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研究生:吳佳鴻
研究生(外文):Chia-Hung Wu
論文名稱:丹參抑制大鼠初代星狀細胞活化之研究
論文名稱(外文):Studies on the Antifibrotic Activity of Salvia miltiorrhiza in Rat Primary Hepatic Stellate Cells
指導教授:黃怡超黃怡超引用關係林雲蓮林雲蓮引用關係
指導教授(外文):Yi-Tsau HungYun-Lian Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:傳統醫藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:108
中文關鍵詞:肝臟星狀細胞肝纖維化a-平滑肌肌動蛋白膠原蛋白活性氧化物丹參
外文關鍵詞:hepatic stellate cellliver fibrosisa-SMAcollagenROSSalvia miltiorrhiza
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丹參抑制初代大鼠肝臟星狀細胞活化之研究
中文摘要
在肝纖維化的過程中,肝臟星狀細胞的活化扮演了一個關鍵的角色。目前已有許多證據說明過量的氧化壓力會造成星狀細胞活化。轉型生長因子(transforming growth factor-β1,TGF-β1)是目前已知會誘導星狀細胞活化而造成胞外基質堆積。傳統的中草藥-丹參具有活血化瘀之功效,已經被證實具有良好的抗脂質過氧化能力。本研究之目的是要從雄性Sprgue-Dawley品系之大鼠肝臟中分離出星狀細胞,探討丹參是否可以抑制由四氯化碳誘導之星狀細胞的氧化損傷以及由TGF-β1誘發之星狀細胞胞外基質增生;並且由膽管結紮造成肝纖維化之大鼠取得星狀細胞,探討丹參對病態大鼠取得之星狀細胞的作用。
本研究首先使用MDA-TBA分析方法來觀察丹參是否可以抑制由四氯化碳所導致之脂質過氧化現象。接著利用TGF-β1來刺激星狀細胞活化導致α-平滑肌動蛋白(α-smooth muscle actin,α-SMA)和膠原蛋白(collagen)增生;利用ELISA assay分析α-SMA,以ELISA reader 讀取Sirus Red之吸光值來分析膠原蛋白含量。依據結果顯示丹參粗萃取物(Sm)部份純化物(PSA)及其主要成份丹參酚酸A(Sal A)和丹參酚酸B(Sal B)可以顯著抑制MDA(malondialdehyde)之生成,其EC50分別為74.2 ± 9.5 μg/ml、5.61 ± 1.0 μg/ml、5.7 ± 0.8 μM和3.9 ± 0.5 μM。而Sm 、Sal A和Sal B分別在500 μg/ml、20 μM和280 μM之濃度下皆可以抑制α-SMA,膠原蛋白生成。
其次使用CM-H2DCFDA探針觀察丹參是否能抑制四氯化碳和TGF-β1導致星狀細胞產生的活性氧化物質(reactive oxygen species,ROS)。結果顯示Sm,Sal A和Sal B分別在50 μg/ml、5 μM和17.5 μM與Sal A 和Sal B在5 μM、35 μM之濃度下可以有效清除四氯化碳和TGF-β1所造成之活性氧化物質之增加。
由膽管結紮造成肝纖維化大鼠之肝所分離出星狀細胞,比較丹參給予四氯化碳之藥效。結果顯示四氯化碳在假手術組中之星狀細胞誘導之ROS為其對照組之1.6倍,而在誘發膽管結紮組之ROS為其對照組之1.2倍,兩者有統計差異,在此實驗中丹參仍然具有清除活性氧化物質之能力。
由上述結果顯示,丹參對於四氯化碳所導致星狀細胞之氧化性損傷具有抑制MDA及ROS之生成,抑制TGF-β1誘發星狀細胞活化產生α-SMA與膠原蛋白之累積;因此丹參可能藉減少氧化壓力所造成之肝纖維化,而達到保護肝臟之目的。
Studies on the Antifibrotic Activity of Salvia miltiorrhiza in Rat Primary Hepatic Stellate Cells
Abstract
Activation of hepatic stellate cells (HSCs) plays a central role in liver fibrosis, in which oxidative stress has been implicated. Transforming growth factor-β1(TGF-β1)is known to be the most potent factor to induce HSCs activation and accumulation of exrtacellular matrix(ECM). Salvia miltiorrhiza (SM), a Chinese traditional herb, was reported to have effect on blood circulation and anti-lipid peroxidative activity. The aim of this study is to investigate whether SM could inhibit HSCs activation by carbon tetrachloride and TGF-β1,with primary stellate cells from Sprgue-Dawely rats as a cellular model.
Firstly, MDA(malondialdehyde)-TBA assay was used to evaluate the effects of SM on CCl4-induced lipid peroxidation. Then, HSCs were stimulated with TGF-β1, and the production of α-smooth muscle actin (α-SMA) and collagen measured by ELISA. Results showed that SM, partial purified(PSA)and its active principles, salvianolic acid A (Sal A) and salvianolic acid B(Sal B) significantly inhibited MDA formation. Their EC50 values were 74.2 ± 9.5 μg/ml, 5.61 ± 1.0 μg/ml, 5.7 ± 0.8 μM and 3.9 ± 0.5 μM, respectively. Both α-SMA and collagen expression could also be suppressed by Sm, Sal A and Sal B at 500 μg/ml, 20 μM and 280 μM, respectively.
Furthermore, we have measured reactive oxygen species(ROS) by CM-H2DCFDA probe under CCl4 and TGF-β1challenge. According to our data, Sm, Sal A and Sal B at 50 μg/ml, 5 μM and 17.5 μM, Sal A and Sal B at 5 μM and 35 μM respectively could scavenge ROS formation stimulated separately by CCl4 and TGF-β1.
In the last part, stellate cells separately isolated from bile duct ligation(BDL)and sham rats were stimulated by CCl4 to observe the effects of SM. The results showed that CCl4 would significantly induce ROS formation in HSCs from sham and BDL rats at 1.6 times and 1.2 times, respatively and SM could still reduce ROS formation in these cells.
Our results showed that SM inhibited MDA, α-SMA, collagen and ROS formation in stimulated HSCs. Moreover we demonstrated that SM scavenged ROS formation in HSCs from normal and BDL rats. It suggested that SM might attenuate hepatic fibrosis in vivo via ROS scavenging .
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