乳黄制剂对肝硬化模型大鼠晚期糖基化终末产物（AGEs）的影响
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摘要
目的:晚期糖基化终末产物(AGEs)是指蛋白质、脂质或核酸等大分子在没有酶参与的条件下,自发地与葡萄糖或其他还原单糖反应所生成的稳定的共价化合物。近来研究认为肝脏在AGEs的代谢中起主要作用。其中肝硬化与AGEs关系密切,肝硬化患者血清AGEs水平是升高的。其发生机制在于:一方面,肝脏是AGEs主要的代谢部位,肝硬化时伴随的氧应激及内毒素血症、肝肾功能不全等可促进AGEs的产生和(或)抑制其降解;另一方面,血液和肝组织内AGEs增加可通过促进肝脏的氧化应激/脂质过氧化损伤、炎症反应以及肝纤维化等途径,诱发或加重肝脏损伤。肝硬化时普遍存在的肠源性内毒素血症(IETM)可能有助于AGEs的形成,因为内毒素可以通过激活单核巨噬细胞系统介导的细胞毒性作用,单核巨噬细胞系统包括单核细胞和枯否细胞,被脂多糖(LPS)激活后,可表达、分泌各种细胞因子和炎性介质,如肿瘤坏死因子-a(TNF-a)、白细胞介素(IL-1、IL-6、IL-8)、白三烯(LTs)、血小板活化因子(PAF),氧自由基、一氧化氮(NO)以及内皮素(ET-1)等,这些介质构成一个独特的网络系统,共同参与对肝组织及其它器官损伤,乃至出现多器官衰竭。这也可能与内毒素诱导氧应激,从而增加AGEs形成有关。降低或抑制AGEs水平,可以减少氧应激和促进炎症反应,缓解肝纤维化程度。而治疗内毒素血症,抑制内毒素的生成和对内毒素进行清除,减少氧应激,可以降低AGEs水平,减轻肝损伤,有利于肝硬化程度的好转。乳黄制剂是国家名老中医张赤志教授根据中医理论和临床经验总结出治疗肝性脑病的中药制剂,在前期防治急性肝性脑病和肝硬化IETM中的实验研究中发现乳黄制剂能降低血清内毒素水平,为了进一步研究该制剂对肝硬化模型大鼠AGEs的影响,我们将从细胞分子水平进行探讨,为肝硬化的防治提供新的理论依据。
方法:SPF级雄性Wister大鼠88只,体重200～250克,随机分为6组:正常组、模型组、预防组、预防对照组、模型治疗组、模型治疗对照组。除正常组外,其余各组均采用CCL4复合因素法制造肝硬化模型,饲养10周。正常组、模型组生理盐水1ml/100g灌胃;预防组、预防对照组在造模同时分别给予乳黄制剂、乳果糖2ml/d灌胃;造模第9周开始模型治疗组、模型治疗对照组分别给予乳黄制剂、乳果糖2ml/d灌胃连续2周。第10周末处死大鼠取材。(1)酶联免疫分析法(ELISA)定量测定大鼠肝组织匀浆AGEs含量(2).在无热源条件下采右心室血5 ml检测血清ALT、AST、ALB、TP、TBil含量;(3)取肝左叶作病检。
结果:(1)乳黄制剂可明显降低肝硬化大鼠AGEs含量水平(P＜0.05);(2)乳黄制剂可明显降低肝硬化大鼠血清ALT、AST、TBil水平(P＜0.05)尤以预防组效果明显;(3)乳黄制剂能改善预防组和模型治疗组肝组织的肝硬化以及纤维组织增生、炎性细胞浸润程度,其中预防组肝组织的病理变化改善明显。
结论:乳黄制剂能有效降低肝组织中AGEs的水平,有利于肝功能的改善,肝硬化程度的好转,可能有下列机制实现:①乳黄制剂通过减少内毒素的生成,促进肝功能恢复,使肝细胞清除AGEs的能力增强;②加快肠道内毒素的清除,减少氧应激,从而减少AGEs的形成。
Objective:Advanced glycation end products(AGEs) refers to protein,lipid or nucleic acid molecules in the absence of enzyme under the conditions of participation,spontaneous with glucose or other monosaccharides to restore the response generated by a stable covalent compounds.Recent studies suggest that the liver in the metabolism of AGEs play a major role.AGEs are closely related and one of liver cirrhosis,liver cirrhosis,the level of serum AGEs are elevated.Its mechanism is to happen:on the one hand,liver AGEs are the major site of metabolism,liver cirrhosis,when accompanied by oxidative stress and endotoxemia,liver and kidney dysfunction,such as AGEs can promote the generation and(or) inhibiting its degradation;another connection,the blood and liver tissue AGEs increase through the promotion of liver oxidative stress/lipid peroxidation injury,inflammatory response and liver fibrosis,such as ways to induce or aggravate liver damage.When the prevalence of cirrhosis intestinal endotoxemia(IETM) probably contribute to the formation of AGEs,because endotoxin can activate monocyte-macrophage system-mediated cytotoxicity,monocytemacr-ophage system,including mononuclear cells and Kupffer cells,the lipopolysaccharide(LPS) activated,can express and secrete various cytokines and inflammatory mediators,such as tumor necrosis factor-a(TNF-a),interleukin-(IL-1,IL-6,IL-8), leukotrienes(LTs),platelet-activating factor(PAF),oxygen free radicals,nitric oxide(NO) and endothelin(ET-1),which constitute a unique medium network system,the joint participation of the liver tissue and other organ damage,and even the emergence of multi-organ failure.This also may be associated with endotoxin-induced oxidative stress,thus increasing the formation of AGEs.Reduce or suppress the level of AGEs can reduce oxidative stress and promote the inflammatory response and alleviate the degree of liver fibrosis.And treatment of endotoxemia and suppress the generation of endotoxin and endotoxin removal,reducing oxidative stress,can reduce the level of AGEs to reduce liver injury and is conducive to the improvement of the degree of liver cirrhosis.RuHuang preparation is old country TCM Professor Zhang Chizhi According to Chinese medicine theories and clinical experience summarize the treatment of hepatic encephalopathy in Chinese medicine preparations,at early prevention and treatment of acute hepatic encephalopathy and cirrhosis IETM in the experimental study of RuHuang preparation is found to reduce serum endotoxin level in order to further study of the preparation on liver cirrhosis rat model the effects of AGEs,we will explore the cellular and molecular level,in order to provide a new prevention and treatment of cirrhosis of the theoretical basis.
