硫酸乙酰肝素多糖类似物的抗乳腺癌活性研究进展*

硫酸乙酰肝素（heparan sulfate，HS）参与乳腺癌发生和发展的多个环节，随着HS对细胞生长因子调节机制研究的深入，HS多糖类似物的研发已经成为当前研究的热点。现综述HS结构及在乳腺癌发生发展中的作用和机制、HS多糖类似物的分类、天然产物中提取的多糖和化学修饰的多糖衍生物的抗癌活性及构效关系的研究进展。     

肝素类似物合成方法的研究进展

肝素及低分子肝素是目前临床广泛应用的抗凝药物,其原料来源主要是猪小肠黏膜和牛肺黏膜,这不仅依赖屠宰业而且还被微生物污染,因此人工合成具有肝素类似结构及活性的物质是目前研究的热点。硫酸乙酰肝素是在肝素之后被发现的一类肝素类似物,在体内广泛存在。人工合成肝素类似物即是以天然肝素或硫酸乙酰肝素结构为模板,采用不同的方法合成。此文对国外报道的肝素类似物的几种合成方法进行综述。     

低分子多糖在阿尔茨海默病防治中的研究进展

β淀粉样蛋白(Aβ)级联学说揭示了Aβ在阿尔茨海默病(AD)的发病过程中起到了关键作用。越来越多的研究发现硫酸乙酰肝素蛋白聚糖及其糖链硫酸乙酰肝素(HS)能够与Aβ相结合并促进Aβ的产生与聚积,因此硫酸乙酰肝素蛋白聚糖和HS已成为研究AD防治方法的重要靶点。此文主要介绍了近年来低分子多糖尤其是HS类似物在AD防治中的研究进展。     

不同来源的硫酸乙酰肝素的制备及理化性质研究

目的从不同来源制备硫酸乙酰肝素 (HS) ,并测定其理化性质。方法利用酶解法提取分离糖胺聚糖混合物 ,采用乙醇分级沉淀和离子交换柱色谱、凝胶过滤柱色谱等方法将HS纯化 ,醋酸纤维素薄膜电泳 (CAME)测定其纯度。结果所得各种来源的HS在CAME电泳显示一条带 ,且理化性质、生物活性和红外光谱各不相同。结论不同来源的HS具有不同的结构和性质     

乙酰肝素酶促进肿瘤转移分子机制的最新研究进展

乙酰肝素酶是目前发现的哺乳动物细胞中唯一能切割细胞外基质中硫酸肝素蛋白多糖侧链的内源性糖苷酶,参与许多病理及生理的过程。本文对乙酰肝素酶与肿瘤转移的高度相关性以及该酶参与肿瘤转移的分子机制等方面进行了综述,乙酰肝素酶会通过促进肿瘤血管生成、影响细胞分化以及促进肿瘤细胞黏附作用和侵袭能力等途径促进肿瘤的播散,因此可以将乙酰肝素酶作为抗肿瘤药物的靶点。本文对用筛选乙酰肝素酶抑制剂的方法、寻找抗肿瘤新药的最新进展做了概述,旨在为肿瘤转移机制研究,寻找治疗方法提供一些线索。     

抗肿瘤活性的肝素衍生物研究进展

在应用肝素及低分子量肝素(LMWH)防治肿瘤患者血栓栓塞性并发症时发现它们还具有显著的抗肿瘤活性,但其强大的抗凝活性成为抗肿瘤药物应用时的制约因素。对肝素进行化学修饰或将其与其他化合物偶联可获得抗凝活性低、抗肿瘤活性高的肝素衍生物。肝素衍生物的抗肿瘤机制有抑制类肝素酶活性、抑制P、L选择素介导的细胞间相互作用及抑制血管生长因子活性等。类肝素酶降解硫酸乙酰肝素(HS)侧链与肿瘤转移及肿瘤血管生成密切相关,P、L选择素介导的细胞间相互作用对肿瘤细胞的血源性转移过程有重要作用,血管生长因子所触发的血管生成是肿瘤生长、转移的必要条件。不同结构的肝素衍生物其抗肿瘤机制不完全相同。文章对抗肿瘤活性肝素衍生物的结构及其抗肿瘤机制作了综述。     

硫酸乙酰肝素及其相关药物的研究新进展

硫酸乙酰肝素是存在于所有动物组织细胞及胞外基质中的一类多糖物质,它通过与蛋白的相互作用参与各种生理病理过程,而其结构的改变,特别是硫酸化程度的改变,可干扰其与蛋白的相互作用,从而影响多种疾病的发生和发展。鉴于硫酸乙酰肝素在疾病进程中扮演的重要角色,硫酸乙酰肝素相关药物的设计与合成引起了药学研究者的广泛兴趣。综述硫酸乙酰肝素的结构、形成和功能以及与蛋白相互作用的机制,介绍硫酸乙酰肝素相关药物的研究与开发新进展。     

