注射用黄芪多糖研究进展与二次开发思路
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摘要
注射用黄芪多糖(国药准字Z20040086)是20世纪90年代初山西省中医药研究院根据山西省黄芪资源优势研发的中药静脉用粉针剂,其采用先进的生产工艺,截留得到黄芪多糖的有效部位(阿拉伯半乳聚糖混合物),临床上用于放化疗后病人血象的改善。然而,受多糖分离纯化的技术瓶颈且结构难于精准测定的困难,导致其作用机制并不明确,风险不易控制。近年来,多糖受体理论研究成果表明多糖在与蛋白受体结合时,仅是多糖分子中的寡糖片段与受体相结合,多糖分子中也存在1种或多种寡糖片段"活性中心"。因此将多糖降解为寡糖,从寡糖水平研究多糖的活性中心,为突破多糖结构研究技术瓶颈提供了新策略。因此该文对注射用黄芪多糖的研究现状及多糖受体理论等进行综述,结合实际成功案例,提出注射用黄芪多糖的二次开发思路。研究结果将为中药多糖的新药研发奠定物质基础,为多糖类药物质量控制等国际性难题的解决提供依据,同时为糖生物学深入研究提供分子模型,丰富多糖受体理论。
Astragali Radix( AR) polysaccharide for injection( Guoyao Zhunzi Z20040086) is a traditional Chinese medicine for intravenous powder injection developed by Shanxi Academy of Traditional Chinese Medicine in early 1990 s by taking advantage of AR resources in Shanxi province. The effective parts of AR polysaccharides were obtained by advanced technology. The hemogram of patients with radiotherapy and chemotherapy showed alleviations in clinic. However,due to the technical bottleneck in separation of the complex polysaccharides mixture and the difficulties in accurate measurement of the polysaccharide structures,the pharmacodynamic mechanism of the drug remained unclear,and the side effect was hard to control. In recent years,the theoretical studies for polysaccharide receptors have indicated that when polysaccharides bound to protein receptors,only the oligosaccharide fragments of the polysaccharide molecule bound to the receptors,and one or more active sites of oligosaccharide fragments may existed in the polysaccharide molecule.Therefore,the active center of polysaccharides can be studied based on the level of oligosaccharides through degradation of the polysaccharides,which provided a new strategy for breaking through the bottleneck in polysaccharide structure determination. Therefore,this paper reviews the current status of studies for AR polysaccharides for injection,the polysaccharide receptors theory and successful cases,in order to propose the secondary development ideas of AR polysaccharides for injection. The study results will lay a material foundation for the development of new drugs of polysaccharides from traditional Chinese medicine,and provide a basis for the resolution of international difficulties in quality control of polysaccharide drugs and molecular models,so as to further study of glycobiology,and enrich the polysaccharide receptors theory.
Astragali Radix( AR) polysaccharide for injection( Guoyao Zhunzi Z20040086) is a traditional Chinese medicine for intravenous powder injection developed by Shanxi Academy of Traditional Chinese Medicine in early 1990 s by taking advantage of AR resources in Shanxi province. The effective parts of AR polysaccharides were obtained by advanced technology. The hemogram of patients with radiotherapy and chemotherapy showed alleviations in clinic. However,due to the technical bottleneck in separation of the complex polysaccharides mixture and the difficulties in accurate measurement of the polysaccharide structures,the pharmacodynamic mechanism of the drug remained unclear,and the side effect was hard to control. In recent years,the theoretical studies for polysaccharide receptors have indicated that when polysaccharides bound to protein receptors,only the oligosaccharide fragments of the polysaccharide molecule bound to the receptors,and one or more active sites of oligosaccharide fragments may existed in the polysaccharide molecule.Therefore,the active center of polysaccharides can be studied based on the level of oligosaccharides through degradation of the polysaccharides,which provided a new strategy for breaking through the bottleneck in polysaccharide structure determination. Therefore,this paper reviews the current status of studies for AR polysaccharides for injection,the polysaccharide receptors theory and successful cases,in order to propose the secondary development ideas of AR polysaccharides for injection. The study results will lay a material foundation for the development of new drugs of polysaccharides from traditional Chinese medicine,and provide a basis for the resolution of international difficulties in quality control of polysaccharide drugs and molecular models,so as to further study of glycobiology,and enrich the polysaccharide receptors theory.
引文
[1]中国药典.一部[S]. 2015:302.