Methods:SPF level 88 male Wister rats,weighing 200 to 230 grams,were randomly divided into 6 groups:normal group,model group,prevention group,the prevention of the control group,model group,model control group.Except the normal group,the rest of the group factor method used to create composite CCL4 liver cirrhosis model,reared for 10 weeks.Normal group,model group distilled water 1ml/100g orally;prevention group,the prevention model in the control group were given RuHuang preparation at the same time,lactulose 2ml/d orally;model the first nine weeks beginning model of the treatment group,model control group Wong agents were given RuHuang preparation,lactulose 2ml/d orally for 2 weeks.No.10 rats were killed over the weekend based.(1) enzyme-linked immunosorbent assay(ELISA) quantitative determination of rat liver tissue homogenate AGEs content(2) in the absence of heat mining right ventricle under the conditions of 5 ml of serum ALT,AST,ALB,TP,TBil content;(3) check for diseases of liver left lobe seizure.
Results:(1) RuHuang preparation can significantly reduce the concentration level of AGEs in rats with cirrhosis(P＜0.05);(2) RuHuang preparation can be significantly reduced in cirrhotic rat serum ALT,AST levels(P＜0.05) particularly effective prevention group;(3) RuHuang preparation can improve the preventive treatment group and model group cirrhotic liver tissue and fibrous tissue hyperplasia,the extent of inflammatory cell infiltration,one of the preventive group,the pathological changes in liver tissue to improve significantly.
Conclusion:RuHuang preparation can effectively reduce the liver tissue levels of AGEs,there is conducive to the improvement of liver function,cirrhosis degree of improvement possible implementation has the following mechanisms:①to reduce the generation of endotoxin,and promote the restoration of liver function,so that removal of liver cells enhance the ability of AGEs;②to speed up the removal of intestinal endotoxin to reduce oxidative stress,thereby reducing the formation of AGEs.
方法:SPF级雄性Wister大鼠88只,体重200～250克,随机分为6组:正常组、模型组、预防组、预防对照组、模型治疗组、模型治疗对照组。除正常组外,其余各组均采用CCL4复合因素法制造肝硬化模型,饲养10周。正常组、模型组生理盐水1ml/100g灌胃;预防组、预防对照组在造模同时分别给予乳黄制剂、乳果糖2ml/d灌胃;造模第9周开始模型治疗组、模型治疗对照组分别给予乳黄制剂、乳果糖2ml/d灌胃连续2周。第10周末处死大鼠取材。(1)酶联免疫分析法(ELISA)定量测定大鼠肝组织匀浆AGEs含量(2).在无热源条件下采右心室血5 ml检测血清ALT、AST、ALB、TP、TBil含量;(3)取肝左叶作病检。
结果:(1)乳黄制剂可明显降低肝硬化大鼠AGEs含量水平(P＜0.05);(2)乳黄制剂可明显降低肝硬化大鼠血清ALT、AST、TBil水平(P＜0.05)尤以预防组效果明显;(3)乳黄制剂能改善预防组和模型治疗组肝组织的肝硬化以及纤维组织增生、炎性细胞浸润程度,其中预防组肝组织的病理变化改善明显。
结论:乳黄制剂能有效降低肝组织中AGEs的水平,有利于肝功能的改善,肝硬化程度的好转,可能有下列机制实现:①乳黄制剂通过减少内毒素的生成,促进肝功能恢复,使肝细胞清除AGEs的能力增强;②加快肠道内毒素的清除,减少氧应激,从而减少AGEs的形成。
Objective:Advanced glycation end products(AGEs) refers to protein,lipid or nucleic acid molecules in the absence of enzyme under the conditions of participation,spontaneous with glucose or other monosaccharides to restore the response generated by a stable covalent compounds.Recent studies suggest that the liver in the metabolism of AGEs play a major role.AGEs are closely related and one of liver cirrhosis,liver cirrhosis,the level of serum AGEs are elevated.Its mechanism is to happen:on the one hand,liver AGEs are the major site of metabolism,liver cirrhosis,when accompanied by oxidative stress and endotoxemia,liver and kidney dysfunction,such as AGEs can promote the generation and(or) inhibiting its degradation;another connection,the blood and liver tissue AGEs increase through the promotion of liver oxidative stress/lipid peroxidation injury,inflammatory response and liver fibrosis,such as ways to induce or aggravate liver damage.When the prevalence of cirrhosis intestinal endotoxemia(IETM) probably contribute to the formation of AGEs,because endotoxin can activate monocyte-macrophage system-mediated cytotoxicity,monocytemacr-ophage system,including mononuclear cells and Kupffer cells,the lipopolysaccharide(LPS) activated,can express and secrete various cytokines and inflammatory mediators,such as tumor necrosis