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系統識別號 U0007-3007201117190200
論文名稱(中文) 不同粒徑丹參的萃取物於C3H/He小鼠之馬兜鈴酸引起腎炎模型的藥效評估
論文名稱(英文) The effects of extracts from different particle sizes of Salvia multiorrhiza on aristolochic acid-induced nephropathy in C3H/He Mice
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 99
學期 2
出版年 100
研究生(中文) 邱資婷
研究生(英文) Tzu-Ting Chiu
學號 M301098032
學位類別 碩士
語文別 中文
口試日期 2011-06-23
論文頁數 93頁
口試委員 委員-方嘉佑
委員-李宗徽
指導教授-陳世銘
中文關鍵字 馬兜鈴酸腎病變  丹參  丹參酮IIA  丹參酚酸B 
英文關鍵字 Aristolochic acid nephropathy ( AAN )  Danshen  tanshinone IIA ( TS IIA )  salvianolic acid B ( SAL B ) 
學科別分類
中文摘要 馬兜鈴酸腎病變 ( aristolochic acid-induced nephropathy, AAN ) 在中草藥引起的腎病變中扮演重要的角色,目前許多學者正致力於尋找可有效延緩馬兜鈴酸所引起之慢性腎病變的治療藥物。本研究分別利用超微粉碎技術及傳統粉碎技術,備製兩種不同粒徑的丹參粉末,以掃描式電子顯微鏡及雷射粒徑分析儀進行粒徑分析,進一步以high performance liquid chromatographic method coupled with ultraviolet detection ( HPLC-UV ),針對其主要活性成分-丹參酮IIA ( tanshinone ⅡA ) 及丹參酚酸B ( salvianolic acid B ) 對丹參細粉的乙醇萃取物 ( fine-grained ethanolic extract of Salvia miltiorrhiza Bunge,簡稱FE ) 或丹參粗粉的乙醇萃取物 ( coarse-grained ethanolic extract of Salvia miltiorrhiza Bunge,簡稱CE ) 進行含量分析,藉由投予六週齡純系雄鼠C3H/He 3.0 μg/mL AA當飲用水連續服用56天後,於治療組分別經口投予FE或CE各300 mg/kg、600 mg/kg及1200 mg/kg連續14天,對照組投予等量蒸餾水,而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 )、血中blood urea nitrogen ( BUN ) 及serum creatinine ( Scr ) 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, HGF, MMP-9 ) 以辨識損傷部位之特異性抗原。
粒徑分析結果顯示丹參平均細粉粒徑為3 μm,粗粉為600μm,含量分析的結果顯示,FE與CE兩者間僅丹參酚酸B含量有顯著差異。所有治療組的小鼠體重皆有增加,而尿蛋白、NAG、BUN、Scr值皆有降低;組織學及免疫螢光染色觀察發現腎組織損傷的情形亦有緩解。整體而言,FE與CE皆能改善AA所造成的腎損傷,推測除了丹參酮IIA及丹參酚酸B,建議日後研究應針對丹參對於AAN的作用機轉與其療效成分作更深入地探討。
英文摘要 Aristolochic acid-induced nephropathy ( AAN ) has been demonstrated to play a crucial role in Chinese herbs nephropathy. Presently, many scientists are attended to looking for a drug which can successfully improve AA-induced chronic kidney disease. In the study, we prepared the different particle sizes of Salvia miltiorrhiza Bunge ( Danshen ) by using the superfine pulverizing technology and traditional grinding methods, the scanning electron microscope ( SEM ) and nano-piratical size analyzer were used to evaluate the particle size of the Danshen. Furthermore, to quantitatively determine the content of tanshinone IIA ( TS IIA ) and salvianolic acid B ( SAL B ) by high performance liquid chromatography coupled with ultraviolet detection ( HPLC-UV ) in fine-grained ethanolic extract of Salvia miltiorrhiza Bunge ( FE ) and coarse-grained ethanolic extract of Salvia miltiorrhiza Bunge ( CE ). AA was dissolved in distilled water ( 3 μg/ml ) as drinking water to C3H/He mice ( 6 week-old male ) for 56 days. The treatment groups were administered orally with either FE or CE ( 300 mg/kg, 600 mg/kg and 1200 mg/kg ) per day for 14 days and following the induction of AAN in mice. 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 subjected to histological examination ( PAS stain and immunofluorescence ). The antibodies, including TGF-β ( transforming growth factor-β ), HGF ( hepatocyte growth factor ), and MMP-9 ( matrix metalloproteinase-9 ), were chosen to recognize the specific antigens in the injury sites.
