8-烷基小檗碱同系物的合成与药理活性
|
摘要
小檗碱属异喹啉类生物碱,为黄连等传统中药的主要活性成分,在临床上被广泛用于治疗细菌感染引起的胃肠道疾病。现代科学研究显示,小檗碱不但具有良好的体内外抗菌作用,而且还表现出很好的调脂,降血糖,抗肿瘤,降血压,抗传染性原虫和抗心率失常等多种药理活性。本实验以小檗碱为先导化合物,通过在小檗碱分子C8位引入直链烷基的方法制备了不同碳链取代的8-烷基小檗碱同系物(Ber-C8-n,n=2,4,6,8,10,12,16),并采用相应的实验方法研究了Ber-C8-n的体外抗菌活性,体内调脂活性和体内毒性。实验方法与结果如下:
1.8-烷基小檗碱同系物的合成与鉴定
采用格氏试剂引入烷基的方法进行中间体8-烷基二氢小檗碱的合成,研究了反应溶剂(乙醚,二氧六环和四氢呋喃)对中间体8-烷基二氢小檗碱合成产率的影响。结果发现以THF为反应溶剂时中间体的合成产率最高,与乙醚比较产率提高近4倍,最后以THF为溶剂顺利制备了不同碳数烷基特别是长链烷基取代的Ber-C8-n。合成化合物的分子结构分别通过元素分析,UV,IR,~1H NMR和~(13)C NMR等方法进行了确认。
2.8-烷基小檗碱同系物的体外抗菌活性
抑菌圈法研究了18种微生物(包括G~+菌,G~-菌和真菌)对Ber-C8-n的敏感性,并采用比浊法测定了6种敏感微生物的MIC值。实验结果显示,G~+菌对Ber-C8-n敏感性明显强于G~-菌和真菌;Ber-C8-n的抗菌活性规律为:在小檗碱C8位接入烷基后抗菌活性随烷基碳数的增加而提高,但当烷基碳数＞8时,Ber-C8-n的抗菌活性则随烷基碳数的增加而下降,即8-辛基小檗碱(Ber-C8-8)在同系物中表现出最高抗菌活性。
3.8-烷基小檗碱同系物的抗菌活性差异的机理
分别以兔血红细胞及细胞膜,枯草杆菌和大肠杆菌完整细胞为实验材料,采用比色法和荧光分析方法研究了Ber-C8-n对兔血红细胞的溶血作用,Ber-C8-n对兔血红细胞膜和完整细菌细胞膜流动性以及Ber-C8-n对膜蛋白或菌体蛋白荧光的淬灭作用。
实验结果表明,抗菌活性越大的Ber-C8-n,其溶血作用越大;抗菌活性越大的Ber-C8-n,对细胞膜流动性的干扰作用和膜蛋白或菌体蛋白荧光的淬灭作用也越强。如在所有同系物中抗菌活性最强的Ber-C8-8和Ber-C8-6在红细胞溶血能力,细胞膜流动性的干扰能力和对膜蛋白或菌体蛋白荧光的淬灭能力上均表现为最强。定量分析与比较Ber-C8-n对枯草杆菌(G~+菌)和大肠杆菌(G~-菌)完整细菌细胞膜及菌体蛋白的影响作用发现,相同Ber-C8-n对枯草杆菌(G~+菌)细胞膜流动性的影响能力远大于对大肠杆菌(G~-菌)膜流动性的影响能力,但对两类细菌完整细胞蛋白的荧光淬灭作用无明显差异。
4.8-烷基小檗碱同系物的体内调脂活性
实验性高脂血症大鼠为动物模型,对Ber-C8-n的调脂活性及兴趣分子8-十六烷基小檗碱调脂作用的剂量效应进行了研究。
实验结果表明,接入亲脂性烷基有利于8-烷基小檗碱同系物体内调脂活性的发挥。长链烷基化合物8-月桂基小檗碱和8-十六烷基小檗碱的调脂活性高于小檗碱和其他8-烷基小檗碱同系物。与盐酸小檗碱比较,对高脂血症实验大鼠TC均值的下调能力分别提高了83%和97%,其它相关血清指标亦有明显改善趋势。剂量效应实验结果表明,8-十六烷基小檗碱能剂量依赖性的降低高脂血症实验大鼠血清TC和TG含量,减少腹腔脂肪和肝脏脂肪的积累,提高血清HDL-C含量,并能有效改善高脂血症实验大鼠的动脉硬化指数,食物利用率等相关病理指标。
5.8-烷基小檗碱同系物的体内毒性
昆明种小鼠为实验动物模型,采用改良寇氏法测定了8-烷基小檗碱同系物的LD_(50)值,并以SD大鼠为实验动物,经口125mg/kg·bw剂量处理6周,对兴趣分子8-辛基小檗碱,8-月桂基小檗碱和8-十六烷基小檗碱的肝肾毒性进行了初步评价。
实验结果表明,接入短链烷基后8-烷基小檗碱同系物的LD_(50)值与其先导化合物盐酸小檗碱比较大幅度减小,即毒性大幅增加。但随着接入烷基碳数的增加,8-烷基同系物的LD_(50)值随之增加,即毒性逐步下降。兴趣分子8-辛基小檗碱,8-月桂基小檗碱和8-十六烷基小檗碱的肝肾毒性实验结果表明,3个化合物在所设定实验条件下对实验大鼠的肝肾功能生化指标均无显著影响。
The isoquinoline alkaloids berberine, is an important active component of Rhizoma Coptidis, and used in the treatment of bacterial gastrointestinal diseases such as diarrhea. Modern scientific research indicated that berberine has not only antimicrobial activity in vitro and in vivo, but also other important pharmacological activities such as lipid-modulating, antihyperglycemic, antitumor, antihypertension and antiarrhythmia. To increase the pharmaceutica activity of berbeine 8-alkyl-berberine homologues with seriate different lipophilic property were synthesized in our laboratory by introducing different length alkyl at C8 position, some pharmacological effects of 8-alkyl-berberine homologues were studied including the antimicrobial activity, lipid-modulating effect, antihyperglycemic effect and toxicity. The methods and results are as follows:
1. The synthesis and molecular structure identification of 8-alkyl-berberine homologues
The synthesis approaches to 8-alkyl-dihydroberberine were carried out in three solvent, aether, dioxane and tetrahydrofuran. The result showed that the highest recovery of the compound had been achieved when synthesized in tetrahydrofuran. Compared with aether, the synthesized yield of 8-alkyl-dihydroberberine enhanced 4 times. The structure of 8-alkyl-berberine homologues synthesized was affirmed with element analysis, Ultraviolet spectrum, Infrared spectrum, ~1H NMR and ~(13)CNMR.
2. The antimicrobial activity of 8-alkyl-berberine homologues in vitro
The sensitivity of 18 microorganism come from G~+ bacteria, G~- bacteria and fungus to 8-alkyl-berberine homologues respectively were evaluated by inhibition zone method and MICs of 8-alkyl-berberine homologues against 6 sensitive microorganisms were determined by turbidimetric method respectively.
The result showed that G~+ bacteria were more sensitive than G~- bacteria and fungus. The antimicrobial activity increased as the length of aliphatic chain elongated and then decreased gradually when the alkyl chain exceeded 8 carbon atoms. 8-octyl-berberine showed the highest antimicrobial activity among all compounds.
3. The antimicrobial mechanism of 8-alkyl-berberine homologues in vitro
With rabbit red-blood cell and its cell membrane, B. subtilis (G~+) and E. coli (G~- ) as experimental material, the hemolysis effect on rabbit red-blood cell, disturbing effect on cell membrane stability and fluorescence quenching effect of 8-alkyl-berberine homologues on membrane protein or bacterial protein were determined by fluorescence spectrum analytical method.
Results showed that antimicrobial activity of the compound was stronger, the effect including hemolysis effect, disturbing effect on cell membrane stability and fluorescence quenching effect on membrane protein were stronger. 8-hexyl-berberine or 8-octyl-berberine showed highest disturbing effect on cell membrane stability and membrane protein of rabbit red-blood cell membrane, whole cell membrane stability and bacterial protein of B. subtilis (G~+) and E. coli (G~-). The experimental data were compared by quantitative analysis method between B. subtilis (G~+) and E. coli (G~- ), result showed that the disturbing ability to cell membrane stability of B. subtilis (G~+) is far more than E. coli (G~-), but fluorescence quenching ability to whole cells of B. subtilis (G~+) and E. coli (G~- ) is nearly same while same compound.
4. The lipid-modulating effect of 8-alkyl-berberine homologues in vivo
With experimental hyperlipidemia rats as animal model, the Lipid-modulating effects of 8-alkyl-berberine homologues are studied.
Result showed that the lipophilic properties of 8-alkyl-berberine homologues are beneficial to exerting Lipid-modulating effect in vivo. The long chain homologue 8-dodecyl-berberine and 8-cetyl-berberine showed better Lipid-modulating effect than berberine and other 8-alkyl-berberine homologues. For example, the serum TC value of 8-dodecyl-berberine and 8-cetyl-berberine group decreased respectively by 83% and 97% compared with berberine group. Dose-effect experiment showed that the decreasing of serum TC, serum TG and AI, and increasing of serum HDL-C of 8-dodecyl-berberine and 8-cetyl-berberine in experimental hyperlipidemia rats are dose dependent.
5. Preliminary study on toxicity of 8-alkyl-berberine homologues in vivo
With kuming mouse or SD rats as animal model, the LD_(50) of 8-alkyl-berberine homologues was determined according to modified karber's method, and the liver and kidney toxicity of interesting molecule 8-octyl-berberine, 8-dodecyl-berberine and 8-cetyl-berberine were observed at dosage of 125mg/kg.bw for 6 weeks.
Result showed that the toxicity of 8-alkyl berberine derivatives was stronger than that of berberine. However, by elongating the aliphatic chain, toxicity decreased gradually. 8-ethyl-berberine showed highest toxicity. 8-octyl-berberine, 8-dodecyl-berberine and 8-cetyl-berberine didn't showed obvious liver and kidney toxicity on the experimental condition of dosage and time.