factor-a(TNF-a),interleukin-(IL-1,IL-6,IL-8), leukotrienes(LTs),platelet-activating factor(PAF),oxygen free radicals,nitric oxide(NO) and endothelin(ET-1),which constitute a unique medium network system,the joint participation of the liver tissue and other organ damage,and even the emergence of multi-organ failure.This also may be associated with endotoxin-induced oxidative stress,thus increasing the formation of AGEs.Reduce or suppress the level of AGEs can reduce oxidative stress and promote the inflammatory response and alleviate the degree of liver fibrosis.And treatment of endotoxemia and suppress the generation of endotoxin and endotoxin removal,reducing oxidative stress,can reduce the level of AGEs to reduce liver injury and is conducive to the improvement of the degree of liver cirrhosis.RuHuang preparation is old country TCM Professor Zhang Chizhi According to Chinese medicine theories and clinical experience summarize the treatment of hepatic encephalopathy in Chinese medicine preparations,at early prevention and treatment of acute hepatic encephalopathy and cirrhosis IETM in the experimental study of RuHuang preparation is found to reduce serum endotoxin level in order to further study of the preparation on liver cirrhosis rat model the effects of AGEs,we will explore the cellular and molecular level,in order to provide a new prevention and treatment of cirrhosis of the theoretical basis.
Methods:SPF level 88 male Wister rats,weighing 200 to 230 grams,were randomly divided into 6 groups:normal group,model group,prevention group,the prevention of the control group,model group,model control group.Except the normal group,the rest of the group factor method used to create composite CCL4 liver cirrhosis model,reared for 10 weeks.Normal group,model group distilled water 1ml/100g orally;prevention group,the prevention model in the control group were given RuHuang preparation at the same time,lactulose 2ml/d orally;model the first nine weeks beginning model of the treatment group,model control group Wong agents were given RuHuang preparation,lactulose 2ml/d orally for 2 weeks.No.10 rats were killed over the weekend based.(1) enzyme-linked immunosorbent assay(ELISA) quantitative determination of rat liver tissue homogenate AGEs content(2) in the absence of heat mining right ventricle under the conditions of 5 ml of serum ALT,AST,ALB,TP,TBil content;(3) check for diseases of liver left lobe seizure.
Results:(1) RuHuang preparation can significantly reduce the concentration level of AGEs in rats with cirrhosis(P＜0.05);(2) RuHuang preparation can be significantly reduced in cirrhotic rat serum ALT,AST levels(P＜0.05) particularly effective prevention group;(3) RuHuang preparation can improve the preventive treatment group and model group cirrhotic liver tissue and fibrous tissue hyperplasia,the extent of inflammatory cell infiltration,one of the preventive group,the pathological changes in liver tissue to improve significantly.
Conclusion:RuHuang preparation can effectively reduce the liver tissue levels of AGEs,there is conducive to the improvement of liver function,cirrhosis degree of improvement possible implementation has the following mechanisms:①to reduce the generation of endotoxin,and promote the restoration of liver function,so that removal of liver cells enhance the ability of AGEs;②to speed up the removal of intestinal endotoxin to reduce oxidative stress,thereby reducing the formation of AGEs.
引文
[1]费新应,张赤志.大黄乳酸菌素泡腾片对肝性脑病大鼠内毒素的影响.中华实用中西医结合杂志,2003;5:622.
[2]韩德五,马学慧,赵元昌.肝硬化动物模型的研究.山西医药杂志,1979;4:1-4.
[3]周忠信,王捷.肝硬化动物模型研究进展.上海实验动物科学,2002:22(4):245-248.
[4]贾林,张美华,杜洪等.双歧三联活菌对鼠轻微肝性脑病模型的实验治疗及机制.中华消化杂志,2004;24(9):552-553.
[5]Bielecka M,Biedrzycka E,Najkowska A,et al.Effect of non-digestible oligosaccharides on gut microecosystem in rats.Food ResInter,2002;35:139-144.
[6]于中麟,钱林学.乳果糖在肝病中的应用.中华内科杂志,1996;35:65-66.
[7]Liao W,Cui XS,Jin XY,et al.Lactulosea potential drug for thetreatment of inflammatory bowel disease[J].Med ttypotheses,1994;43(4):234.