[2]肖宇,宋壁伶,张弘毅.现代科技创造黄芪真正价值——中药二类新药注射用黄芪多糖[J].天津药学,2007,19(1):77.
[3]王莹,王赵,安锦华,等.黄芪多糖对照品标化方法研究[J].中草药,2017,48(23):4897.
[4]范慧红. 2010年版《中国药典》中多糖类药物标准的修订[J].中国药学杂志,2010,45(17):1294.
[5]郭志烨,韩丽,杨明,等.中药多糖定量测定方法的探讨[J].中成药,2014,36(10):2172.
[6]高怡婷,柳文媛.多糖的制备工艺与质量控制研究进展[J].药学进展,2016,40(3):205.
[7]戴慧,高晓明.多糖特异性免疫识别的分子机制及其免疫生物学意义[J].中国免疫学杂志,2009,25(1):35.
[8] Jiang M H,Zhu L,Jiang J G. Immunoregulatory actions of polysaccharides from Chinese herbal medicine[J]. Expert Opin Ther Targets,2010,14(12):1367.
[9]苗月,任桂红,金周雨,等.巨噬细胞真菌多糖受体研究进展[J].中国细胞生物学学报,2017,39(5):675.
[10] Pu X Y,Ma X L,Liu L,et al. Structural characterization and antioxidant activity in vitro of polysaccharides from angelica and astragalus[J]. Carbohydr Polym,2016,137(10):154.
[11] Xu S Y,Huang X S,Cheong K L. Recent advances in marine algae polysaccharides:isolation,structure,and activities[J]. Mar Drugs,2017,15(12):388.
[12] Lever R,Page C P,段荣帅.肝素的新药研发[J].食品与药品,2012,14(7):85.
[13]张洪涛,朱莉,张爽,等.基于ESI-CID-MS/MS离子碎片峰特征的香菇多糖水解机制及系列香菇寡糖的制备[J].高等学校化学学报,2014,3(11):2329.
[14]刘冬.新型超纯低分子肝素的制备方法研究[D].苏州:苏州大学,2010.
[15]王淑民,赵秀丽,李健,等. D-聚甘酯的分子量与抗FXa/抗FⅡa活性比值的相关性研究[J].中国临床药理学杂志,2013,29(9):695.
[16]李晓霞,王迪,李科,等.基于人工胃酸水解的黄芪糖指纹图谱的建立及不同种质资源黄芪鉴别[J].中国现代中药,2018,20(2):41.
[17]李娜.叉枝松藻抗凝血多糖及其寡糖的制备和结构研究[D].青岛:中国海洋大学,2015.
[18] Zhang Z S,Wang X M,Liu C B,et al. The degradation,antioxidant and antimutagenic activity of the mucilage polysaccharide from Dioscorea opposita[J]. Carbohydr Polym,2016,150:227.
[19] Guan J,Li S P. Discrimination of polysaccharides from traditional Chinese medicines using saccharide mapping-enzymatic digestion followed by chromatographic analysis[J]. J Pharm Biomed Anal,2010,51:590.
[20] Xu J,Guan J,Chen X J,et al. Comparison of polysaccharides from different dendrobium using saccharide mapping[J]. J Pharm Biomed Anal,2011,55:977.
[21] Guan J,Zhao J,Feng K,et al. Comparison and characterization of polysaccharides from natural and cultured Cordyceps using saccharide mapping[J]. Anal Bioanal Chem,2011,399:3465.
[22]李绍平,吴定涛,赵静.糖谱及其在中药多糖质量控制中的应用[J].中国中药杂志,2015,40(17):3505.
[23]陈丽娟.银耳多糖快速提取及可控降解的研究[D].广州:华南理工大学,2017.
[24]李健军,许昭,王仲孚,等.果胶多糖可控性降解及果胶寡糖的制备[J].西北药学杂志,2017,32(6):726.
[25]傅青,王军,梁图,等.糖类化合物亲水作用色谱保留行为评价[J].色谱,2013,31(11):1051.
[26] Fu Q,Guo Z M,Liang T,et al. Chemically bonded maltose via click chemistry as stationary phase for HLIC[J]. Anal Methods,2010,2:217.
[27] Xiao X,Wen J Y,Wang Y Y,et al. NMR and ESI-MS spectrometry characterization of autohydrolysis xylooligosaccharides separated by gel permeation chromatography[J]. Carbohydr Polym,2018,195:303.
[28]卫冰,许闽,于雷,等.黄精低聚糖的分离纯化及结构分析[J].中成药,2012,34(4):694.
