rg1) 及其藥效研究 40
7.1 人參皂苷之結構特性 40
7.2 人參皂苷Rg1的藥效學研究 44
第八節 去氫羥化腎上腺皮質素 46
第三章 研究目的 50
第四章 材料與方法 51
第一節 人參濃縮劑與合併藥物在AAN之藥效評估 51
1.1實驗動物 51
1.2實驗藥物 51
1.3實驗設計 51
1.4尿液收集 53
1.5動物犧牲法、血液及組織切片製作 53
1.6尿蛋白、NAG含量測定 54
1.7血清中BUN及Creatinine的含量測定 54
1.8 Periodoic Acid Schiff’s (PAS) stain組織染色 54
1.9組織損傷程度的量化 55
1.10免疫螢光染色 (Immunofluorescence) 56
1.11統計方法 56
第二節 Ginsenoside Rg1與合併藥物在AAN之藥效評估 57
2.1實驗動物 57
2.2實驗藥物 57
2.3實驗設計 57
2.4尿液收集 59
2.5動物犧牲法、血液及組織切片製作 59
2.6尿蛋白、NAG含量測定 59
2.7血清中BUN及Creatinine的含量測定 59
2.8 PAS組織染色 59
2.9組織損傷程度的量化 59
2.10免疫螢光染色 59
2.11統計方法 59
第五章 結果 60
第一節 人參濃縮劑與合併藥物對慢性AAN的藥效評估 60
1.1尿蛋白、NAG含量分析 60
1.2血清中BUN分析 64
1.3血清中Creatinine分析 64
1.4組織病理PAS染色 66
1.5組織損傷量化分析 66
1.6免疫螢光染色及量化分析 69
第二節Ginsenoside Rg1與合併藥物對慢性AAN的藥效評估 72
2.1尿蛋白、NAG含量分析 72
2.2血清中BUN分析 75
2.3血清中Creatinine分析 75
2.4組織病理PAS染色 77
2.5組織損傷量化分析 77
2.6免疫螢光染色及量化分析 80
第六章 討論 84
第一節 人參濃縮劑及人參皂苷Rg1在AAN之藥效評估 84
第二節 去氫羥化腎上腺皮質素在AAN之藥效評估 89
第三節 人參濃縮劑及人參皂苷Rg1合併去氫羥化腎上腺皮質素在AAN之藥效評估 92
第七章 結論 94
參考文獻 96

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