[8]项明洁,刘明,李云珠等.乳果糖对肠道菌群及SIgA含量的影响[J].江西医学检验,2002;20(2):72.
[9]王浴生,邓文龙,薛春生.中药药理与应用,北京:人民卫生出版社,2000,2:70-74.
[10]吴新娟.生大黄防治肝炎后肝硬化并发肝性脑病16例.浙江中西医结合杂志,1999;9(3):194.
[11]陈德昌.大黄对危重患者胃肠道的保护作用.中国危重症急救医学,2000;2:87.
[12]陈馥馨,高小山等.大黄十种不同煎煮法的部分药效学比较研究.中成药,1990;12(7):2-4.
[13]熊德鑫主编.现代微生物学[M].北京:中国科技出版社,2000,20-63.
[14]张达荣.肠道菌群,肠源性内毒素与慢性肝病.见:邱德凯,主编.慢性肝病临床并发症.上海:上海科学技术出版社,2001,258-259.
[15]林敏西.肝病与肠源性内毒素血症防治.中国感染控制杂志,2003,2(1):74-77.
[16]郭恩建,戴建红,林敏西等.体外乳酸菌素促双歧杆菌生长实验初步观察.中国微生态学杂志,2000;12(5):266.
[17]高福生,刘宾,展玉涛等.肝纤维化大鼠晚期糖基化终末产物变化及氨基胍的干预作用.中华肝脏病杂志[J],2006;14(3):178-181.
[18]Wang Z,Li DD.New development in clinical pathological actions and inhibitors of advanced glycation end products.Zhongguo Xinyao Zazhi,2002;11:113-116.
[1]焦东海.大黄在急救医学中的应用概述.中国中西医结合急救杂志,2000;7(1):3-4.
[2]廖树琪,毛德文.大黄煎剂保留灌肠治疗重型肝炎40例总结.湖南中医杂志,2002;18(4):9-10.
[3]张民庆,张名伟,唐德才.现代临床中药学.上海:上海中医药大学出版社,2002;174.
[4]那淑敏,李立波.嗜酸乳杆菌发酵代谢产物分析.中国微生态学杂志,1999;11(5):266.
[1]夏德馨.扶正为主治疗肝硬化腹水[M].上海:上海科技文献出版社,1987:13.
[2]张定国,李则藩.治疗肝硬化经验IJ].吉林中医药,2002;2:7-8.
[3]朱慧民,程雅君,朱天民.肝硬化防治机理探讨[J].安徽中医临床杂志,2 001;13(1):21-22.
[4]穆齐金,王著敏.肝炎后肝硬化临床证治疗特点[J].上海中医药杂志,2001;(4):21-22.
[5]蒋建.养正消积法治疗早期肝硬化的体会[J].实用中医内科杂志,1998;12(4):20.
[6]周后全.中医辨证治疗156例肝硬化临床疗效观察[J].中国中西医结合脾胃杂志,2000;8(5):289.
[7]姚泽民,杨必金.肝硬化的辨证施治[J].湖北中医杂志,2003;25(12):37.
[8]骆丰等.毒邪辨析.江苏中医,1999;20(11):7-8.
[9]谢颖桢等.试论毒邪致病及症侯特征.北京中医药大学学报,2001;24(1):11-12.
[10]陈秀斌.大黄清除活性氧的作用.中国药学杂志,1996;18:461.
[11]焦东海.单味精制大黄片治疗病毒性肝炎(黄疸型)的临床疗效观察[J].上海中医药杂志,1993;(1):32-33.
[12]温枫.大黄的药理作用及其临床应用.山西中医,2000;16(3):53-54.
[13]黄以群.大黄对黄疸型肝炎中TNF—毗、IL 6的影响.中华传染病杂志,2003;21(2):137-139.
[14]陈德昌.大黄对危重患者胃肠道的保护作用.中国危重症急救医学,2000;2:87.
[15]吴连英.中药大黄炮制研究(Ⅵ)炮制对大黄解热作用的影响.中药通报,1986;(6):24.
[1]Horiuchi S.The liver is the main site for metabolism of circulating advanced glycation end products J Heptato[,2002;36:1 23-1 25.
[2]Fehrenbach H.Weiskrchen R,Kasper M.et al.Up—regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to my of ibroblat-s.Hepatology,2001;34:943-952.
[3]Bastaa G,Schmidtb AM,Caterina RF.Cardiovasc Res,2004;63: 582-592.
[4]蔡晓波 糖基化终末产物与肝病,国际消化病杂志,2006;26(1),8.
[5]Smedsrod B.Melkko J.Araki NH.et al.Biochem J,1997;332:567-573.
[6]Matsumoto K,Sano H,Nagai R,et al.Biochem J,2000;352:233-240.
[7]Chavakis T,Bierhaus B,Peter P.Microbes Infect,2004;6:1219-I 225.
[8]Ebekov(?) K,Kupovd V,Schinzel R,et al.J Hepatol,2002;36:66-71.
[9]高福生,刘宾,展玉涛等.肝纤维化大鼠晚期糖基化终末产物变化及氨基胍的干预作用.中华肝脏病杂志[J],2006;14(3):178-181.