[29] Zhai X C,Zhao H T,Zhang M,et al. New stationary phase for hydrophilic interaction chromatography to separate chito-oligosaccharides with degree of polymerization 2-6[J]. J Chromatogr B,2018,1081:33.
[30] Shi J F,Zhang W Y,Su Y L,et al. Composite polyelectrolyte multilayer membranes for oligosaccharides nanofiltration separation[J]. Carbohydr Polym,2013,94:106.
[31] Laremore T N,Ly M,Solakyildirim K,et al. High-resolution preparative separation of glycosaminoglycan oligosaccharides by polyacrylamide gel electrophoresis[J]. Anal Biochem,2010,401:236.
[32] Rice P J,Adams E L,Ozment-Skelton T,et al. Oral delivery and gastrointestinal absorptionof soluble glucans stimulate increased resistance to infectious challenge[J]. J Pharmacol Exp Ther,2005,314(3):l079.
[33] Garthoff J A,Heemskerk S,Hempenius R A,et al. Safety evaluation of pectin-derived acidic oligosaccharides(pAOS):genotoxicity and subchronic studies[J]. Regul Toxicol Pharmacol,2010,57(1):31.
[34] Kailemia M J,Ruhaak L R,Lebrilla C B,et al. Oligosaccharide analysis by massspectrometry:a review of recent developments[J]. Anal Chem,2014,86(1):196.
[35]王耀君,黄纯翠,高枫,等.串联质谱寡糖结构解析方法评价[J].生物化学与生物物理进展,2017,44(10):830.
[36]张伟宾,刘丹,许竞男,等.琼胶寡糖鉴定方法的研究进展[J].中国海洋药物,2017(6):96.
[37] Xiao X,Wen J Y,Wang Y Y,et al. NMR and ESI-MS spectrometry characterization of autohydrolysis xylo-oligosaccharides separated by gel permeation chromatography[J]. Carbohydr Polym,2018,195:303.
[38] Minna Juvonen,Markus Kotiranta,Jouni Jokela,et al. Identification and structural analysis of cereal arabinoxylan-derived oligosaccharides by negative ionization HILIC-MS/MS[J]. Food Chem,2019,275:176.
[39]吕友晶.不同来源果胶多糖的结构解析及抗肿瘤活性研究[D].青岛:中国海洋大学,2015.
[40] Liu Z Q,Simone Rochfort. Identification and quantitative analysis of oligosaccharides in wheat flour using LC-MS[J]. J Cereal Sci,2015,63:128.
[41] Lata Gangwar,Rinku Singh,Desh Deepak. Structure elucidation of a novel oligosaccharide(Medalose)from camel milk[J]. J Mol Struct,2018,1153:157.
[42]陈欢欢,赵峡,栾晓红,等.电喷雾质谱在寡糖序列分析中的应用[J].高等学校化学学报,2015,36(1):1.
[43]陈卓,于卫江.注射用黄芪多糖对非小细胞肺癌放疗的作用及对机体免疫的影响[J].中国实验方剂学杂志,2013,19(6):309.
[44]郑召鹏,杨卫兵,李宁,等.注射用黄芪多糖预防非小细胞肺癌化疗后骨髓抑制的疗效观察[J].中草药,2013,44(2):208.
[45] Huyan X H,Lin Y P,Gao T,et al. Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb/c mice[J]. Int Immunopharmacol,2011,11(9):1293.
[46]赵锐,张波,王光建,等.环磷酰胺、卡铂、表阿霉素、吉西他滨致小鼠血小板及白细胞等降低模型复制方法的探索[J].陕西中医药大学学报,2011,34(3):43.
[47]曹瑞,张波,王光建,等.丝裂霉素和5-氟尿嘧啶诱发小鼠血小板减少、白细胞减少动物模型的建立[J].西北药学杂志,2011,26(6):432.
[48]宋淑军,左晓勇,司少艳,等.不同剂量X射线照射对小鼠免疫系统的影响[J].癌症进展,2016,14(6):578.
[49]陈增边.注射用黄芪多糖对鼻咽癌放射治疗患者免疫功能的影响[J].临床医学,2010,30(5):23.
[50]娄晓芬,张炳华,宋京,等.注射用黄芪多糖对人外周血单个核细胞分泌造血细胞因子的影响[C].桂林:中国药学会学术年会,2002.
[51]李海花.低聚甘露糖醛酸升高白细胞作用及机理研究[D].青岛:中国海洋大学,2013.