1.8-烷基小檗碱同系物的合成与鉴定
采用格氏试剂引入烷基的方法进行中间体8-烷基二氢小檗碱的合成,研究了反应溶剂(乙醚,二氧六环和四氢呋喃)对中间体8-烷基二氢小檗碱合成产率的影响。结果发现以THF为反应溶剂时中间体的合成产率最高,与乙醚比较产率提高近4倍,最后以THF为溶剂顺利制备了不同碳数烷基特别是长链烷基取代的Ber-C8-n。合成化合物的分子结构分别通过元素分析,UV,IR,~1H NMR和~(13)C NMR等方法进行了确认。
2.8-烷基小檗碱同系物的体外抗菌活性
抑菌圈法研究了18种微生物(包括G~+菌,G~-菌和真菌)对Ber-C8-n的敏感性,并采用比浊法测定了6种敏感微生物的MIC值。实验结果显示,G~+菌对Ber-C8-n敏感性明显强于G~-菌和真菌;Ber-C8-n的抗菌活性规律为:在小檗碱C8位接入烷基后抗菌活性随烷基碳数的增加而提高,但当烷基碳数＞8时,Ber-C8-n的抗菌活性则随烷基碳数的增加而下降,即8-辛基小檗碱(Ber-C8-8)在同系物中表现出最高抗菌活性。
3.8-烷基小檗碱同系物的抗菌活性差异的机理
分别以兔血红细胞及细胞膜,枯草杆菌和大肠杆菌完整细胞为实验材料,采用比色法和荧光分析方法研究了Ber-C8-n对兔血红细胞的溶血作用,Ber-C8-n对兔血红细胞膜和完整细菌细胞膜流动性以及Ber-C8-n对膜蛋白或菌体蛋白荧光的淬灭作用。
实验结果表明,抗菌活性越大的Ber-C8-n,其溶血作用越大;抗菌活性越大的Ber-C8-n,对细胞膜流动性的干扰作用和膜蛋白或菌体蛋白荧光的淬灭作用也越强。如在所有同系物中抗菌活性最强的Ber-C8-8和Ber-C8-6在红细胞溶血能力,细胞膜流动性的干扰能力和对膜蛋白或菌体蛋白荧光的淬灭能力上均表现为最强。定量分析与比较Ber-C8-n对枯草杆菌(G~+菌)和大肠杆菌(G~-菌)完整细菌细胞膜及菌体蛋白的影响作用发现,相同Ber-C8-n对枯草杆菌(G~+菌)细胞膜流动性的影响能力远大于对大肠杆菌(G~-菌)膜流动性的影响能力,但对两类细菌完整细胞蛋白的荧光淬灭作用无明显差异。
4.8-烷基小檗碱同系物的体内调脂活性
实验性高脂血症大鼠为动物模型,对Ber-C8-n的调脂活性及兴趣分子8-十六烷基小檗碱调脂作用的剂量效应进行了研究。
实验结果表明,接入亲脂性烷基有利于8-烷基小檗碱同系物体内调脂活性的发挥。长链烷基化合物8-月桂基小檗碱和8-十六烷基小檗碱的调脂活性高于小檗碱和其他8-烷基小檗碱同系物。与盐酸小檗碱比较,对高脂血症实验大鼠TC均值的下调能力分别提高了83%和97%,其它相关血清指标亦有明显改善趋势。剂量效应实验结果表明,8-十六烷基小檗碱能剂量依赖性的降低高脂血症实验大鼠血清TC和TG含量,减少腹腔脂肪和肝脏脂肪的积累,提高血清HDL-C含量,并能有效改善高脂血症实验大鼠的动脉硬化指数,食物利用率等相关病理指标。
5.8-烷基小檗碱同系物的体内毒性
昆明种小鼠为实验动物模型,采用改良寇氏法测定了8-烷基小檗碱同系物的LD_(50)值,并以SD大鼠为实验动物,经口125mg/kg·bw剂量处理6周,对兴趣分子8-辛基小檗碱,8-月桂基小檗碱和8-十六烷基小檗碱的肝肾毒性进行了初步评价。
实验结果表明,接入短链烷基后8-烷基小檗碱同系物的LD_(50)值与其先导化合物盐酸小檗碱比较大幅度减小,即毒性大幅增加。但随着接入烷基碳数的增加,8-烷基同系物的LD_(50)值随之增加,即毒性逐步下降。兴趣分子8-辛基小檗碱,8-月桂基小檗碱和8-十六烷基小檗碱的肝肾毒性实验结果表明,3个化合物在所设定实验条件下对实验大鼠的肝肾功能生化指标均无显著影响。
The isoquinoline alkaloids berberine, is an important active component of Rhizoma Coptidis, and used in the treatment of bacterial gastrointestinal diseases such as diarrhea. Modern scientific research indicated that berberine has not only antimicrobial activity in vitro and in vivo, but also other important pharmacological activities such as lipid-modulating, antihyperglycemic, antitumor, antihypertension and antiarrhythmia. To increase the pharmaceutica activity of berbeine 8-alkyl-berberine homologues with seriate different lipophilic property were synthesized in our laboratory by introducing different length alkyl at C8 position, some pharmacological effects of 8-alkyl-berberine homologues were studied including the antimicrobial activity, lipid-modulating effect, antihyperglycemic effect and toxicity. The methods and results are as follows:
1. The synthesis and molecular structure identification of 8-alkyl-berberine homologues
The synthesis approaches to 8-alkyl-dihydroberberine were carried out in three solvent, aether, dioxane and tetrahydrofuran. The result showed that the highest recovery of the compound had been achieved when synthesized in tetrahydrofuran. Compared with aether, the synthesized yield of 8-alkyl-dihydroberberine enhanced 4 times. The structure of 8-alkyl-berberine homologues synthesized was affirmed with element analysis, Ultraviolet spectrum, Infrared spectrum, ~1H NMR and ~(13)CNMR.
2. The antimicrobial activity of 8-alkyl-berberine homologues in vitro
The sensitivity of 18 microorganism come from G~+ bacteria, G~- bacteria and fungus to 8-alkyl-berberine homologues respectively were evaluated by inhibition zone method and MICs of 8-alkyl-berberine homologues against 6 sensitive microorganisms were determined by turbidimetric method respectively.
The result showed that G~+ bacteria were more sensitive than G~- bacteria and fungus. The antimicrobial activity increased as the length of aliphatic chain elongated and then decreased gradually when the alkyl chain exceeded 8 carbon atoms. 8-octyl-berberine showed the highest antimicrobial activity among all compounds.
3. The antimicrobial mechanism of 8-alkyl-berberine homologues in vitro
With rabbit red-blood cell and its cell membrane, B. subtilis (G~+) and E. coli (G~- ) as experimental material, the hemolysis effect on rabbit red-blood cell, disturbing effect on cell membrane stability and fluorescence quenching effect of 8-alkyl-berberine homologues on membrane protein or bacterial protein were determined by fluorescence spectrum analytical method.
Results showed that antimicrobial activity of the compound was stronger, the effect including hemolysis effect, disturbing effect on cell membrane stability and fluorescence quenching effect on membrane protein were stronger. 8-hexyl-berberine or 8-octyl-berberine showed highest disturbing effect on cell membrane stability and membrane protein of rabbit red-blood cell membrane, whole cell membrane stability and bacterial protein of B. subtilis (G~+) and E. coli (G~-). The experimental data were compared by quantitative analysis method between B. subtilis (G~+) and E. coli (G~- ), result showed that the disturbing ability to cell membrane stability of B. subtilis (G~+) is far more than E. coli (G~-), but fluorescence quenching ability to whole cells of B. subtilis (G~+) and E. coli (G~- ) is nearly same while same compound.
4. The lipid-modulating effect of 8-alkyl-berberine homologues in vivo
With experimental hyperlipidemia rats as animal model, the Lipid-modulating effects of 8-alkyl-berberine homologues are studied.
Result showed that the lipophilic properties of 8-alkyl-berberine homologues are beneficial to exerting Lipid-modulating effect in vivo. The long chain homologue 8-dodecyl-berberine and 8-cetyl-berberine showed better Lipid-modulating effect than berberine and other 8-alkyl-berberine homologues. For example, the serum TC value of 8-dodecyl-berberine and 8-cetyl-berberine group decreased respectively by 83% and 97% compared with berberine group. Dose-effect experiment showed that the decreasing of serum TC, serum TG and AI, and increasing of serum HDL-C of 8-dodecyl-berberine and 8-cetyl-berberine in experimental hyperlipidemia rats are dose dependent.
5. Preliminary study on toxicity of 8-alkyl-berberine homologues in vivo
With kuming mouse or SD rats as animal model, the LD_(50) of 8-alkyl-berberine homologues was determined according to modified karber's method, and the liver and kidney toxicity of interesting molecule 8-octyl-berberine, 8-dodecyl-berberine and 8-cetyl-berberine were observed at dosage of 125mg/kg.bw for 6 weeks.
Result showed that the toxicity of 8-alkyl berberine derivatives was stronger than that of berberine. However, by elongating the aliphatic chain, toxicity decreased gradually. 8-ethyl-berberine showed highest toxicity. 8-octyl-berberine, 8-dodecyl-berberine and 8-cetyl-berberine didn't showed obvious liver and kidney toxicity on the experimental condition of dosage and time.
引文
1.于俊林,杨文娣.小檗碱的植物资源[J].中草药,2005,36(9):1434-1436.
2.潘清平.黄连[M].北京:中国中医药出版社,2001,3-4.
3.江苏新医学院编.中药大辞典[M].上海:上海科学技术出版社,1996:2024-2025.
4.谭仁祥.植物成分分析[M].北京:科学出版社,2002:371-372.
5.吴立军.天然药物化学(第四版)[M].北京:人民卫生出版社,2003:10.
6.余园媛,王伯初,彭亮.黄连的药理研究进展[J].重庆大学学报(自然科学版),2006,29(2):107-110
7.刘继林.黄连治疗消渴病及其功能的草本学研究[J].四川中医.1999(11):17.
8.Cernakova M,Kostalova D,Antimicrobial activity of berberine - A constituent of Mahonia aquifolium.Folia Microbiol.,2002,247(4):375-378.
9.Amin A H,Subbaiah T V,Abbasi K M.Berberine sulfate:antimicrobial activity,bioassay,and mode of action[J].Can.J.Microbiol.,1969,15:1067-1076.
10.Rabbani G H,Butler T,Knight J,et al.Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae[J].J.Infect.Dis.,1987,155:979-984.
11.Sack R B,Froehlich J L.berberine inhibits intestinal secretory response of Vibrio cholerae and Escherichia coli enterotoxins[J].Infect.Immun.,1982,35:471-475.
12.Akhter M H,Sabir M,Bhide N K.Anti-inflammatory effect of berberine in rats injected locally with cholera toxin[J].Indian.J.Med.Res.,1977,65:133-141.
13.Zhu B,Ahrens F A.Effect of berberine on intestinal secretion mediated by Escherichia coli heat-stable enterotoxin in jejunum of pigs[J].Am.J.Vet.Res.,1982,43:1594-1598.
14.Sun D,Abraham S N,Beachey E H.Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli[J].Antimicrob.Agents Chemother.,1988,32:1274-1277.
15.吴静,王克霞,李朝品,等.黄连与盐酸小檗碱对幽门螺杆菌的体外抗菌活性[J].中药药理与临床,2006,22(2):37-38.
16.Freile M L,Giannini F,Pucci G,et al.Antimicrobial activity of aqueous extracts and of berberine isolated from Berberis heterophylla.Fitoterapia,2003,74(7-8):702-705.
17.罗和生,黄晓东,操寄望,等.小檗碱治疗分泌性腹泻的实验研究[J].中药药理与临床,2000,16(3):15-16.
18.Li T K,Bathory E,Lavoie E J et al.Human topoisomerase Ⅰ poising by protoberberine:potential roles for both drug-DNA and drug-emzyme interaction[J].Biochem.,2000,39(24):7107-7116.
19.Yoshinori K,Yoshinori Y,Noboru F,et al.Inhibitors of DNA topoisomerase Ⅰ and Ⅱ isolated from the coptis Rhizomes[J].Planta med.,1995,61:414-418.
20.Krishnan P,Bastow K F.The 9-position in berberine analogs is an important determinant of DNA topoisomerase Ⅱ inhibition[J].Anticancer Drug Des.,2000,15(4):255-264.
21.Paterson G K,Mitchell T J.The biology of Gram-positive sortase enzymes[J].Trends Microbiol.,2004,12(2):89-95.