[10]王真,李电东.晚期糖基化终末产物的临床病理机制及抑制剂的研究进展.中国新药杂志,2002;11:113-116.
Wang Z,Li DD.New development in clinical pathological actions and inhibitors of advanced glycation end products.Zhongguo Xinyao.Zazhi,2002;11:113-116.
[11]Sebekova K,Kupeova V,Schinzcl et al.Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis,amelioration by liver transplantation.J Hepatol,2002;36:66-71.
[12]Clot P,Tabone M,Arico S,et al.Monitoring oxidative damage in patients with liver cirhosis an d different daily alcohol intake.Gut,1994;35:1637-1643.
[13]Monnier VM.Arch Biochem Biophys,2003;419:1-15.
[14]Liehr H,Grun M,Brunswig D,et al.Letter:Endotoxaemia in liver cirhosis:treatment with polymyxin B.Lancet,1975;1:810-811.
[15]Bastaa G.Schmidtb AM.Caterina RF.Cardiovasc Res,2004;63: 582-592.
[16]Zeng S,Feirt N,Goldstein M,et al.Hepatology,2004;39:422-432.
[17]Bidasee KR,Nallani K,Yu YQ,et al.Diabetes,2003;52;1825-1836.
[18]Sano H,Higashi T,M atsumoto K.et al.J Bid Chem.1998;273:8630-8637.
[19]Bomzon A.Ljubuncic P.Pharmacol Ther,2001;89:295-308.
[20]Nolan J P.Endotoxin as mediations of heptic injury —an idea "whose time come again"[J].Hepatology,1989;10:887-891.
[21]孙毅,王进军,张淑英.慢性肝病患者血清肿瘤坏死因子的研究[J].中华肝脏病杂志,1999;7:5 7.
[22]李惠珍,邓明德,李爱月等.慢性乙型肝炎患者血清中TGFβ、TNFα含量与肝纤维化程度的关系探讨[J].肝脏,2001;6(1):33.
[23]Miyata T,Kurokawa K,Van Y,et al.Kidney Int,2000;76:S120-S125.
[1]夏德馨.扶正为主治疗肝硬化腹水[M].上海:上海科技文献出版社,1987:13.
[2]张定国,李则藩.治疗肝硬化经验[J].吉林中医药,2002;(2):7-8.
[3]朱慧民,程雅君,朱天民.肝硬化防治机理探讨[J].安徽中医临床杂志,2001;13(1):21-22.
[4]穆齐金,王著敏.肝炎后肝硬化临床证治疗特点[J].上海中医药杂志,2001;(4):21-22.
[5]蒋建.养正消积法治疗早期肝硬化的体会[J].实用中医内科杂志,1998:12(4):20.
[6]王署东.丹参及其制剂的药理研究及临床应用[J].中国中医药科技,2000:7(4):720.
[7]曹文晓.三七粉对慢性肝病纤维组织代谢指标的影响[J].河北中西医结合杂志,1998;7(5):671.
[8]李旭红,王崇国,庄岳鹏.苦参素注射液治疗肝纤维化42例[J].中国中西医结合消化杂志,2002;10(2):117.
[9]陈颖伟,李国定.汉防已甲素抗肝纤维化研究进展[J].中华消化杂志,2000;20(1):47-48.
[10]姜国峰,姚至伟,徐说钦.藻草软肝灵胶囊治疗肝炎后肝硬化76例临床观察[J].中华实用中西医杂志,2003;3(7):1350.
[11]于海玲.中药益肝元颗粒抗肝硬化的实验研究[J].成都医药杂志,2002;28(1):3.
[12]彭天吉.双参柔肝颗粒对实验性肝硬化大鼠的治疗作用[J].中国药科大学学报,2000;31(5):379.382.
[13]叶光华,王新宽,赵大同等.实验研究益活1号逆转肝纤维化的实验研究[J].中国中西医结合外科杂志,1999;5(1):40-42.
[14]吴孟超,杨少顺.大鼠肝硬变模型复制的研究[J].中华实验外科杂志,1984(4):145.
[15]温志坚,彭龙玲,曹毓等.小柴胡汤提取物治疗大鼠实验性肝损伤肝硬化的研究[J].中西医结合肝病杂志,2001;11(1):21-23.
[16]钦丹萍,蒋挺英,韩建新等.下瘀血汤防治肝硬化的实验研究[J].中国实验方剂学杂志,1999;5(6):19-21.
[17]彭天吉,蒋永培.双参柔肝颗粒剂对实验性肝硬化大鼠的治疗作用[J].中国药科大学学报,2000;31(5):379-382.
[18]汤日鹂,卢秉久.软肝冲剂治疗肝硬化的实验研究[J].中医药学刊,2002:20(2):223-224.
[19]孙殿兴,齐建民,郗德圣等.中西医结合治疗1126例肝硬化的疗效分析[J].上海中医药杂志,1999;4:26-27.
[20]周发洋.肝硬化诊治心得[J].中医杂志,2000;41(10):588-589.
