杞蓟制剂防治非酒精性脂肪性肝炎大鼠的分子机制
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摘要
目的：随着人民生活水平的提高，非酒精性脂肪性肝炎(nona lcoholic steatohepatitis，NASH)发病逐渐增多。其病理机制比较复杂，有广泛的因素参与，迄今尚未完全阐明。其中，游离脂肪酸(free fatty acids，FFA)过多、氧化应激、细胞因子(cytokines，CKs)相关性损害等是其重要的病理环节。核转录因子-κB(nuelear factot-κB，NF-κB)是与氧化应激(oxidative stress)、CKs相关的真核细胞转录因子，可调控多种促炎因子基因的表达，推测在NASH发病中发挥着重要作用。NASH尚无理想的防治药物。中医在防治NASH方面具有一定的优势。导师张赤志教授临床体会：NASH多因长期过食肥甘，痰湿内生，致脾失健运，肝失疏泄，郁久化热，暗耗阴精，形成本虚标实的病理特点。治宜滋补肝肾、清热利湿。临床应用杞蓟制剂(枸杞子水提物、水飞蓟宾组成)治疗NASH取得很好效果。本课题采用国内外公认的研究模型，结合NASH的现代研究成果，用病理学、生物化学、分子生物学等技术，探讨NASH状态下肝组织NF-κB及其抑制因子(inhibitor of nuclear factor-κB，IκB)蛋白和mRNA表达情况，阐明杞蓟制剂的作用机制，为中医药治疗本病提供理论依据。
方法：实验分两部分进行：
第一部分：杞蓟制剂药效学研究(实验Ⅰ)清洁级SD大鼠，80只，雌雄各半，体重190±20g。普通饲料正常喂养1周，随机分为8组，每组10只。正常对照组(A组)、空白模型组(B组)、杞蓟制剂小剂量组(C_1组)、杞蓟制剂中剂量组(C_2组)、杞蓟制剂大剂量组(C_3组)、西药对照组(复方蛋氨酸胆碱片组，D组)、枸杞子组(E组)、水飞蓟宾组(F组)。参考钟岚等报道的方法配制高脂饲料(在普通饲料基础上加10％猪油、2％胆固醇)，用之复制大鼠NASH模型。8周后各造模组继用高脂饲料喂养同时，将杞蓟制剂稀释成1：2：4不同浓度(最低剂量为中药常规剂量提取物)，C_1、C_2、C_3组分别按不同浓度杞蓟制剂混悬液1ml／100g．d灌胃，每日1次；D组予东宝肝泰混悬液0.09g／1ml／100g．d灌胃，每日1次；B组予生理盐水1ml／100g．d灌胃，每日1次；E组、F组分别予枸杞子水提物、水飞蓟宾混悬液1ml／100g．d灌胃，每日1次。给药4周后(即实验12周)，所有大鼠禁食12h，以2％戊巴比妥钠溶液麻醉处死所有动物，迅速分离血清，提取肝组织。于模型建立及给药期间观察记录动物体重、食欲、行为、状态、毛发及死亡情况。计算肝指数。用Olympus Au560全自动生化分析仪检测血清丙氨酸氨基转移酶(alanine aminotransferase，ALT)、天门冬氨酸氨基转移酶(aspartate aminottansferase，AST)。肝组织中性福尔马林固定，石蜡包埋，切片，HE染色，光学显微镜下观察，评估脂肪变性和炎症活动程度。
第二部分：NASH的分子机制及杞蓟制剂的药理学研究(实验Ⅱ-Ⅴ)动物分组：清洁级SD大鼠，40只，雌雄各半体重190±20g。普通饲料正常喂养1周，随机分为4组，每组10只：正常对照组(A组)、空白模型组(B组)、杞蓟制剂组(C组)、复方蛋氨酸胆碱片组(D组)。模型复制方法同实验Ⅰ。8周后各模型组继用高脂饲料喂养同时，B组予生理盐水1ml／100g．d灌胃，每日1次；C组予
Objectives: With the improvement of the standard of living, more and more people are suffering nonalcoholic steatohepatitis (NASH). The me chanism of NASH is complicated and still unclear. It appears that a 1 ot of factors are concerned with pathological factors of it. Thereint o, overabundance of free fatty acid (FFA), oxidative stress and inju res to cytokines (CKs) are the important pathological taches. Nuclear factor-κB( NF-κB) is eukaryocyte transcription factor relating with oxidative stress and CKs, which can modulate the expression of many inflammatory factors,which may have important effect on NASH. There a ren't any ideal medications to prevent NASH. Chinese traditional medi cine (TCM) possesses some superiority on it. My tutor, professor Zhan g Chi-zhi, realized in his clinical work that NASH may be caused by e ating fat and sweet excessively for a long time, which lead to phlegm and blood stasis generating inside, constrained liver qi, heat being transformed due to stagnation for a long time, yin essence being was ted secretly, coming into being that the pathological characteristic of which the nature is insufficient but the signs are looked like exc ess. The principle of its treatment should be to supplement liver and kidney, to clear away heat evil and disinhibit water. He chose QI Ji Preparation(made up of medlar fruit and silybin ) to treat it and ga ined good effects. Using the model of NASH recognized by the world an d linking to the evolution of modern research of NASH, we observed th e hepatic tissue expression of NF-κB/IκB protein and mRNA in the esta te of NASH and threw light on the mechanism of QI Ji Preparation to p revent it by the technique of pathology, biochemistry and molecular b iology in the research, to offer deep study of pathogenesis and preve ntion of NASH.