22.Kim S-H,Shin D-S,Oh M-N,et al.Inhibition of the bacterial surface protein anchoring transpeptiase by isoquinoline alkaloids[J].Biosci.Biotechnol.Biochem.,2004,68(2):421-424.
23.郑洪艳.原小檗碱类生物碱作用差异的机理研究.天津医科大学硕士学位论文,2004:44.
24.Domadia P N,Bhunia A,Sivaraman J,et al.Berberine targets assembly of Escherichia coli cell division protein FtsZ.Biochem.,47(10):3225-3234.
25.Yi Z B,Yu Y,Liang Y Z,et al.Evaluation of the antimicrobial mode of berberine by LC/ESI-MS combined with principal component analysis[J].J.Pharm.Biomed.Anal.,2007,44:301-304.
26.Wang D C,Yu L,Xiang H,et al.Global transcriptional profiles of Staphylococcus aureus treated with berberine chloride.Ferns Microbial.Lett.,2008,279:217-225.
27.Zhu B,Ahrens F.Antisecretory effects of berberine with morphine,clonidine,L-phenylephrine,yohimbine or neostigmine in pig jejunum[J].Eur.J.Pharmacol.,1983,96:11-19.
28.Sun D,Courtney H S,Beachey E H.berberine sulfate blocks adherence of Streptococcus pyogenes to epithelial cells,fibronectin,and hexadecane[J].Antimicrob.Agents Chemother 1988,32:1370-1374.
29.Subbaiah T V,Amin A H.Effect of berberine sulphate on Entamoeba histolytica[j].Nature,1967,215:527-528.
30.Kaneda Y,Torii M,Tanaka T,et al.In vitro effects of berberine sulphate on the growth and structure of Entamoeba hlstolytica,Giardia lamblia and Trichomonas vaginalis[J].Ann.Trop.Med.Parasitol.,1991,85:417-425.
31.Choudhry V P,Sabir M,Bhide V N.Berberine in giardiasis[J].Indian Pediatr.,1972,9:143-146.
32.Elford B C.L-Glutarnine influx in malaria-infected erythrocytes:a target for antimalarials[J].Parasitol.Today,1986,2(11):309-312.
33.Vennerstrom J L,Klayman D L.Protoberberine alkaloids as antimalarials[J].J.Med.Chem.,1988,31(6):1084-1087.
34.Deborah L.C.McCall,James A,et al.The first protoberberine alkaloid analogue with in vivo antimalarial activity[J].Bio.Med.Chem.Lett.,1994,4(14):1663-1666.
35.张明发,沈雅琴.小檗碱的抗腹泻和抗炎作用[J].中国药理学报,1989,10:174-176.
36.Yasukawa K,Takido M,Ikekawa T,et al.Relative inhibitory activity of berberine-type alkaloids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation in mice[J].Chem.Pharm Bull.,1991,39:1462-1465.
37.黄才国,储钟禄.小檗碱对兔血小板TXA2和血浆中PGI2生成的影响[J].中国药理学报,1991,12:526-528.
38.吴俊芳,刘天培.小檗碱对局灶性脑缺血大鼠血小板聚集及血浆TXB2和6-keto-PGF1α水平的影响[J].药学学报,1995,30:98-102.
39.耿东升,刘发.硫酸黄连素对免疫系统的影响[J].中国药理学通报,1996,12(6):536-539.
40.郝钰,邱全瑛,吴瑶等.小檗碱对淋巴细胞与血管内皮细胞粘附及粘附分子的影响[J].中国免疫学杂志,1999,15(11):523-525.
41.何贤辉,曾耀英,徐丽慧,等.黄连素对T淋巴细胞活化和增殖的抑制作用[J].中国病理生理杂志,2002,18(19):1183-1186.
42.Yang J,Wang H D,Lu D X,et al.Effect s of neutral sulfateberberine on LPS-reduced cardiomyocyte TNF-alpha secretion,abnormal calcium cycling,and cardiac dysfunction[J].Acta.Pharmacol.Sin.,2006,27(2):173-178.
43.吕燕宁,邱全瑛.小檗碱对小鼠DTH及其体内几种细胞因子的影响[J].中国免疫学杂志,2000,16(3):139-141.
44.蒋激扬,耿东升,吐尔逊江等.黄连素的抗炎作用及其机制[J].中国药理学通报,1998,14(5):434-437.
45.Lee C H,Chen J C,Hsiang C Y,et al.Berberine suppresses inflammatory agents-induced intedeukin-1 beta and tumor necrosis factor-alpha productions via the inhibition of I kappa B degradation in human lung cells[J].Pharmacol.Res.,2007,56(3):193-201.
46.黄伟民,吴子达,干以庆等.黄连素抗缺血性室性心律失常的作用[J].中华心血管病杂志,1989,17(5):300.
47.黄伟民,严桦.小檗碱对实验性室性心律失常的作用[J].中国药学杂志,1990,25(6):335-337.
48.徐智,曹宏宇.小檗碱对犬心肌梗塞后自发性室颤的防治作用[J].中国药理学报,1989,10(4):320-324.
49.黄伟民,干以庆.任建英等.黄连素治疗室性快速心律失常[J].中华心血管病杂志,1990,18(3):155-156.
50.黄伟民,徐尚忠,徐有秋.黄连素抗心律失常机制-电压钳制术观察延迟激活钾离子流的变化[J].中华心血管病杂志,1992,20(5):310-312.
51.华峥,王晓良.黄连素对豚鼠心肌钾离子通道的抑制作用[J].药学学报,1994,29(8):576.
52.智光 黄大显 杨兴生.黄连素治疗心功能衰竭的实验和临床观察[J].中华内科杂志,1991,30(9):581-582.
53.杨顺裕.黄连素的正性肌力作用及其研究[J].中国中西医结合杂志,1994,14(9):569.
54.Shaffer J E.Inotropic and chronotropic activity of berberine on isolated guinea pig atria[J].J.Cardiovasc.Pharmacol.,1985,7(2):307.
55.汪永孝,赵广跃,谭月华等.小檗碱的负性变时作用[J].中国药理学与毒理学杂志,1991,5:12.
56.徐尚忠,张翼.小檗碱对豚鼠心室肌细胞L-及T-型钙离子通道的影响[J].中国药理学报,1997,18(6):515.
57.智光,黄大显,杨兴生.黄连素治疗心功能衰竭的实验和临床观察[J].中华内科杂志,1991,30(9):581-582.
58.Wang J L,Fang O C.Influence of berberine on rat cardiac output and on the effect of ouabain in guinea pig left atria[J].Chin.J.Pharmacol.Toxicol.,1991,5(1):1.
59.黄效永,刘卫华.黄连素降压作用临床研究.现代中西医结合杂志,2003,12(5):479-480.
60.张思坦,潘俊亭.黄连素治疗高血压病82例临床观察.包头医学院学报,1996,12(1):46-47.
61.Kang D G,Sohn E J,Kwon E K,et al.Effects of berberine on angiotensin-converting enzyme and NO/cGMP system in vessels[J].Vascular Pharmacol.,2002,39(6):281-286.
62.王文雅,陈克敏.盐酸小檗碱对毒草碱性受体的激动作用[J].中国药理学与毒理学杂志,1999,13(3):187-190.
63.Ko W H,Yao X Q,Lau C W,et al.Vasorelaxant and antiproliferative effects of berberine[J].Eur.J.Pharmacol.,2000,399(2-3):187-196.
64.殷峻,陈名道,杨颖等.小檗碱对实验大鼠糖脂代谢的影响[J].中华糖尿病杂志,2004,3:215-218.
65.Kong W,Wei J,Abidi P,et al.Berberine is a novel cholesterol-lowering drugworking through a unique mechanism distinct from statins[J].Nat.Med.,2004,10:1344-1351.
66.左彦方,郭毅,姜昕,等.小檗碱对兔动脉粥样硬化及其血脂的影响[J].中国脑血管病杂志,2006,3(5):204-207.
67.魏敬,蒋建东,吴锦丹,等.盐酸小檗碱的调脂作用的研究[J].中华糖尿病杂志,2005,13(1):49-51.
68.王树海,王文健,汪雪峰,等.黄芪多糖和小檗碱对3T3-L1脂肪细胞糖代谢及细胞分化的影响[J].中国中西医结合杂志,2004,10:112-115.
69.周丽斌,陈名道,王晓,等.小檗碱对脂肪细胞分化的影响[J].中华医学杂志,2003,83(4):338-340.
70.Lee S,Lim H J,Park J H,et al.Berberine-induced LDLR up-regulation involves JNK pathway[J].Biochem.Biophys.Res.Commun.,2007,362:853-857.
71.郝静梅,戴德哉,于锋.L-甲状腺素增强氧化应激及四氢小檗碱衍生物CPU86017的对抗作用.药学进展,2005,29(9):417-421.
72.Shirwaikar A,Shirwaikar A,Rajendran K,et al.In vitro antioxidant studies on the benzyl tetra isoquinoline alkaloid berberine.Biol.Pharm.Bull.,2006,29(9):1906-1910.
73.金昔陆,胡江元.四氢原小檗碱同类物抗氧化和神经保护作用.中国药理学会通讯,2000,17(3):22-22.
74.乔利,林娜.黄连抗氧化作用的研究进展.第三届国际传统医药大会文集(A).2004,273.
75.陈其明,谢明智.黄连及小檗碱降血糖作用的研究[J].药学学报,1986,21(6):401.
76.陈其明,谢明智.小檗碱对正常小鼠血糖调节的影响[J].药学学报,1987(3):161.
77.殷峻,胡仁明,唐金凤,等.小檗碱的体外降糖作用[J].上海第二医科大学学报,2001,21(5):425-427.
78.谢琳,王蓉蓉,王文艳,等.小檗碱对2型糖尿病大鼠肝脏保护作用的实验性研究[J].中华实用 中西医杂志,2006,19(20):2450-2453.
79.Tang L Q,Wei W,Chen L M,et al.Effects of berberine on diabetes induced by alloxan and a high-fat/high-cholesterol diet in rats[J].Journal of Ethnopharmacol.,2006,108:109-115.
80.Bian X L,He L C,Yang G D.Synthesis and antihyperglycemic evaluation of various protoberberine derivatives[J].Bio.Med.Chem.Lett.,2006,16:1380-1383.
81.李素迎,姚运纬,伍忍.盐酸小檗碱对链脲霉素致大鼠离体胰岛β细胞损伤的影响[J].中国现代医学杂志,2002,12(18):6-8.
82.Erzirik D L,Sandier S,Palmer J P.Repair of pancreatic B-cells,A relevant phenomeon in early IDDM?[J].Diabetes,1993,42:1383-1391.
83.宋菊敏,毛良,李有良.黄连对Ⅱ型糖尿病的抗氧化作用[J].中草药,1992,23(11):540.
84.Ko B S,Choi S B,Park S K,et al.Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma[J].Bio.Pharm.Bull.,2005,28(8):1431-1437.
85.殷峻,胡仁明,唐金凤,等.小檗碱的体外降糖作用[J].上海第二医科大学学报,2001,21(5):425-427.
86.Pan G Y,Huang Z J,Wang G J,et al.The antihyperglycaemic activity of berberine arises from a decrease of glucose absorption[J].Planta Med.,2003,69(7):632-636.
87.Li Y H,Wen S P,Kota B P,et al.Punica granatum flower extract,a potent alpha-glucosidase inhibitor,improves postprandial hyperglycemia in Zucker diabetic fatty rats[J].J.Ethnopharmacol.,2005,99(2):239-244.