[21]霍清萍,张延超.临床研究肝瘀热互结与肝纤维化关系的临床研究[J].新中医,1999;31(4):36-37.
[22]周后全.中医辨证治疗156例肝硬化临床疗效观察[J].中国中西医 结合脾胃杂志,2000;8(5):289.
[23]朱方石,陆伟,朱海杭等.肝硬化不同证型对TP、ALB、A＼G比值的影响[J].中医药研究,1997;(3):13-15.
[24]骆群,张导文.血清透明质酸含量测定慢性肝炎及肝硬化与中医分型关系[J].浙江中西医结合杂志,1997;7(3):136-137.
[25]李平.费开扬教授治疗肝硬化用药经验[J].新中医,2000;32(5):11-12.
[26]汪平,陈新渝,张洪雷.王希知老中医治疗肝硬化经验[J].中国中医急症,1999;8(6):264.
[27]王尚金.自拟清化软肝汤辨证治疗肝硬化[J].中医研究,2002;15(1):50-51.
[28]黄洪沛.补气活血法治疗肝硬化25例[J].实用中医内科杂志,2001;15(2):27.
[29]马作峰.解毒活血扶正法治疗肝硬化308例[J].山西中医,2002;18(2):13-15.
[30]陈兰.软肝抗纤方治疗肝炎后肝硬化96例[J].湖北中医杂志,2003:25(2):20.
[31]沙琪,程慧桢,谢秀英.复方丹参滴丸治疗活动性肝硬化47例[J].中西医结合肝病杂志,1999;9(6):50.
[32]张伟,张木森,司慧远.和络舒肝胶囊治疗肝炎肝硬化72例[J].中西医结合肝病杂志,2002;12(5):302.
[33]薛爱荣.黄芪注射液联合阿拓莫兰治疗肝硬化50例[J].中西医结合肝病杂志,2002;12(3):179.
[34]姚泽民,杨必金.肝硬化的辨证施治[J].湖北中医杂志,2003;25(12):37.
[35]刘宜进.中药内外合治肝硬化32例临床观察[J].湖南中医杂志,1999;15(2):17.
[36]董希.内外合治肝炎后肝硬化60例临床观察[J].湖南中医杂志, 1998;14(5):12-15.
[2]韩德五,马学慧,赵元昌.肝硬化动物模型的研究.山西医药杂志,1979;4:1-4.
[3]周忠信,王捷.肝硬化动物模型研究进展.上海实验动物科学,2002:22(4):245-248.
[4]贾林,张美华,杜洪等.双歧三联活菌对鼠轻微肝性脑病模型的实验治疗及机制.中华消化杂志,2004;24(9):552-553.
[5]Bielecka M,Biedrzycka E,Najkowska A,et al.Effect of non-digestible oligosaccharides on gut microecosystem in rats.Food ResInter,2002;35:139-144.
[6]于中麟,钱林学.乳果糖在肝病中的应用.中华内科杂志,1996;35:65-66.
[7]Liao W,Cui XS,Jin XY,et al.Lactulosea potential drug for thetreatment of inflammatory bowel disease[J].Med ttypotheses,1994;43(4):234.
[8]项明洁,刘明,李云珠等.乳果糖对肠道菌群及SIgA含量的影响[J].江西医学检验,2002;20(2):72.
[9]王浴生,邓文龙,薛春生.中药药理与应用,北京:人民卫生出版社,2000,2:70-74.
[10]吴新娟.生大黄防治肝炎后肝硬化并发肝性脑病16例.浙江中西医结合杂志,1999;9(3):194.
[11]陈德昌.大黄对危重患者胃肠道的保护作用.中国危重症急救医学,2000;2:87.
[12]陈馥馨,高小山等.大黄十种不同煎煮法的部分药效学比较研究.中成药,1990;12(7):2-4.
[13]熊德鑫主编.现代微生物学[M].北京:中国科技出版社,2000,20-63.
[14]张达荣.肠道菌群,肠源性内毒素与慢性肝病.见:邱德凯,主编.慢性肝病临床并发症.上海:上海科学技术出版社,2001,258-259.
[15]林敏西.肝病与肠源性内毒素血症防治.中国感染控制杂志,2003,2(1):74-77.
[16]郭恩建,戴建红,林敏西等.体外乳酸菌素促双歧杆菌生长实验初步观察.中国微生态学杂志,2000;12(5):266.
[17]高福生,刘宾,展玉涛等.肝纤维化大鼠晚期糖基化终末产物变化及氨基胍的干预作用.中华肝脏病杂志[J],2006;14(3):178-181.
[18]Wang Z,Li DD.New development in clinical pathological actions and inhibitors of advanced glycation end products.Zhongguo Xinyao Zazhi,2002;11:113-116.
[1]焦东海.大黄在急救医学中的应用概述.中国中西医结合急救杂志,2000;7(1):3-4.
[2]廖树琪,毛德文.大黄煎剂保留灌肠治疗重型肝炎40例总结.湖南中医杂志,2002;18(4):9-10.
[3]张民庆,张名伟,唐德才.现代临床中药学.上海:上海中医药大学出版社,2002;174.
[4]那淑敏,李立波.嗜酸乳杆菌发酵代谢产物分析.中国微生态学杂志,1999;11(5):266.