[2]肖宇,宋壁伶,张弘毅.现代科技创造黄芪真正价值——中药二类新药注射用黄芪多糖[J].天津药学,2007,19(1):77.
[3]王莹,王赵,安锦华,等.黄芪多糖对照品标化方法研究[J].中草药,2017,48(23):4897.
[4]范慧红. 2010年版《中国药典》中多糖类药物标准的修订[J].中国药学杂志,2010,45(17):1294.
[5]郭志烨,韩丽,杨明,等.中药多糖定量测定方法的探讨[J].中成药,2014,36(10):2172.
[6]高怡婷,柳文媛.多糖的制备工艺与质量控制研究进展[J].药学进展,2016,40(3):205.
[7]戴慧,高晓明.多糖特异性免疫识别的分子机制及其免疫生物学意义[J].中国免疫学杂志,2009,25(1):35.
[8] Jiang M H,Zhu L,Jiang J G. Immunoregulatory actions of polysaccharides from Chinese herbal medicine[J]. Expert Opin Ther Targets,2010,14(12):1367.
[9]苗月,任桂红,金周雨,等.巨噬细胞真菌多糖受体研究进展[J].中国细胞生物学学报,2017,39(5):675.
[10] Pu X Y,Ma X L,Liu L,et al. Structural characterization and antioxidant activity in vitro of polysaccharides from angelica and astragalus[J]. Carbohydr Polym,2016,137(10):154.
[11] Xu S Y,Huang X S,Cheong K L. Recent advances in marine algae polysaccharides:isolation,structure,and activities[J]. Mar Drugs,2017,15(12):388.
[12] Lever R,Page C P,段荣帅.肝素的新药研发[J].食品与药品,2012,14(7):85.
[13]张洪涛,朱莉,张爽,等.基于ESI-CID-MS/MS离子碎片峰特征的香菇多糖水解机制及系列香菇寡糖的制备[J].高等学校化学学报,2014,3(11):2329.
[14]刘冬.新型超纯低分子肝素的制备方法研究[D].苏州:苏州大学,2010.
[15]王淑民,赵秀丽,李健,等. D-聚甘酯的分子量与抗FXa/抗FⅡa活性比值的相关性研究[J].中国临床药理学杂志,2013,29(9):695.
[16]李晓霞,王迪,李科,等.基于人工胃酸水解的黄芪糖指纹图谱的建立及不同种质资源黄芪鉴别[J].中国现代中药,2018,20(2):41.
[17]李娜.叉枝松藻抗凝血多糖及其寡糖的制备和结构研究[D].青岛:中国海洋大学,2015.
[18] Zhang Z S,Wang X M,Liu C B,et al. The degradation,antioxidant and antimutagenic activity of the mucilage polysaccharide from Dioscorea opposita[J]. Carbohydr Polym,2016,150:227.
[19] Guan J,Li S P. Discrimination of polysaccharides from traditional Chinese medicines using saccharide mapping-enzymatic digestion followed by chromatographic analysis[J]. J Pharm Biomed Anal,2010,51:590.
[20] Xu J,Guan J,Chen X J,et al. Comparison of polysaccharides from different dendrobium using saccharide mapping[J]. J Pharm Biomed Anal,2011,55:977.
[21] Guan J,Zhao J,Feng K,et al. Comparison and characterization of polysaccharides from natural and cultured Cordyceps using saccharide mapping[J]. Anal Bioanal Chem,2011,399:3465.
[22]李绍平,吴定涛,赵静.糖谱及其在中药多糖质量控制中的应用[J].中国中药杂志,2015,40(17):3505.
[23]陈丽娟.银耳多糖快速提取及可控降解的研究[D].广州:华南理工大学,2017.
[24]李健军,许昭,王仲孚,等.果胶多糖可控性降解及果胶寡糖的制备[J].西北药学杂志,2017,32(6):726.
[25]傅青,王军,梁图,等.糖类化合物亲水作用色谱保留行为评价[J].色谱,2013,31(11):1051.
[26] Fu Q,Guo Z M,Liang T,et al. Chemically bonded maltose via click chemistry as stationary phase for HLIC[J]. Anal Methods,2010,2:217.
[27] Xiao X,Wen J Y,Wang Y Y,et al. NMR and ESI-MS spectrometry characterization of autohydrolysis xylooligosaccharides separated by gel permeation chromatography[J]. Carbohydr Polym,2018,195:303.
[28]卫冰,许闽,于雷,等.黄精低聚糖的分离纯化及结构分析[J].中成药,2012,34(4):694.