88.谭宇蕙,陈冠林.小檗碱对人胃癌MGC-803细胞生长抑制及诱导凋亡的作用[J].中国药理学通报,2001,17(1):40-43.
89.林菁.小檗碱对K562细胞生长的抑制作用[J].福建医学院学报,1996,30(4):309-311.
90.Wu S N,Yu H S,Jan C R.et al.Inhibitory effects of berberine on Voltage- and calcium-activated potassium currents in human myeloma cells[J].Life Sci.,1998,62(25):2283-2294.
91.Chi C W,Chang Y F,Chao T W,et al.Flowcytometric analysis of the effect of berberine on the expression of glucocorticoid receptors in human hepatoma HepG2 cells[J].Life Sci.,1994,54(26):2099-2107.
92.Kettmann V,Kostalova D,Jantova S,et al.In vitro cytotoxicity of berberine against HeLa and L1210 cancer cell lines[J].Pharmazie,2004,59(7):548-551.
93.Kuo C L,Chou C C,Yung B Y.Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells[J].Cancer Lett.,1995,93(2):193-200.
94.Jantova S,Cipak L,Cernakova M,et al.Effect of berberine on proliferation,cell cycle and apoptosis in HeLa and L1210 cells[J].J.Pharm.Pharmacol.,2003,55(8):1143-1149.
95.Anis K V,Rajeshkumar N V,Kuttan R.Inhibition of chemical carcinogenesis by berberine in rats and mice[J].J.Pharm.Pharmacol.,2001,53(5):763-768.
96.陈冠林,谭宇蕙,徐勤,等.盐酸小檗碱诱导人胃癌MGC-803细胞凋亡的研究[J].中药药理与临床,2000,16(5):16-17.
97.陈蔚文,李燕红,郭淑杰,等.小檗碱对人胃癌MGC-803细胞生长抑制及诱导凋亡的作用[J].中国药理学通报,2001,17(1):40.
98.Wu H L,Hu C Y,Liu W H,et al.Berberine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of nucleophosm in/B23 and telomerase activity[J].Int.J.Cancer,1999,81(6):923-929.
99.Manohar L S.Enzyme inhibition:inhibition of reverse transcriptase activity by protoberberine alkaloids and structure-activity relationships[J].J.Pharm.Sci.,1983,72(5):538-541.
100.Gatto B,Sanders M M,Yu C,et al.Identification of topoisomerase Ⅰ as the cytotoxic target of the protoberberine alkaloid coralyne[J].Cancer Res.,1996,56(12):2795-2800.
101.Sanders M M,Liu A A,Li T K,et al.Selective cytotoxicity of topoisomerase-directed protoberberines against glioblastoma cells[J].Biochem.Pharmacol.,1998,56(9):1157-1166.
102.Fukuda K,Hibiya Y,Mutoh M,et al.Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells[J].J.Ethnopharmacol.,1999,66(2):227-233.
103.Wu H L,Hu C Y,Liu W H,et al.Berberine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of nucleophosmin/B23 and telomerase activity[J].Int.J.Cancer,1999,81(6):923-929.
104.Lin J G,Chung J G,Wu L T,et al.Effects of berberine on arylamine N-acetyltransferase activity in human colon tumor cells[J].Am.J.Chin.Med.,1999,27(2):265-275.
105.Chang K S.Down-regulation of c-Ki-ras2gene expression associated with morphologic differentiation in human embryonal carcinoma cells treated with berberine[J].J.Formos.Med.Assoc.,1991,90(1):10-14.
106.马伟,王建华,陈蔚文,等.盐酸小檗碱促进胃癌细胞系分化的作用[J].中药新药与临床药理.1998,9(2):90-91.
107.Huang J M,Wang C J,Chou F P,et al.Inhibitory effect of berberine on tert-butyl hydroperoxide-induced oxidative damage in rat liver[J].Arch.Toxicol.,2002,76(11):664-670.
108.吴俊芳,史以菊.小檗碱对小鼠和大鼠脑缺血的保护作用[J].中国药理学与毒理学杂志,1995,9(2):100-103.
109.Iwasa K,Kamigauchi M,Uekl M,et al.Structure-activity relationships of berberine analogs[J].Eur.J.Med.Chem.,1996,31:469-478.
110.Iwasa K,Nanba H,Lee D-U,etal.Structure-activity relationships of protoberberines having antimicrobial activity[J].Planta Med.,1998,64:748-751.
111.Yah D,Jin C,Xiao X H,et al.Antimicrobial properties of berberines alkaloids in Coptis chinensis Franch by microcalorimetry[J].J.Biochem.Biophys.Methods.(In Press,Corrected Proof).
112.Iwasa K,Lee D-U,Kang S-I,etal.Antimicrobial activity of 8-alkayl- and 8-phenyl- substituted berberines and their 12-bromo derivatives[J].J.Nat.Prod.,1998,61(9):1150-1153.
113.Park K S,Kang K C,Kim K Y,et al.HWY-289,a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albican[J]s.J.Antimicrob.Chemother.,2001,47(5):513-519.
114.Hong S W,Kim S H,Jeun J A,et al.Antimicrobial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines[J].Planta Med.,2000,66(4):361-363.
115.Kim S H,Lee S J,Lee J H,et al.Antimicrobial activity of 9-O-acyl- and 9-O-alkylberberrubine derivatives[J].Planta Med.,2002,68(3):277-281.
116.Iwasa K,Kamiguauchi M,Suglura M,etal.Antimicrobial activity of some 13-alkayl-substituted protoberberinium salts[J].Planta Med.,1997,63:196-198.
117.Park K D,Lee J H,Kim S H,et al.Synthesis of 13-(substituted benzyl)berberine and berberrubine derivatives as antifungal agents[J].Bio.Med.Chem.Lett.,2006,16:3913-3916.
118.Hoshi A,Ikekawa T,Ikeda Y,et al.Antitumor activity of berberrubine derivatives[J].Gann,1976,67(2):321-325.
119.Ikekawa T,Ikeda Y.Antitumor activity of 13-methyl-berberrubine derivatives[J].J.Pharmacobiodyn.,1982,5(7):469-474.
120.Kobayashi Y,Yamashita Y,Fuji N,etal.Inhibitors of DNA topoisomerase and isolated from the coptisrhizomes[J].Planta Med.,1995,61:414-418.
121.Luz O,Maria R,Trina C,et al.Structural modification of berberine alkaloids in relation to cytotoxic activity in vitro[J].J.Ethnopharmacol.,2000,71:449-456.
122.Hoshi A,Ikekawa T,Ikeda Y,et al.Antitumor activity of berberrubine derivatives[J].Gann,1976,67(2):321-325.
123.翁尊尧,王肇瀛,业晓明.抗肿瘤物质-恩其明(UNGERMING,AT-1840)及其有关化合物的合成和构效关系[J].药学学报,1982,10:744-748.
124.Iwasa K,Kim H-S,Wataya Y,etal.Antimalarial activity and structure-activity relationships of protoberberine alkaloids[J].Eur.J.Med.Chem.,1998,33:65-69.
125.Bordor N,Brewster M E.Improved delivery through biological membranes-sustained brain delivery of berberine[J].Eur.J.Med.Chem.,1983,18:235-240.
126.黄枕亚,冯玫华,彭司勋.四氢原小檗碱型季铵化合物的合成及某些参数的测定[J].中国药科大学学报,1988,19(4):249-252.
127.Dai D Z,An L F,Wang Y Q,et al.CPU 86017 suppression of arrhythmias induced by ischemia/reperfusion,ouabain,aconitune and elevation of ventricular fibrillatory threshold[J].Drug Develop.Res.,1996,39:184-189.
128.张灿,黄文龙.原小檗碱季铵类化合物的合成及抗心律失常活性研究[J].中国药科大学学报,2003,34(1):7-12.
129.高晓山,陈馥馨,杨守业等.黄连致溶血性黄疸毒性及其防治研究综合报告[J].中国中药杂志,2002,27(1):70-71,74.
130.高晓山.黄连致溶血性黄疸毒性的提取与争议(续)[J].中国中医药信息杂志[J],1996,3(7):6-7.
131.曾美怡,李敏民.国外有关小檗碱毒性反应的报道[J].中国新药与临床药理,1995,6(3):47-48.
132.李建荣,高晓山,刘岱.配伍对黄连急性毒性和小檗碱含量的影响[J].中国中医药信息杂志,1999,6(10):32-33.
133.Pasqual M S,Lauer C P,Moyna P.Genotoxicity of the isoquinoline alkaloid berberine in prokaryotic and eukaryotic organisms[J].Mutat.Res.,1993,286(2):243-252.
134.陈春林,郑小波,曾秀,等.小檗碱透皮制剂对小鼠骨髓细胞的微核效应[J].四川畜牧兽医学院学报,1999,13(4):29-31.
135.张宪印,安丽华,邵智.黄连及其制品的不良反应和治疗[J].时珍国医国药.2003,14(11):714.
1.Iwasa K,Kamigauchi M,Uekl M,et al.Structure-activity relationships of berberine analogs[J].Eur.J.Med.Chem.,1996,31:469-478.
2.Iwasa K,Kamiguauchi M,Suglura M,etal.Antimicrobial activity of some 13-alkyl-substituted protoberberininm salts[J].Planta Med.,1997,63:196-198.
3.Iwasa K,Nanba H,Lee D-U,etal.Structure-activity relationships of protoberberines having antimicrobial activity[J].Planta Med.,1998,64:748-751.
4.Park K S,Kang K C,Kim K Y,et al.HWY-289,a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans[J].J.Antimicrob.Chemother.,2001,47(5):513-519.
5.Park K D,Lee J H,Kim S H,et al.Synthesis of 13-(substituted benzyl)berberine and berberrubine derivatives as antifungal agents[J].Bio.Med.Chem.Lett.,2006,16:3913-3916.
6.Park K S,Kang K C,Kim K Y,et al.HWY-289,a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans[J].J.Antimicrob.Chemother.,2001,47(5):513-519.
7.Hong S W,Kim S H,Jeun J A,et al.Antirnicrobial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines[J].Planta Med.,2000,66(4):361-363.
8.Kim S H,Lee S J,Lee J H,et al.Antimicrobial activity of 9-O-acyl- and 9-O-alkylberberrubine derivatives[J].Planta Med.,2002,68(3):277-281.
9.Iwasa K,Lee D-U,Kang S-I,et al.Antimicrobial activity of 8-alkayl and 8-phenyl substituted berberines and their 12-bromo derivatives[J].J.Nat.prod.,1998,61(9):1150-1153.
10.Bian X L,He L C,Yang G D.Synthesis and antihyperglycemic evaluation of various protoberberine derivatives[J].Bio.Med.Chem.Lett.,2006,16:1380-1383.
11.Küpeli E,Kosar M,Yesilada E,et al.A comparative study on the anti-inflammatory,anti-nociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish berberis species[J].Life Sci.,2002,72(6):6452-6571.
12.殷峻,胡仁明,唐金凤,等.小檗碱的体外降糖作用[J].上海第二医科大学学报,2001,21(5):425-427.
13.魏敬,蒋建东,吴锦丹,等.盐酸小檗碱的调脂作用的研究[J].中华糖尿病杂志,2005,13(1):49-51.