[1]夏德馨.扶正为主治疗肝硬化腹水[M].上海:上海科技文献出版社,1987:13.
[2]张定国,李则藩.治疗肝硬化经验IJ].吉林中医药,2002;2:7-8.
[3]朱慧民,程雅君,朱天民.肝硬化防治机理探讨[J].安徽中医临床杂志,2 001;13(1):21-22.
[4]穆齐金,王著敏.肝炎后肝硬化临床证治疗特点[J].上海中医药杂志,2001;(4):21-22.
[5]蒋建.养正消积法治疗早期肝硬化的体会[J].实用中医内科杂志,1998;12(4):20.
[6]周后全.中医辨证治疗156例肝硬化临床疗效观察[J].中国中西医结合脾胃杂志,2000;8(5):289.
[7]姚泽民,杨必金.肝硬化的辨证施治[J].湖北中医杂志,2003;25(12):37.
[8]骆丰等.毒邪辨析.江苏中医,1999;20(11):7-8.
[9]谢颖桢等.试论毒邪致病及症侯特征.北京中医药大学学报,2001;24(1):11-12.
[10]陈秀斌.大黄清除活性氧的作用.中国药学杂志,1996;18:461.
[11]焦东海.单味精制大黄片治疗病毒性肝炎(黄疸型)的临床疗效观察[J].上海中医药杂志,1993;(1):32-33.
[12]温枫.大黄的药理作用及其临床应用.山西中医,2000;16(3):53-54.
[13]黄以群.大黄对黄疸型肝炎中TNF—毗、IL 6的影响.中华传染病杂志,2003;21(2):137-139.
[14]陈德昌.大黄对危重患者胃肠道的保护作用.中国危重症急救医学,2000;2:87.
[15]吴连英.中药大黄炮制研究(Ⅵ)炮制对大黄解热作用的影响.中药通报,1986;(6):24.
[1]Horiuchi S.The liver is the main site for metabolism of circulating advanced glycation end products J Heptato[,2002;36:1 23-1 25.
[2]Fehrenbach H.Weiskrchen R,Kasper M.et al.Up—regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to my of ibroblat-s.Hepatology,2001;34:943-952.
[3]Bastaa G,Schmidtb AM,Caterina RF.Cardiovasc Res,2004;63: 582-592.
[4]蔡晓波 糖基化终末产物与肝病,国际消化病杂志,2006;26(1),8.
[5]Smedsrod B.Melkko J.Araki NH.et al.Biochem J,1997;332:567-573.
[6]Matsumoto K,Sano H,Nagai R,et al.Biochem J,2000;352:233-240.
[7]Chavakis T,Bierhaus B,Peter P.Microbes Infect,2004;6:1219-I 225.
[8]Ebekov(?) K,Kupovd V,Schinzel R,et al.J Hepatol,2002;36:66-71.
[9]高福生,刘宾,展玉涛等.肝纤维化大鼠晚期糖基化终末产物变化及氨基胍的干预作用.中华肝脏病杂志[J],2006;14(3):178-181.
[10]王真,李电东.晚期糖基化终末产物的临床病理机制及抑制剂的研究进展.中国新药杂志,2002;11:113-116.
Wang Z,Li DD.New development in clinical pathological actions and inhibitors of advanced glycation end products.Zhongguo Xinyao.Zazhi,2002;11:113-116.
[11]Sebekova K,Kupeova V,Schinzcl et al.Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis,amelioration by liver transplantation.J Hepatol,2002;36:66-71.
[12]Clot P,Tabone M,Arico S,et al.Monitoring oxidative damage in patients with liver cirhosis an d different daily alcohol intake.Gut,1994;35:1637-1643.
[13]Monnier VM.Arch Biochem Biophys,2003;419:1-15.
[14]Liehr H,Grun M,Brunswig D,et al.Letter:Endotoxaemia in liver cirhosis:treatment with polymyxin B.Lancet,1975;1:810-811.
[15]Bastaa G.Schmidtb AM.Caterina RF.Cardiovasc Res,2004;63: 582-592.
[16]Zeng S,Feirt N,Goldstein M,et al.Hepatology,2004;39:422-432.
[17]Bidasee KR,Nallani K,Yu YQ,et al.Diabetes,2003;52;1825-1836.
[18]Sano H,Higashi T,M atsumoto K.et al.J Bid Chem.1998;273:8630-8637.
[19]Bomzon A.Ljubuncic P.Pharmacol Ther,2001;89:295-308.
[20]Nolan J P.Endotoxin as mediations of heptic injury —an idea "whose time come again"[J].Hepatology,1989;10:887-891.
[21]孙毅,王进军,张淑英.慢性肝病患者血清肿瘤坏死因子的研究[J].中华肝脏病杂志,1999;7:5 7.
[22]李惠珍,邓明德,李爱月等.慢性乙型肝炎患者血清中TGFβ、TNFα含量与肝纤维化程度的关系探讨[J].肝脏,2001;6(1):33.
[23]Miyata T,Kurokawa K,Van Y,et al.Kidney Int,2000;76:S120-S125.