[29] Zhai X C,Zhao H T,Zhang M,et al. New stationary phase for hydrophilic interaction chromatography to separate chito-oligosaccharides with degree of polymerization 2-6[J]. J Chromatogr B,2018,1081:33.
[30] Shi J F,Zhang W Y,Su Y L,et al. Composite polyelectrolyte multilayer membranes for oligosaccharides nanofiltration separation[J]. Carbohydr Polym,2013,94:106.
[31] Laremore T N,Ly M,Solakyildirim K,et al. High-resolution preparative separation of glycosaminoglycan oligosaccharides by polyacrylamide gel electrophoresis[J]. Anal Biochem,2010,401:236.
[32] Rice P J,Adams E L,Ozment-Skelton T,et al. Oral delivery and gastrointestinal absorptionof soluble glucans stimulate increased resistance to infectious challenge[J]. J Pharmacol Exp Ther,2005,314(3):l079.
[33] Garthoff J A,Heemskerk S,Hempenius R A,et al. Safety evaluation of pectin-derived acidic oligosaccharides(pAOS):genotoxicity and subchronic studies[J]. Regul Toxicol Pharmacol,2010,57(1):31.
[34] Kailemia M J,Ruhaak L R,Lebrilla C B,et al. Oligosaccharide analysis by massspectrometry:a review of recent developments[J]. Anal Chem,2014,86(1):196.
[35]王耀君,黄纯翠,高枫,等.串联质谱寡糖结构解析方法评价[J].生物化学与生物物理进展,2017,44(10):830.
[36]张伟宾,刘丹,许竞男,等.琼胶寡糖鉴定方法的研究进展[J].中国海洋药物,2017(6):96.
[37] Xiao X,Wen J Y,Wang Y Y,et al. NMR and ESI-MS spectrometry characterization of autohydrolysis xylo-oligosaccharides separated by gel permeation chromatography[J]. Carbohydr Polym,2018,195:303.
[38] Minna Juvonen,Markus Kotiranta,Jouni Jokela,et al. Identification and structural analysis of cereal arabinoxylan-derived oligosaccharides by negative ionization HILIC-MS/MS[J]. Food Chem,2019,275:176.
[39]吕友晶.不同来源果胶多糖的结构解析及抗肿瘤活性研究[D].青岛:中国海洋大学,2015.
[40] Liu Z Q,Simone Rochfort. Identification and quantitative analysis of oligosaccharides in wheat flour using LC-MS[J]. J Cereal Sci,2015,63:128.
[41] Lata Gangwar,Rinku Singh,Desh Deepak. Structure elucidation of a novel oligosaccharide(Medalose)from camel milk[J]. J Mol Struct,2018,1153:157.
[42]陈欢欢,赵峡,栾晓红,等.电喷雾质谱在寡糖序列分析中的应用[J].高等学校化学学报,2015,36(1):1.
[43]陈卓,于卫江.注射用黄芪多糖对非小细胞肺癌放疗的作用及对机体免疫的影响[J].中国实验方剂学杂志,2013,19(6):309.
[44]郑召鹏,杨卫兵,李宁,等.注射用黄芪多糖预防非小细胞肺癌化疗后骨髓抑制的疗效观察[J].中草药,2013,44(2):208.
[45] Huyan X H,Lin Y P,Gao T,et al. Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb/c mice[J]. Int Immunopharmacol,2011,11(9):1293.
[46]赵锐,张波,王光建,等.环磷酰胺、卡铂、表阿霉素、吉西他滨致小鼠血小板及白细胞等降低模型复制方法的探索[J].陕西中医药大学学报,2011,34(3):43.
[47]曹瑞,张波,王光建,等.丝裂霉素和5-氟尿嘧啶诱发小鼠血小板减少、白细胞减少动物模型的建立[J].西北药学杂志,2011,26(6):432.
[48]宋淑军,左晓勇,司少艳,等.不同剂量X射线照射对小鼠免疫系统的影响[J].癌症进展,2016,14(6):578.
[49]陈增边.注射用黄芪多糖对鼻咽癌放射治疗患者免疫功能的影响[J].临床医学,2010,30(5):23.
[50]娄晓芬,张炳华,宋京,等.注射用黄芪多糖对人外周血单个核细胞分泌造血细胞因子的影响[C].桂林:中国药学会学术年会,2002.
[51]李海花.低聚甘露糖醛酸升高白细胞作用及机理研究[D].青岛:中国海洋大学,2013.