14.Lizuka N,Miyamoto K,Okita K,et al.Inhibitory effect of Coptidis Rhizoma and berberine on the proliferation of human esophageal cancer cell lines[J].Cancer Lett.,2000,148(1):192-251.
15.Elford B C.L-Glutamine influx in malaria-infected erythrocytes:a target for antimalarials[J].Parasitol.Today,1986,2(11):309-312.
16.国家药典委员会.中国药典二部(M).北京:化学出版社,2005,464-465.
17.邢其毅,裴伟伟,徐瑞秋,裴坚.基础有机化学上册(第三版)(M),北京:高等教育出版社,2005.
18.宁永成.有机化合物结构鉴定与有机波谱学(第二版)(M).北京:科学出版社,2000.
1.季宇彬.中草药有效成分药理与其应用[M].哈尔滨:黑龙江科学技术出版社,1994,69-80.
2.Amin A H,Subbaiah T V,Abbasi K M.Berberine sulfate:antimicrobial activity,bioassay,and mode of action[J].Cancer J.Microbiol.,1969,15:1067-1076.
3.Iwasa K,Lee D-U,Kang S-I,etal.Antimicrobial activity of 8-alkayl- and 8-phenyl- substituted berberines and their 12-bromo derivatives[J].J.Nat.Prod.,1998,61(9):1150-1153.
4.Iwasa K,Nanba H,Lee D-U,etal.Structure-activity relationships of protoberberines having antimicrobial activity[J].Planta Med.,1998,64:748-751.
5.Iwasa K,Kamigauchi M,Uekl M,et al.Structure-activity relationships of berberine analogs[J].Eur.J.Med.Chem.,1996,31:469-478.
6.Hong S W,Kim S H,Jeun J A,et al.Antimicrobial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines[J].Planta Med.,2000,66(4):361-363.
7.Kim S H,Lee S J,Lee J H,et al.Antimicrobial activity of 9-O-acyl- and 9-O-alkylberberrubine derivatives[J].Planta Med.,2002,68(3):277-281.
8.Iwasa K,Kamiguauchi M,Suglura M,etal.Antimicrobial activity of some 13-alkayl-substimted protoberberinium salts[J].Planta Med.,1997,63:196-198.
1.Frank G,Friedrich M G,Heberle J,et al.The protein-tethered lipid bilayer:a novel mimic of the biological membrane[J].Biophys.J.,2004,87(5):3213-3220.
2.Trudy M,James R M.Biochemistry:An Introduction,second,ed.(M).Beijing:Science Publishing House,2000:236-240.
3.Engelman D M.Crossing the hydrophobic barrier:insertion of membrane proteins[J].Science,1996,274:1850-1851.
4.Ye X L,Li X G,Yuan L J,et al.Interaction between houttuyfonate homologues and erythrocyte plasma membrane of rabbit in vitro[J].Colloids and Surfaces A:Physicochem.Eng.Aspects,2006,279(1-3):218-224.
5.Ye X L,Li X G,Yuan L J,et al.Effect of the surface activity on the antibacterial activity of octadecanoyl acetal sodium sulfite series[J].Colloids Surf.A Physicochem.Eng.Aspects,2005,268(1-3):85-89.
6.Iwasa K,Kamiguauchi M,Suglura M,etal.Antimicrobial activity of some 13-alkayl-substituted protoberberinium salts[J].Planta Med.,1997,63:196-198.
7.Iwasa K,Lee D-U,Kang S-I,etal.Antimicrobial activity of 8-alkayl- and 8-phenyl- substituted berberines and their 12-bromo derivatives[J].J.Nat.Prod.,1998,61(9):1150-1153.
8.Kim S H,Lee S J,Lee J H,et al.Antimicrobial activity of 9-O-acyl- and 9-O-alkyl- berberrubine derivatives[J].Planta Med.,2002,68(3):277-281.
9.刘丰.应用荧关探针DPH测定完整细胞膜的流动性[J].南京医科大学学报,1996(6):527-529.
10.程书梅,陈宝江,顾金兰,等.应用荧光偏振法测定酿酒酵母完整细胞膜的流动性[J].河北农业大学学报,2005,28(6):95-103.
11.刘雪锋,夏咏梅,方云等.中药黄连有效成分盐酸小檗碱与牛血清白蛋白的相互作用[J].高等学校化学学报,2004,25(11):2099-2103.
12.赵长春,郑维发,李梦秋.小檗碱与人血清白蛋白的相互作用[J].光谱学与光谱分析,2004,11(124):111-113.
13.Li Y,He W Y,Tian J N,et al.The effect of Berberine on the secondary structure of human serum albumin[J].J.Mol.Struct.,2005,743:79-84.
14.汪谦.现代医学实验方法[M].北京:人民卫生出版社,1997,315-331.
15.Gelamo E L,Silva C H,Imasato H,et al.Interaction of bovine(BSA)and human(HSA)serum albumins with ionic surfactants:spectroscopy and modeling[J].Biochim.Biophys.Acta,2002,1594:84-99.
16.Jiang C Q,Gao M X,Meng X Z.Study of the interaction between daunorubicin and human serum albumin,and the determination of daunorubicin in blood serum samples[J].Spectrochim.Acta A Mol.,2003,59:1605-1610.
17.陶慰孙,李惟,姜涌明.蛋白质分子基础(第二版)[M].北京:高等教育出版社,1995,260-262.
18.周德庆.微生物学教程[M].北京:高等教育出版社.2002,21.
1.赵水平.高脂血症的病因及分类[J].中国冶金工业医学杂志,1997,14(5):289-295.
2.赵水平,王钟林,陆宗良.临床血脂学[M].长沙:湖南科技出版社,1997:81-82.
3.殷峻,陈名道,杨颖等.小檗碱对实验大鼠糖脂代谢的影响.中华糖尿病杂志,2004,3:215-218.
4.Kong W,Wei J,Abidi P,et al.Berberine is a novel cholesterol-lowering drugworking through a unique mechanism distinct from statins[J].Nat.Med.,2004,10:1344-1351.
5.勾祥辉.黄连素治疗高血脂59例[J].人民军医,1995(2):35.
6.王庆斌,高芳,岳桂华,等.黄连素治疗高脂血症39例[J].滨州医学院学报,2001,24(2):157.
7.孙杰.黄连素降脂作用的临床观察[J].中国中西医结合杂志.2002,22(4):269.
8.魏敬,蒋建东,吴锦丹,等.盐酸小檗碱的调脂作用的研究[J].中华糖尿病杂志,2005,13(1):49-51.
9.周丽斌,陈名道,王晓,等.小檗碱对脂肪细胞分化的影响[J].中华医学杂志,2003,83(4):338-340.
10.陈明卫,杨明功.他汀类药物肌毒性及其他毒副反应的发现与警惕.实用糖尿病杂志,2005,14:13-15
11.Trudy M,James R M.Biochemistry:An Introduction,second,ed.,Science Publishing House,Beijing,2000,236-240.
12.江苏新医学院编.中药大辞典.上海:上海科学技术出版社,1996:2024-2025.
13.Bian X L,He L C,Yang G D.Synthesis and anti.hyperglycemic evaluation of various protoberberine derivatives[J].Bio.Med.Chem.Lett.,2006,16:1380-1383.
14.徐淑云,卞如濂,陈修.药理实验方法学(第三版).北京:人民卫生出版社,2003:1203.
15.潘华,杨丽萍,周文江.金高尔胶囊对ICR小鼠食物利用率和生长发育的影响[J].上海实验动物科学.2003,23(2):99-102.
16.王省,李明,王俊岭,等.高脂饲料对大鼠体质量及毛发变化的影响[J].中国临床康复,2005,9(7):78-79.
17.陈欣如,燕顺生,徐艺玫,等.维生素C对豚鼠生长发育影响的初步研究[J].地方病通报,2001,16(1):90-91。.
18.张陆勇,周素娣.西红花总甙对鹌鹑实验性动脉粥样硬化的影响[J].中国药科大学学报,1999,30(5):383-386.
19.钱学贤,魏丁柱.血脂及其脂蛋白和冠状动脉病变相关性研究[J].解放军医学情报,1990,4(2):63-64.
20.张柏丽,陆一竹,范英昌.调肝导浊法中药抗高血脂及动脉粥样硬化的研究[J].辽宁中医杂志,2002,29(8):509-510.
1.徐淑云,卞如濂,陈修.药理实验方法学(第三版)(M).北京:人民卫生出版社,2003:1203.
2.吴堃,童曾寿,戴昌世,等.香豆素衍生物的合成及其活性与相对亲脂水性的关系[J].药学学报,1993,28(4):266-272.
3.金一年,黄德生,刘延令.利用线性回归诊断分析芳香族化合物结构参数和大鼠LD50构效关系[J].数理医药学杂志,2004,14(2):126-129.
4.李佐静,闰心丽,孙也之,等.苯甲酸类化合物小鼠经口LD50定量构效关系的研究[J].分子科学学报,2007,23(5):332-334.
5.高晓山,陈馥馨,杨守业等.黄连致溶血性黄疸毒性及其防治研究综合报告[J].中国中药杂志,2002,27(1):70-71,74.
6.高晓山.黄连致溶血性黄疸毒性的提取与争议(续)[J].中国中医药信息杂志[J],1996,3(7):6-7.
7.曾美怡,李敏民.国外有关小檗碱毒性反应的报道[J].中国新药与临床药理,1995,6(3):47-48.
8.李建荣,高晓山,刘岱.配伍对小檗碱毒性和小檗碱含量的影响[J].中国中医药信息杂志,1999,6(10):32-33.
9.李寿祺.毒理学原理与方法(第二版)(M).成都:四川大学出版社,2003:77.
10.黄雨三.保健食品检验与评价技术规范实施手册[M].北京:清华同方电子出版社,2003,832-837.
2.潘清平.黄连[M].北京:中国中医药出版社,2001,3-4.
3.江苏新医学院编.中药大辞典[M].上海:上海科学技术出版社,1996:2024-2025.
4.谭仁祥.植物成分分析[M].北京:科学出版社,2002:371-372.
5.吴立军.天然药物化学(第四版)[M].北京:人民卫生出版社,2003:10.
6.余园媛,王伯初,彭亮.黄连的药理研究进展[J].重庆大学学报(自然科学版),2006,29(2):107-110
7.刘继林.黄连治疗消渴病及其功能的草本学研究[J].四川中医.1999(11):17.
8.Cernakova M,Kostalova D,Antimicrobial activity of berberine - A constituent of Mahonia aquifolium.Folia Microbiol.,2002,247(4):375-378.
9.Amin A H,Subbaiah T V,Abbasi K M.Berberine sulfate:antimicrobial activity,bioassay,and mode of action[J].Can.J.Microbiol.,1969,15:1067-1076.
10.Rabbani G H,Butler T,Knight J,et al.Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae[J].J.Infect.Dis.,1987,155:979-984.
11.Sack R B,Froehlich J L.berberine inhibits intestinal secretory response of Vibrio cholerae and Escherichia coli enterotoxins[J].Infect.Immun.,1982,35:471-475.
12.Akhter M H,Sabir M,Bhide N K.Anti-inflammatory effect of berberine in rats injected locally with cholera toxin[J].Indian.J.Med.Res.,1977,65:133-141.
13.Zhu B,Ahrens F A.Effect of berberine on intestinal secretion mediated by Escherichia coli heat-stable enterotoxin in jejunum of pigs[J].Am.J.Vet.Res.,1982,43:1594-1598.