[1]夏德馨.扶正为主治疗肝硬化腹水[M].上海:上海科技文献出版社,1987:13.
[2]张定国,李则藩.治疗肝硬化经验[J].吉林中医药,2002;(2):7-8.
[3]朱慧民,程雅君,朱天民.肝硬化防治机理探讨[J].安徽中医临床杂志,2001;13(1):21-22.
[4]穆齐金,王著敏.肝炎后肝硬化临床证治疗特点[J].上海中医药杂志,2001;(4):21-22.
[5]蒋建.养正消积法治疗早期肝硬化的体会[J].实用中医内科杂志,1998:12(4):20.
[6]王署东.丹参及其制剂的药理研究及临床应用[J].中国中医药科技,2000:7(4):720.
[7]曹文晓.三七粉对慢性肝病纤维组织代谢指标的影响[J].河北中西医结合杂志,1998;7(5):671.
[8]李旭红,王崇国,庄岳鹏.苦参素注射液治疗肝纤维化42例[J].中国中西医结合消化杂志,2002;10(2):117.
[9]陈颖伟,李国定.汉防已甲素抗肝纤维化研究进展[J].中华消化杂志,2000;20(1):47-48.
[10]姜国峰,姚至伟,徐说钦.藻草软肝灵胶囊治疗肝炎后肝硬化76例临床观察[J].中华实用中西医杂志,2003;3(7):1350.
[11]于海玲.中药益肝元颗粒抗肝硬化的实验研究[J].成都医药杂志,2002;28(1):3.
[12]彭天吉.双参柔肝颗粒对实验性肝硬化大鼠的治疗作用[J].中国药科大学学报,2000;31(5):379.382.
[13]叶光华,王新宽,赵大同等.实验研究益活1号逆转肝纤维化的实验研究[J].中国中西医结合外科杂志,1999;5(1):40-42.
[14]吴孟超,杨少顺.大鼠肝硬变模型复制的研究[J].中华实验外科杂志,1984(4):145.
[15]温志坚,彭龙玲,曹毓等.小柴胡汤提取物治疗大鼠实验性肝损伤肝硬化的研究[J].中西医结合肝病杂志,2001;11(1):21-23.
[16]钦丹萍,蒋挺英,韩建新等.下瘀血汤防治肝硬化的实验研究[J].中国实验方剂学杂志,1999;5(6):19-21.
[17]彭天吉,蒋永培.双参柔肝颗粒剂对实验性肝硬化大鼠的治疗作用[J].中国药科大学学报,2000;31(5):379-382.
[18]汤日鹂,卢秉久.软肝冲剂治疗肝硬化的实验研究[J].中医药学刊,2002:20(2):223-224.
[19]孙殿兴,齐建民,郗德圣等.中西医结合治疗1126例肝硬化的疗效分析[J].上海中医药杂志,1999;4:26-27.
[20]周发洋.肝硬化诊治心得[J].中医杂志,2000;41(10):588-589.
[21]霍清萍,张延超.临床研究肝瘀热互结与肝纤维化关系的临床研究[J].新中医,1999;31(4):36-37.
[22]周后全.中医辨证治疗156例肝硬化临床疗效观察[J].中国中西医 结合脾胃杂志,2000;8(5):289.
[23]朱方石,陆伟,朱海杭等.肝硬化不同证型对TP、ALB、A＼G比值的影响[J].中医药研究,1997;(3):13-15.
[24]骆群,张导文.血清透明质酸含量测定慢性肝炎及肝硬化与中医分型关系[J].浙江中西医结合杂志,1997;7(3):136-137.
[25]李平.费开扬教授治疗肝硬化用药经验[J].新中医,2000;32(5):11-12.
[26]汪平,陈新渝,张洪雷.王希知老中医治疗肝硬化经验[J].中国中医急症,1999;8(6):264.
[27]王尚金.自拟清化软肝汤辨证治疗肝硬化[J].中医研究,2002;15(1):50-51.
[28]黄洪沛.补气活血法治疗肝硬化25例[J].实用中医内科杂志,2001;15(2):27.
[29]马作峰.解毒活血扶正法治疗肝硬化308例[J].山西中医,2002;18(2):13-15.
[30]陈兰.软肝抗纤方治疗肝炎后肝硬化96例[J].湖北中医杂志,2003:25(2):20.
[31]沙琪,程慧桢,谢秀英.复方丹参滴丸治疗活动性肝硬化47例[J].中西医结合肝病杂志,1999;9(6):50.
[32]张伟,张木森,司慧远.和络舒肝胶囊治疗肝炎肝硬化72例[J].中西医结合肝病杂志,2002;12(5):302.
[33]薛爱荣.黄芪注射液联合阿拓莫兰治疗肝硬化50例[J].中西医结合肝病杂志,2002;12(3):179.
[34]姚泽民,杨必金.肝硬化的辨证施治[J].湖北中医杂志,2003;25(12):37.
[35]刘宜进.中药内外合治肝硬化32例临床观察[J].湖南中医杂志,1999;15(2):17.
[36]董希.内外合治肝炎后肝硬化60例临床观察[J].湖南中医杂志, 1998;14(5):12-15.