Methods : the research was divided into two steps. The first step to study the effect of QI Ji Preparation on NASH (Expe riment I): Eighty clean graded male Spraque-Dawley rats, weight 190± 20g . ware feed 1W normally, then were randomly divided into 8 groups, namely normal control group (A), blank model group (B), QI Ji Preparat ion groups: low dose, common dose, high dose (C1,C2,C3), Compound Meth ionine and Choline Bitarte Tablets (CMCBT) group(D), medlar fruit grou
方法：实验分两部分进行：
第一部分：杞蓟制剂药效学研究(实验Ⅰ)清洁级SD大鼠，80只，雌雄各半，体重190±20g。普通饲料正常喂养1周，随机分为8组，每组10只。正常对照组(A组)、空白模型组(B组)、杞蓟制剂小剂量组(C_1组)、杞蓟制剂中剂量组(C_2组)、杞蓟制剂大剂量组(C_3组)、西药对照组(复方蛋氨酸胆碱片组，D组)、枸杞子组(E组)、水飞蓟宾组(F组)。参考钟岚等报道的方法配制高脂饲料(在普通饲料基础上加10％猪油、2％胆固醇)，用之复制大鼠NASH模型。8周后各造模组继用高脂饲料喂养同时，将杞蓟制剂稀释成1：2：4不同浓度(最低剂量为中药常规剂量提取物)，C_1、C_2、C_3组分别按不同浓度杞蓟制剂混悬液1ml／100g．d灌胃，每日1次；D组予东宝肝泰混悬液0.09g／1ml／100g．d灌胃，每日1次；B组予生理盐水1ml／100g．d灌胃，每日1次；E组、F组分别予枸杞子水提物、水飞蓟宾混悬液1ml／100g．d灌胃，每日1次。给药4周后(即实验12周)，所有大鼠禁食12h，以2％戊巴比妥钠溶液麻醉处死所有动物，迅速分离血清，提取肝组织。于模型建立及给药期间观察记录动物体重、食欲、行为、状态、毛发及死亡情况。计算肝指数。用Olympus Au560全自动生化分析仪检测血清丙氨酸氨基转移酶(alanine aminotransferase，ALT)、天门冬氨酸氨基转移酶(aspartate aminottansferase，AST)。肝组织中性福尔马林固定，石蜡包埋，切片，HE染色，光学显微镜下观察，评估脂肪变性和炎症活动程度。
第二部分：NASH的分子机制及杞蓟制剂的药理学研究(实验Ⅱ-Ⅴ)动物分组：清洁级SD大鼠，40只，雌雄各半体重190±20g。普通饲料正常喂养1周，随机分为4组，每组10只：正常对照组(A组)、空白模型组(B组)、杞蓟制剂组(C组)、复方蛋氨酸胆碱片组(D组)。模型复制方法同实验Ⅰ。8周后各模型组继用高脂饲料喂养同时，B组予生理盐水1ml／100g．d灌胃，每日1次；C组予
Objectives: With the improvement of the standard of living, more and more people are suffering nonalcoholic steatohepatitis (NASH). The me chanism of NASH is complicated and still unclear. It appears that a 1 ot of factors are concerned with pathological factors of it. Thereint o, overabundance of free fatty acid (FFA), oxidative stress and inju res to cytokines (CKs) are the important pathological taches. Nuclear factor-κB( NF-κB) is eukaryocyte transcription factor relating with oxidative stress and CKs, which can modulate the expression of many inflammatory factors,which may have important effect on NASH. There a ren't any ideal medications to prevent NASH. Chinese traditional medi cine (TCM) possesses some superiority on it. My tutor, professor Zhan g Chi-zhi, realized in his clinical work that NASH may be caused by e ating fat and sweet excessively for a long time, which lead to phlegm and blood stasis generating inside, constrained liver qi, heat being transformed due to stagnation for a long time, yin essence being was ted secretly, coming into being that the pathological characteristic of which the nature is insufficient but the signs are looked like exc ess. The principle of its treatment should be to supplement liver and kidney, to clear away heat evil and disinhibit water. He chose QI Ji Preparation(made up of medlar fruit and silybin ) to treat it and ga ined good effects. Using the model of NASH recognized by the world an d linking to the evolution of modern research of NASH, we observed th e hepatic tissue expression of NF-κB/IκB protein and mRNA in the esta te of NASH and threw light on the mechanism of QI Ji Preparation to p revent it by the technique of pathology, biochemistry and molecular b iology in the research, to offer deep study of pathogenesis and preve ntion of NASH.
Methods : the research was divided into two steps. The first step to study the effect of QI Ji Preparation on NASH (Expe riment I): Eighty clean graded male Spraque-Dawley rats, weight 190± 20g . ware feed 1W normally, then were randomly divided into 8 groups, namely normal control group (A), blank model group (B), QI Ji Preparat ion groups: low dose, common dose, high dose (C1,C2,C3), Compound Meth ionine and Choline Bitarte Tablets (CMCBT) group(D), medlar fruit grou
引文
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