The particle sizes of FE and CE are 3 μm and 600 μm, respectively. Based on quantitative analysis, FE and CE revealed significant difference only in SAL B. Compared to the control group, the body weight increased and UP, NAG, BUN and Scr were decreased in all the treatment groups. Moreover, the treatment groups ameliorated AA-induced renal morphological damage, decreased staining intensity of TGF-β and MMP-9 and increased intensity of and HGF within the injury tissues. In conclusion, the study demonstrates that both Salvia miltiorrhiza extracts can beneficially improve the renal outcomes of AAN. With no doubt, further studies are necessary to confirm the mechanisms and explore the reno-protective effects of active components of Salvia miltiorrhiza with AAN mice model.
論文目次 目 錄 II
表 目 錄 V
圖 目 錄 i
縮 寫 表 ii
中 文 摘 要 iv
Abstract vi
第一章 緒言 1
第二章 文獻回顧 2
2.1馬兜鈴酸腎病變的由來 2
2.2馬兜鈴酸之基本特性 3
2.2.1用途 3
2.2.2含馬兜鈴酸的生藥及使用現況 3
2.2.3馬兜鈴酸之結構與特性 4
2.2.4馬兜鈴酸之代謝 5
2.3馬兜鈴酸腎病變 7
2.3.1臨床表現及病理特徵 7
2.3.2鑑別診斷 8
2.3.3致病機轉 10
2.3.4治療現況 11
2.4馬兜鈴酸腎病變的實驗模型 12
2.4.1馬兜鈴酸急性腎病變 12
2.4.2馬兜鈴酸慢性腎病變 13
2.5腎小管間質性纖維化 ( Tubulointerstitial fibrosis,TIF ) 15
2.5.1 TGF-β 20
2.5.2 HGF 22
2.5.3 MMP-9 26
2.6丹參及其藥效研究 27
2.6.1丹參基本概述 27
2.6.2丹參的藥效研究 29
2.7生藥粒徑與藥效的關係 31
第三章 研究目的 32
第四章 材料與方法 33
4.1不同粒徑的丹參粉末之粒徑及結構安定性分析 33
4.1.1試藥研磨 33
4.1.2儀器裝置 33
4.1.3粒徑分析 34
4.1.4結構安定性分析 34
4.2不同粒徑丹參的萃取物中丹參酮ⅡA及丹參酚酸B之含量分析 35
4.2.1實驗試藥 35
4.2.2儀器裝置 35
4.2.3 HPLC-UV條件 36
4.2.4標準品配置與檢量線製作 37
4.2.5檢品配置 37
4.2.6分析方法之精密度 ( precision ) 與準確度 ( accuracy ) 試驗 37
4.3不同粒徑丹參的萃取物在慢性AAN之藥效評估 39
4.3.1實驗動物 39
4.3.2 實驗藥物 39
4.3.3實驗設計 39
4.3.4體重測量 41
4.3.5尿液收集 41
4.3.6動物犧牲法、血液及組織切片製作 41
4.3.7尿蛋白、NAG含量測定 42
4.3.8血清中BUN及Creatinine的含量測定 43
4.3.9 Periodoic Acid Schiff’s ( PAS ) stain組織染色 43
4.3.10組織損傷程度的量化 43
4.3.11免疫螢光染色 ( Immunofluorescence ) 44
4.3.12統計方法 45
第五章 結果 46
5.1不同粒徑的丹參粉末之粒徑及結構安定性分析 46
5.1.1雷射粒徑分析儀 46
5.1.2掃描式電子顯微鏡 ( SEM ) 46
5.1.3 FT-IR與HPLC圖譜分析 46
5.2不同粒徑丹參的萃取物中丹參酮ⅡA及丹參酚酸B之含量分析 50
5.2.1線性 ( linearity ) 50
5.2.2分析方法之精密度與準確度 50
5.2.3標準品丹參酮ⅡA及丹參酚酸B丹參萃取物之HPLC圖譜 50
5.2.4不同粒徑丹參的萃取物之HPLC圖譜 51
5.2.5不同粒徑丹參的萃取物中丹參酮ⅡA及丹參酚酸B含量分析 51
5.3不同粒徑丹參的萃取物對慢性AAN之藥效評估 59
5.3.1體重變化分析 59
5.3.2蛋白尿含量分析 61
5.3.3 NAG含量分析 63
5.3.4血清中BUN分析 65
5.3.5血清中Creatinine分析 65
5.3.6組織病理PAS染色 67
5.3.7組織損傷量化分析 67
5.3.8免疫螢光染色及量化分析 70
第六章 討論 74
6.1不同粒徑的丹參粉末之粒徑及結構安定性分析 74
6.2不同粒徑丹參的萃取物中丹參酮ⅡA及丹參酚酸B之含量分析 76
6.3 不同粒徑丹參的萃取物在慢性AAN之藥效評估 78
第七章 結論 84
參 考 文 獻 85


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