14.Sun D,Abraham S N,Beachey E H.Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli[J].Antimicrob.Agents Chemother.,1988,32:1274-1277.
15.吴静,王克霞,李朝品,等.黄连与盐酸小檗碱对幽门螺杆菌的体外抗菌活性[J].中药药理与临床,2006,22(2):37-38.
16.Freile M L,Giannini F,Pucci G,et al.Antimicrobial activity of aqueous extracts and of berberine isolated from Berberis heterophylla.Fitoterapia,2003,74(7-8):702-705.
17.罗和生,黄晓东,操寄望,等.小檗碱治疗分泌性腹泻的实验研究[J].中药药理与临床,2000,16(3):15-16.
18.Li T K,Bathory E,Lavoie E J et al.Human topoisomerase Ⅰ poising by protoberberine:potential roles for both drug-DNA and drug-emzyme interaction[J].Biochem.,2000,39(24):7107-7116.
19.Yoshinori K,Yoshinori Y,Noboru F,et al.Inhibitors of DNA topoisomerase Ⅰ and Ⅱ isolated from the coptis Rhizomes[J].Planta med.,1995,61:414-418.
20.Krishnan P,Bastow K F.The 9-position in berberine analogs is an important determinant of DNA topoisomerase Ⅱ inhibition[J].Anticancer Drug Des.,2000,15(4):255-264.
21.Paterson G K,Mitchell T J.The biology of Gram-positive sortase enzymes[J].Trends Microbiol.,2004,12(2):89-95.
22.Kim S-H,Shin D-S,Oh M-N,et al.Inhibition of the bacterial surface protein anchoring transpeptiase by isoquinoline alkaloids[J].Biosci.Biotechnol.Biochem.,2004,68(2):421-424.
23.郑洪艳.原小檗碱类生物碱作用差异的机理研究.天津医科大学硕士学位论文,2004:44.
24.Domadia P N,Bhunia A,Sivaraman J,et al.Berberine targets assembly of Escherichia coli cell division protein FtsZ.Biochem.,47(10):3225-3234.
25.Yi Z B,Yu Y,Liang Y Z,et al.Evaluation of the antimicrobial mode of berberine by LC/ESI-MS combined with principal component analysis[J].J.Pharm.Biomed.Anal.,2007,44:301-304.
26.Wang D C,Yu L,Xiang H,et al.Global transcriptional profiles of Staphylococcus aureus treated with berberine chloride.Ferns Microbial.Lett.,2008,279:217-225.
27.Zhu B,Ahrens F.Antisecretory effects of berberine with morphine,clonidine,L-phenylephrine,yohimbine or neostigmine in pig jejunum[J].Eur.J.Pharmacol.,1983,96:11-19.
28.Sun D,Courtney H S,Beachey E H.berberine sulfate blocks adherence of Streptococcus pyogenes to epithelial cells,fibronectin,and hexadecane[J].Antimicrob.Agents Chemother 1988,32:1370-1374.
29.Subbaiah T V,Amin A H.Effect of berberine sulphate on Entamoeba histolytica[j].Nature,1967,215:527-528.
30.Kaneda Y,Torii M,Tanaka T,et al.In vitro effects of berberine sulphate on the growth and structure of Entamoeba hlstolytica,Giardia lamblia and Trichomonas vaginalis[J].Ann.Trop.Med.Parasitol.,1991,85:417-425.
31.Choudhry V P,Sabir M,Bhide V N.Berberine in giardiasis[J].Indian Pediatr.,1972,9:143-146.
32.Elford B C.L-Glutarnine influx in malaria-infected erythrocytes:a target for antimalarials[J].Parasitol.Today,1986,2(11):309-312.
33.Vennerstrom J L,Klayman D L.Protoberberine alkaloids as antimalarials[J].J.Med.Chem.,1988,31(6):1084-1087.
34.Deborah L.C.McCall,James A,et al.The first protoberberine alkaloid analogue with in vivo antimalarial activity[J].Bio.Med.Chem.Lett.,1994,4(14):1663-1666.
35.张明发,沈雅琴.小檗碱的抗腹泻和抗炎作用[J].中国药理学报,1989,10:174-176.
36.Yasukawa K,Takido M,Ikekawa T,et al.Relative inhibitory activity of berberine-type alkaloids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation in mice[J].Chem.Pharm Bull.,1991,39:1462-1465.
37.黄才国,储钟禄.小檗碱对兔血小板TXA2和血浆中PGI2生成的影响[J].中国药理学报,1991,12:526-528.
38.吴俊芳,刘天培.小檗碱对局灶性脑缺血大鼠血小板聚集及血浆TXB2和6-keto-PGF1α水平的影响[J].药学学报,1995,30:98-102.
39.耿东升,刘发.硫酸黄连素对免疫系统的影响[J].中国药理学通报,1996,12(6):536-539.
40.郝钰,邱全瑛,吴瑶等.小檗碱对淋巴细胞与血管内皮细胞粘附及粘附分子的影响[J].中国免疫学杂志,1999,15(11):523-525.
41.何贤辉,曾耀英,徐丽慧,等.黄连素对T淋巴细胞活化和增殖的抑制作用[J].中国病理生理杂志,2002,18(19):1183-1186.
42.Yang J,Wang H D,Lu D X,et al.Effect s of neutral sulfateberberine on LPS-reduced cardiomyocyte TNF-alpha secretion,abnormal calcium cycling,and cardiac dysfunction[J].Acta.Pharmacol.Sin.,2006,27(2):173-178.
43.吕燕宁,邱全瑛.小檗碱对小鼠DTH及其体内几种细胞因子的影响[J].中国免疫学杂志,2000,16(3):139-141.
44.蒋激扬,耿东升,吐尔逊江等.黄连素的抗炎作用及其机制[J].中国药理学通报,1998,14(5):434-437.
45.Lee C H,Chen J C,Hsiang C Y,et al.Berberine suppresses inflammatory agents-induced intedeukin-1 beta and tumor necrosis factor-alpha productions via the inhibition of I kappa B degradation in human lung cells[J].Pharmacol.Res.,2007,56(3):193-201.
46.黄伟民,吴子达,干以庆等.黄连素抗缺血性室性心律失常的作用[J].中华心血管病杂志,1989,17(5):300.
47.黄伟民,严桦.小檗碱对实验性室性心律失常的作用[J].中国药学杂志,1990,25(6):335-337.
48.徐智,曹宏宇.小檗碱对犬心肌梗塞后自发性室颤的防治作用[J].中国药理学报,1989,10(4):320-324.
49.黄伟民,干以庆.任建英等.黄连素治疗室性快速心律失常[J].中华心血管病杂志,1990,18(3):155-156.
50.黄伟民,徐尚忠,徐有秋.黄连素抗心律失常机制-电压钳制术观察延迟激活钾离子流的变化[J].中华心血管病杂志,1992,20(5):310-312.
51.华峥,王晓良.黄连素对豚鼠心肌钾离子通道的抑制作用[J].药学学报,1994,29(8):576.
52.智光 黄大显 杨兴生.黄连素治疗心功能衰竭的实验和临床观察[J].中华内科杂志,1991,30(9):581-582.
53.杨顺裕.黄连素的正性肌力作用及其研究[J].中国中西医结合杂志,1994,14(9):569.
54.Shaffer J E.Inotropic and chronotropic activity of berberine on isolated guinea pig atria[J].J.Cardiovasc.Pharmacol.,1985,7(2):307.
55.汪永孝,赵广跃,谭月华等.小檗碱的负性变时作用[J].中国药理学与毒理学杂志,1991,5:12.
56.徐尚忠,张翼.小檗碱对豚鼠心室肌细胞L-及T-型钙离子通道的影响[J].中国药理学报,1997,18(6):515.
57.智光,黄大显,杨兴生.黄连素治疗心功能衰竭的实验和临床观察[J].中华内科杂志,1991,30(9):581-582.
58.Wang J L,Fang O C.Influence of berberine on rat cardiac output and on the effect of ouabain in guinea pig left atria[J].Chin.J.Pharmacol.Toxicol.,1991,5(1):1.
59.黄效永,刘卫华.黄连素降压作用临床研究.现代中西医结合杂志,2003,12(5):479-480.
60.张思坦,潘俊亭.黄连素治疗高血压病82例临床观察.包头医学院学报,1996,12(1):46-47.
61.Kang D G,Sohn E J,Kwon E K,et al.Effects of berberine on angiotensin-converting enzyme and NO/cGMP system in vessels[J].Vascular Pharmacol.,2002,39(6):281-286.
62.王文雅,陈克敏.盐酸小檗碱对毒草碱性受体的激动作用[J].中国药理学与毒理学杂志,1999,13(3):187-190.
63.Ko W H,Yao X Q,Lau C W,et al.Vasorelaxant and antiproliferative effects of berberine[J].Eur.J.Pharmacol.,2000,399(2-3):187-196.
64.殷峻,陈名道,杨颖等.小檗碱对实验大鼠糖脂代谢的影响[J].中华糖尿病杂志,2004,3:215-218.
65.Kong W,Wei J,Abidi P,et al.Berberine is a novel cholesterol-lowering drugworking through a unique mechanism distinct from statins[J].Nat.Med.,2004,10:1344-1351.
66.左彦方,郭毅,姜昕,等.小檗碱对兔动脉粥样硬化及其血脂的影响[J].中国脑血管病杂志,2006,3(5):204-207.
67.魏敬,蒋建东,吴锦丹,等.盐酸小檗碱的调脂作用的研究[J].中华糖尿病杂志,2005,13(1):49-51.
68.王树海,王文健,汪雪峰,等.黄芪多糖和小檗碱对3T3-L1脂肪细胞糖代谢及细胞分化的影响[J].中国中西医结合杂志,2004,10:112-115.
69.周丽斌,陈名道,王晓,等.小檗碱对脂肪细胞分化的影响[J].中华医学杂志,2003,83(4):338-340.
70.Lee S,Lim H J,Park J H,et al.Berberine-induced LDLR up-regulation involves JNK pathway[J].Biochem.Biophys.Res.Commun.,2007,362:853-857.
71.郝静梅,戴德哉,于锋.L-甲状腺素增强氧化应激及四氢小檗碱衍生物CPU86017的对抗作用.药学进展,2005,29(9):417-421.
72.Shirwaikar A,Shirwaikar A,Rajendran K,et al.In vitro antioxidant studies on the benzyl tetra isoquinoline alkaloid berberine.Biol.Pharm.Bull.,2006,29(9):1906-1910.
73.金昔陆,胡江元.四氢原小檗碱同类物抗氧化和神经保护作用.中国药理学会通讯,2000,17(3):22-22.
74.乔利,林娜.黄连抗氧化作用的研究进展.第三届国际传统医药大会文集(A).2004,273.
75.陈其明,谢明智.黄连及小檗碱降血糖作用的研究[J].药学学报,1986,21(6):401.
76.陈其明,谢明智.小檗碱对正常小鼠血糖调节的影响[J].药学学报,1987(3):161.
77.殷峻,胡仁明,唐金凤,等.小檗碱的体外降糖作用[J].上海第二医科大学学报,2001,21(5):425-427.
78.谢琳,王蓉蓉,王文艳,等.小檗碱对2型糖尿病大鼠肝脏保护作用的实验性研究[J].中华实用 中西医杂志,2006,19(20):2450-2453.
79.Tang L Q,Wei W,Chen L M,et al.Effects of berberine on diabetes induced by alloxan and a high-fat/high-cholesterol diet in rats[J].Journal of Ethnopharmacol.,2006,108:109-115.
80.Bian X L,He L C,Yang G D.Synthesis and antihyperglycemic evaluation of various protoberberine derivatives[J].Bio.Med.Chem.Lett.,2006,16:1380-1383.
81.李素迎,姚运纬,伍忍.盐酸小檗碱对链脲霉素致大鼠离体胰岛β细胞损伤的影响[J].中国现代医学杂志,2002,12(18):6-8.
82.Erzirik D L,Sandier S,Palmer J P.Repair of pancreatic B-cells,A relevant phenomeon in early IDDM?[J].Diabetes,1993,42:1383-1391.
83.宋菊敏,毛良,李有良.黄连对Ⅱ型糖尿病的抗氧化作用[J].中草药,1992,23(11):540.
84.Ko B S,Choi S B,Park S K,et al.Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma[J].Bio.Pharm.Bull.,2005,28(8):1431-1437.
85.殷峻,胡仁明,唐金凤,等.小檗碱的体外降糖作用[J].上海第二医科大学学报,2001,21(5):425-427.
86.Pan G Y,Huang Z J,Wang G J,et al.The antihyperglycaemic activity of berberine arises from a decrease of glucose absorption[J].Planta Med.,2003,69(7):632-636.
87.Li Y H,Wen S P,Kota B P,et al.Punica granatum flower extract,a potent alpha-glucosidase inhibitor,improves postprandial hyperglycemia in Zucker diabetic fatty rats[J].J.Ethnopharmacol.,2005,99(2):239-244.
88.谭宇蕙,陈冠林.小檗碱对人胃癌MGC-803细胞生长抑制及诱导凋亡的作用[J].中国药理学通报,2001,17(1):40-43.
89.林菁.小檗碱对K562细胞生长的抑制作用[J].福建医学院学报,1996,30(4):309-311.
90.Wu S N,Yu H S,Jan C R.et al.Inhibitory effects of berberine on Voltage- and calcium-activated potassium currents in human myeloma cells[J].Life Sci.,1998,62(25):2283-2294.
91.Chi C W,Chang Y F,Chao T W,et al.Flowcytometric analysis of the effect of berberine on the expression of glucocorticoid receptors in human hepatoma HepG2 cells[J].Life Sci.,1994,54(26):2099-2107.
92.Kettmann V,Kostalova D,Jantova S,et al.In vitro cytotoxicity of berberine against HeLa and L1210 cancer cell lines[J].Pharmazie,2004,59(7):548-551.
93.Kuo C L,Chou C C,Yung B Y.Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells[J].Cancer Lett.,1995,93(2):193-200.
94.Jantova S,Cipak L,Cernakova M,et al.Effect of berberine on proliferation,cell cycle and apoptosis in HeLa and L1210 cells[J].J.Pharm.Pharmacol.,2003,55(8):1143-1149.
95.Anis K V,Rajeshkumar N V,Kuttan R.Inhibition of chemical carcinogenesis by berberine in rats and mice[J].J.Pharm.Pharmacol.,2001,53(5):763-768.
96.陈冠林,谭宇蕙,徐勤,等.盐酸小檗碱诱导人胃癌MGC-803细胞凋亡的研究[J].中药药理与临床,2000,16(5):16-17.
97.陈蔚文,李燕红,郭淑杰,等.小檗碱对人胃癌MGC-803细胞生长抑制及诱导凋亡的作用[J].中国药理学通报,2001,17(1):40.
98.Wu H L,Hu C Y,Liu W H,et al.Berberine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of nucleophosm in/B23 and telomerase activity[J].Int.J.Cancer,1999,81(6):923-929.
99.Manohar L S.Enzyme inhibition:inhibition of reverse transcriptase activity by protoberberine alkaloids and structure-activity relationships[J].J.Pharm.Sci.,1983,72(5):538-541.
100.Gatto B,Sanders M M,Yu C,et al.Identification of topoisomerase Ⅰ as the cytotoxic target of the protoberberine alkaloid coralyne[J].Cancer Res.,1996,56(12):2795-2800.
101.Sanders M M,Liu A A,Li T K,et al.Selective cytotoxicity of topoisomerase-directed protoberberines against glioblastoma cells[J].Biochem.Pharmacol.,1998,56(9):1157-1166.
102.Fukuda K,Hibiya Y,Mutoh M,et al.Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells[J].J.Ethnopharmacol.,1999,66(2):227-233.
103.Wu H L,Hu C Y,Liu W H,et al.Berberine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of nucleophosmin/B23 and telomerase activity[J].Int.J.Cancer,1999,81(6):923-929.
104.Lin J G,Chung J G,Wu L T,et al.Effects of berberine on arylamine N-acetyltransferase activity in human colon tumor cells[J].Am.J.Chin.Med.,1999,27(2):265-275.
105.Chang K S.Down-regulation of c-Ki-ras2gene expression associated with morphologic differentiation in human embryonal carcinoma cells treated with berberine[J].J.Formos.Med.Assoc.,1991,90(1):10-14.
106.马伟,王建华,陈蔚文,等.盐酸小檗碱促进胃癌细胞系分化的作用[J].中药新药与临床药理.1998,9(2):90-91.
107.Huang J M,Wang C J,Chou F P,et al.Inhibitory effect of berberine on tert-butyl hydroperoxide-induced oxidative damage in rat liver[J].Arch.Toxicol.,2002,76(11):664-670.
108.吴俊芳,史以菊.小檗碱对小鼠和大鼠脑缺血的保护作用[J].中国药理学与毒理学杂志,1995,9(2):100-103.
109.Iwasa K,Kamigauchi M,Uekl M,et al.Structure-activity relationships of berberine analogs[J].Eur.J.Med.Chem.,1996,31:469-478.
110.Iwasa K,Nanba H,Lee D-U,etal.Structure-activity relationships of protoberberines having antimicrobial activity[J].Planta Med.,1998,64:748-751.
111.Yah D,Jin C,Xiao X H,et al.Antimicrobial properties of berberines alkaloids in Coptis chinensis Franch by microcalorimetry[J].J.Biochem.Biophys.Methods.(In Press,Corrected Proof).
112.Iwasa K,Lee D-U,Kang S-I,etal.Antimicrobial activity of 8-alkayl- and 8-phenyl- substituted berberines and their 12-bromo derivatives[J].J.Nat.Prod.,1998,61(9):1150-1153.
113.Park K S,Kang K C,Kim K Y,et al.HWY-289,a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albican[J]s.J.Antimicrob.Chemother.,2001,47(5):513-519.
114.Hong S W,Kim S H,Jeun J A,et al.Antimicrobial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines[J].Planta Med.,2000,66(4):361-363.
115.Kim S H,Lee S J,Lee J H,et al.Antimicrobial activity of 9-O-acyl- and 9-O-alkylberberrubine derivatives[J].Planta Med.,2002,68(3):277-281.
116.Iwasa K,Kamiguauchi M,Suglura M,etal.Antimicrobial activity of some 13-alkayl-substituted protoberberinium salts[J].Planta Med.,1997,63:196-198.
117.Park K D,Lee J H,Kim S H,et al.Synthesis of 13-(substituted benzyl)berberine and berberrubine derivatives as antifungal agents[J].Bio.Med.Chem.Lett.,2006,16:3913-3916.
118.Hoshi A,Ikekawa T,Ikeda Y,et al.Antitumor activity of berberrubine derivatives[J].Gann,1976,67(2):321-325.
119.Ikekawa T,Ikeda Y.Antitumor activity of 13-methyl-berberrubine derivatives[J].J.Pharmacobiodyn.,1982,5(7):469-474.
120.Kobayashi Y,Yamashita Y,Fuji N,etal.Inhibitors of DNA topoisomerase and isolated from the coptisrhizomes[J].Planta Med.,1995,61:414-418.
121.Luz O,Maria R,Trina C,et al.Structural modification of berberine alkaloids in relation to cytotoxic activity in vitro[J].J.Ethnopharmacol.,2000,71:449-456.
122.Hoshi A,Ikekawa T,Ikeda Y,et al.Antitumor activity of berberrubine derivatives[J].Gann,1976,67(2):321-325.
123.翁尊尧,王肇瀛,业晓明.抗肿瘤物质-恩其明(UNGERMING,AT-1840)及其有关化合物的合成和构效关系[J].药学学报,1982,10:744-748.
124.Iwasa K,Kim H-S,Wataya Y,etal.Antimalarial activity and structure-activity relationships of protoberberine alkaloids[J].Eur.J.Med.Chem.,1998,33:65-69.
125.Bordor N,Brewster M E.Improved delivery through biological membranes-sustained brain delivery of berberine[J].Eur.J.Med.Chem.,1983,18:235-240.
126.黄枕亚,冯玫华,彭司勋.四氢原小檗碱型季铵化合物的合成及某些参数的测定[J].中国药科大学学报,1988,19(4):249-252.
127.Dai D Z,An L F,Wang Y Q,et al.CPU 86017 suppression of arrhythmias induced by ischemia/reperfusion,ouabain,aconitune and elevation of ventricular fibrillatory threshold[J].Drug Develop.Res.,1996,39:184-189.
128.张灿,黄文龙.原小檗碱季铵类化合物的合成及抗心律失常活性研究[J].中国药科大学学报,2003,34(1):7-12.
129.高晓山,陈馥馨,杨守业等.黄连致溶血性黄疸毒性及其防治研究综合报告[J].中国中药杂志,2002,27(1):70-71,74.
130.高晓山.黄连致溶血性黄疸毒性的提取与争议(续)[J].中国中医药信息杂志[J],1996,3(7):6-7.
131.曾美怡,李敏民.国外有关小檗碱毒性反应的报道[J].中国新药与临床药理,1995,6(3):47-48.
132.李建荣,高晓山,刘岱.配伍对黄连急性毒性和小檗碱含量的影响[J].中国中医药信息杂志,1999,6(10):32-33.
133.Pasqual M S,Lauer C P,Moyna P.Genotoxicity of the isoquinoline alkaloid berberine in prokaryotic and eukaryotic organisms[J].Mutat.Res.,1993,286(2):243-252.
134.陈春林,郑小波,曾秀,等.小檗碱透皮制剂对小鼠骨髓细胞的微核效应[J].四川畜牧兽医学院学报,1999,13(4):29-31.
135.张宪印,安丽华,邵智.黄连及其制品的不良反应和治疗[J].时珍国医国药.2003,14(11):714.
1.Iwasa K,Kamigauchi M,Uekl M,et al.Structure-activity relationships of berberine analogs[J].Eur.J.Med.Chem.,1996,31:469-478.
2.Iwasa K,Kamiguauchi M,Suglura M,etal.Antimicrobial activity of some 13-alkyl-substituted protoberberininm salts[J].Planta Med.,1997,63:196-198.
3.Iwasa K,Nanba H,Lee D-U,etal.Structure-activity relationships of protoberberines having antimicrobial activity[J].Planta Med.,1998,64:748-751.
4.Park K S,Kang K C,Kim K Y,et al.HWY-289,a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans[J].J.Antimicrob.Chemother.,2001,47(5):513-519.
5.Park K D,Lee J H,Kim S H,et al.Synthesis of 13-(substituted benzyl)berberine and berberrubine derivatives as antifungal agents[J].Bio.Med.Chem.Lett.,2006,16:3913-3916.
6.Park K S,Kang K C,Kim K Y,et al.HWY-289,a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans[J].J.Antimicrob.Chemother.,2001,47(5):513-519.
7.Hong S W,Kim S H,Jeun J A,et al.Antirnicrobial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines[J].Planta Med.,2000,66(4):361-363.
8.Kim S H,Lee S J,Lee J H,et al.Antimicrobial activity of 9-O-acyl- and 9-O-alkylberberrubine derivatives[J].Planta Med.,2002,68(3):277-281.
9.Iwasa K,Lee D-U,Kang S-I,et al.Antimicrobial activity of 8-alkayl and 8-phenyl substituted berberines and their 12-bromo derivatives[J].J.Nat.prod.,1998,61(9):1150-1153.
10.Bian X L,He L C,Yang G D.Synthesis and antihyperglycemic evaluation of various protoberberine derivatives[J].Bio.Med.Chem.Lett.,2006,16:1380-1383.
11.Küpeli E,Kosar M,Yesilada E,et al.A comparative study on the anti-inflammatory,anti-nociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish berberis species[J].Life Sci.,2002,72(6):6452-6571.
12.殷峻,胡仁明,唐金凤,等.小檗碱的体外降糖作用[J].上海第二医科大学学报,2001,21(5):425-427.
13.魏敬,蒋建东,吴锦丹,等.盐酸小檗碱的调脂作用的研究[J].中华糖尿病杂志,2005,13(1):49-51.
14.Lizuka N,Miyamoto K,Okita K,et al.Inhibitory effect of Coptidis Rhizoma and berberine on the proliferation of human esophageal cancer cell lines[J].Cancer Lett.,2000,148(1):192-251.
15.Elford B C.L-Glutamine influx in malaria-infected erythrocytes:a target for antimalarials[J].Parasitol.Today,1986,2(11):309-312.
16.国家药典委员会.中国药典二部(M).北京:化学出版社,2005,464-465.
17.邢其毅,裴伟伟,徐瑞秋,裴坚.基础有机化学上册(第三版)(M),北京:高等教育出版社,2005.
18.宁永成.有机化合物结构鉴定与有机波谱学(第二版)(M).北京:科学出版社,2000.
1.季宇彬.中草药有效成分药理与其应用[M].哈尔滨:黑龙江科学技术出版社,1994,69-80.
2.Amin A H,Subbaiah T V,Abbasi K M.Berberine sulfate:antimicrobial activity,bioassay,and mode of action[J].Cancer J.Microbiol.,1969,15:1067-1076.
3.Iwasa K,Lee D-U,Kang S-I,etal.Antimicrobial activity of 8-alkayl- and 8-phenyl- substituted berberines and their 12-bromo derivatives[J].J.Nat.Prod.,1998,61(9):1150-1153.
4.Iwasa K,Nanba H,Lee D-U,etal.Structure-activity relationships of protoberberines having antimicrobial activity[J].Planta Med.,1998,64:748-751.
5.Iwasa K,Kamigauchi M,Uekl M,et al.Structure-activity relationships of berberine analogs[J].Eur.J.Med.Chem.,1996,31:469-478.
6.Hong S W,Kim S H,Jeun J A,et al.Antimicrobial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines[J].Planta Med.,2000,66(4):361-363.
7.Kim S H,Lee S J,Lee J H,et al.Antimicrobial activity of 9-O-acyl- and 9-O-alkylberberrubine derivatives[J].Planta Med.,2002,68(3):277-281.
8.Iwasa K,Kamiguauchi M,Suglura M,etal.Antimicrobial activity of some 13-alkayl-substimted protoberberinium salts[J].Planta Med.,1997,63:196-198.
1.Frank G,Friedrich M G,Heberle J,et al.The protein-tethered lipid bilayer:a novel mimic of the biological membrane[J].Biophys.J.,2004,87(5):3213-3220.
2.Trudy M,James R M.Biochemistry:An Introduction,second,ed.(M).Beijing:Science Publishing House,2000:236-240.
3.Engelman D M.Crossing the hydrophobic barrier:insertion of membrane proteins[J].Science,1996,274:1850-1851.
4.Ye X L,Li X G,Yuan L J,et al.Interaction between houttuyfonate homologues and erythrocyte plasma membrane of rabbit in vitro[J].Colloids and Surfaces A:Physicochem.Eng.Aspects,2006,279(1-3):218-224.
5.Ye X L,Li X G,Yuan L J,et al.Effect of the surface activity on the antibacterial activity of octadecanoyl acetal sodium sulfite series[J].Colloids Surf.A Physicochem.Eng.Aspects,2005,268(1-3):85-89.
6.Iwasa K,Kamiguauchi M,Suglura M,etal.Antimicrobial activity of some 13-alkayl-substituted protoberberinium salts[J].Planta Med.,1997,63:196-198.
7.Iwasa K,Lee D-U,Kang S-I,etal.Antimicrobial activity of 8-alkayl- and 8-phenyl- substituted berberines and their 12-bromo derivatives[J].J.Nat.Prod.,1998,61(9):1150-1153.
8.Kim S H,Lee S J,Lee J H,et al.Antimicrobial activity of 9-O-acyl- and 9-O-alkyl- berberrubine derivatives[J].Planta Med.,2002,68(3):277-281.
9.刘丰.应用荧关探针DPH测定完整细胞膜的流动性[J].南京医科大学学报,1996(6):527-529.
10.程书梅,陈宝江,顾金兰,等.应用荧光偏振法测定酿酒酵母完整细胞膜的流动性[J].河北农业大学学报,2005,28(6):95-103.
11.刘雪锋,夏咏梅,方云等.中药黄连有效成分盐酸小檗碱与牛血清白蛋白的相互作用[J].高等学校化学学报,2004,25(11):2099-2103.
12.赵长春,郑维发,李梦秋.小檗碱与人血清白蛋白的相互作用[J].光谱学与光谱分析,2004,11(124):111-113.
13.Li Y,He W Y,Tian J N,et al.The effect of Berberine on the secondary structure of human serum albumin[J].J.Mol.Struct.,2005,743:79-84.
14.汪谦.现代医学实验方法[M].北京:人民卫生出版社,1997,315-331.
15.Gelamo E L,Silva C H,Imasato H,et al.Interaction of bovine(BSA)and human(HSA)serum albumins with ionic surfactants:spectroscopy and modeling[J].Biochim.Biophys.Acta,2002,1594:84-99.
16.Jiang C Q,Gao M X,Meng X Z.Study of the interaction between daunorubicin and human serum albumin,and the determination of daunorubicin in blood serum samples[J].Spectrochim.Acta A Mol.,2003,59:1605-1610.
17.陶慰孙,李惟,姜涌明.蛋白质分子基础(第二版)[M].北京:高等教育出版社,1995,260-262.
18.周德庆.微生物学教程[M].北京:高等教育出版社.2002,21.
1.赵水平.高脂血症的病因及分类[J].中国冶金工业医学杂志,1997,14(5):289-295.
2.赵水平,王钟林,陆宗良.临床血脂学[M].长沙:湖南科技出版社,1997:81-82.
3.殷峻,陈名道,杨颖等.小檗碱对实验大鼠糖脂代谢的影响.中华糖尿病杂志,2004,3:215-218.
4.Kong W,Wei J,Abidi P,et al.Berberine is a novel cholesterol-lowering drugworking through a unique mechanism distinct from statins[J].Nat.Med.,2004,10:1344-1351.
5.勾祥辉.黄连素治疗高血脂59例[J].人民军医,1995(2):35.
6.王庆斌,高芳,岳桂华,等.黄连素治疗高脂血症39例[J].滨州医学院学报,2001,24(2):157.
7.孙杰.黄连素降脂作用的临床观察[J].中国中西医结合杂志.2002,22(4):269.
8.魏敬,蒋建东,吴锦丹,等.盐酸小檗碱的调脂作用的研究[J].中华糖尿病杂志,2005,13(1):49-51.
9.周丽斌,陈名道,王晓,等.小檗碱对脂肪细胞分化的影响[J].中华医学杂志,2003,83(4):338-340.
10.陈明卫,杨明功.他汀类药物肌毒性及其他毒副反应的发现与警惕.实用糖尿病杂志,2005,14:13-15
11.Trudy M,James R M.Biochemistry:An Introduction,second,ed.,Science Publishing House,Beijing,2000,236-240.
12.江苏新医学院编.中药大辞典.上海:上海科学技术出版社,1996:2024-2025.
13.Bian X L,He L C,Yang G D.Synthesis and anti.hyperglycemic evaluation of various protoberberine derivatives[J].Bio.Med.Chem.Lett.,2006,16:1380-1383.
14.徐淑云,卞如濂,陈修.药理实验方法学(第三版).北京:人民卫生出版社,2003:1203.
15.潘华,杨丽萍,周文江.金高尔胶囊对ICR小鼠食物利用率和生长发育的影响[J].上海实验动物科学.2003,23(2):99-102.
16.王省,李明,王俊岭,等.高脂饲料对大鼠体质量及毛发变化的影响[J].中国临床康复,2005,9(7):78-79.
17.陈欣如,燕顺生,徐艺玫,等.维生素C对豚鼠生长发育影响的初步研究[J].地方病通报,2001,16(1):90-91。.
18.张陆勇,周素娣.西红花总甙对鹌鹑实验性动脉粥样硬化的影响[J].中国药科大学学报,1999,30(5):383-386.
19.钱学贤,魏丁柱.血脂及其脂蛋白和冠状动脉病变相关性研究[J].解放军医学情报,1990,4(2):63-64.
20.张柏丽,陆一竹,范英昌.调肝导浊法中药抗高血脂及动脉粥样硬化的研究[J].辽宁中医杂志,2002,29(8):509-510.
1.徐淑云,卞如濂,陈修.药理实验方法学(第三版)(M).北京:人民卫生出版社,2003:1203.
2.吴堃,童曾寿,戴昌世,等.香豆素衍生物的合成及其活性与相对亲脂水性的关系[J].药学学报,1993,28(4):266-272.
3.金一年,黄德生,刘延令.利用线性回归诊断分析芳香族化合物结构参数和大鼠LD50构效关系[J].数理医药学杂志,2004,14(2):126-129.
4.李佐静,闰心丽,孙也之,等.苯甲酸类化合物小鼠经口LD50定量构效关系的研究[J].分子科学学报,2007,23(5):332-334.
5.高晓山,陈馥馨,杨守业等.黄连致溶血性黄疸毒性及其防治研究综合报告[J].中国中药杂志,2002,27(1):70-71,74.
6.高晓山.黄连致溶血性黄疸毒性的提取与争议(续)[J].中国中医药信息杂志[J],1996,3(7):6-7.
7.曾美怡,李敏民.国外有关小檗碱毒性反应的报道[J].中国新药与临床药理,1995,6(3):47-48.
8.李建荣,高晓山,刘岱.配伍对小檗碱毒性和小檗碱含量的影响[J].中国中医药信息杂志,1999,6(10):32-33.
9.李寿祺.毒理学原理与方法(第二版)(M).成都:四川大学出版社,2003:77.
10.黄雨三.保健食品检验与评价技术规范实施手册[M].北京:清华同方电子出版社,2003,832-837.