卡拉胶寡糖与bFGF的结合活性及其对乙酰肝素酶活性的抑制作用

为探讨卡拉胶寡糖作为硫酸肝素类似物的抗肿瘤和抗血管新生机制,以宫颈肿瘤细胞HeLa和人脐静脉内皮细胞HUVEC为研究对象,考察几种不同聚合范围的寡糖结合bFGF及抑制乙酰肝素酶活性的作用。发现卡拉胶寡糖对正常细胞和肿瘤细胞均表现出低毒特征。在低浓度下,具有结合bFGF并能抑制bFGF引起的细胞增殖能力,其中λ-卡拉胶寡糖(聚合度2～8)效果最明显,在质量浓度为20μg.mL-1时,可达30%的抑制率。几种寡糖对乙酰肝素酶活性有不同趋势的抑制作用,在HeLa细胞中,λ-卡拉胶寡糖的抑制活性最高;在HUVEC细胞中,聚合度在9～17的κ-卡拉胶寡糖活性最高。结果表明,卡拉胶寡糖的类硫酸肝素生物活性与其分子量大小、硫酸取代量有明显的关系,低分子量、高硫酸基取代是其高活性的关键。     

猪肝组织中硫酸乙酰肝素的分离纯化及二糖组成分析

目的从少量猪肝组织中分离纯化硫酸乙酰肝素(HS)并进行二糖组成分析。方法分别采用胰蛋白酶及中性蛋白酶对猪肝组织进行酶解,再分别采用AG 50W-X2强阳离子交换色谱、Sephadex G-10凝胶过滤色谱、Q-Sepharose Fast Flow强阴离子交换色谱法纯化。将纯化的HS分别采用肝素酶Ⅰ和Ⅲ降解,所得到的二糖经2-氨基苯甲酰胺标记后,采用PA03色谱柱分析其二糖组成。结果经色谱和电泳分析,所得到的HS不含蛋白质及其它糖胺聚糖,其二糖组成以非硫酸化和低硫酸化二糖为主。结论该方法可以有效分离、纯化猪肝组织中的HS,并适用于少量组织中HS二糖组成分析。     

HSPG和无HS-GAGs链HSPG体外抗乳腺癌的研究

目的：比较硫酸乙酰肝素蛋白聚糖（简称HSPG）和去硫酸乙酰肝素链（简称HS-GAGs链即HS链）的HSPG的体外抗人乳腺癌细胞MDA-MB-231的抗增殖和凋亡诱导作用。方法：对HSPG进行提取、纯化,硫酸乙酰肝素酶1水解HSPG的HS链;光学显微镜法观察两组分引起的细胞形态学的变化;MTT比色法检测两组分对肿瘤细胞生长曲线的影响;流式细胞术结合Annexin V-FITC及PI双染标记法观察两组分对肿瘤细胞凋亡的影响。结果：HSPG可致MDA-MB-231细胞脱落悬浮;MTT法检测结果显示HSPG对MDA-MB-231细胞增殖的抑制作用随浓度的增加而增强,而去HS链HSPG只有在高浓度时才呈现出抑制作用。HSPG能诱导MDA-MB-231的早期凋亡,而去HS链HSPG在高浓度（4 mg/mL）时对MDA-MB-231早期凋亡有诱导作用。结论：HSPG能诱导MDA-MB-231的早期凋亡和抑制细胞生长增殖。作用机制可能与HSPG的硫酸乙酰肝素链有关。     

Chemogenesis of an Antiangiogenic Glycosaminoglycan

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Heparan sulfate inhibitors and their therapeutic implications in inflammatory illnesses

Introduction: Heparan sulfate (HS) is a polysaccharide that is ubiquitously expressed on the cell surface and in the extracellular matrix and interacts with a wide variety of proteins to mediate numerous biological and pathological functions, including inflammation.

Areas covered: The structural diversity and the multiple biological roles of HS in inflammation are discussed. HS is involved in the recruitment and attachment of leukocytes to the inflamed epithelium, the activation of chemokines and the transmigration of leukocytes to the underlying target tissue. The endoglycosidase heparanase plays a key role in the above processes via the degradation of HS. HS mimetics that inhibit heparanase and block HS-binding proteins have been shown to inhibit inflammation in multiple animal models.

Expert opinion: HS plays important roles in many stages of the inflammation process, in particular the regulation of leukocyte extravasation. Compounds that can inhibit HS–protein interactions thus have considerable potential as anti-inflammatory therapeutics capable of simultaneously interfering with multiple steps of the inflammation process. There are a number of such compounds in various stages of clinical development for cancer, which should also find applications in inflammatory illnesses.     

Heparin as an anticancer therapeutic

Background: Although the pathophysiological mechanisms remain elusive, accumulating experimental and clinical data are showing that anticoagulants, particularly low molecular weight heparin, may have an important role as anticancer agents. Although this concept was first introduced decades ago, advancement in research has been hampered by scepticism and disinterest. The difficulty with understanding and defining the mechanisms of action is reflective of the diverse activity and pharmacological profile of these biological compounds, and the limitations of experimental techniques available to explore the interactions between the coagulation cascade and intracellular pathways that govern cell growth and differentiation. Objectives: This review will address and summarize some of the ongoing basic and clinical research on heparin as an anticancer therapeutic. Methods: A literature review using the keys words ‘heparin’, ‘low molecular weight heparin’, ‘cancer survival’ and ‘neoplasm’ was performed. Meeting proceedings from recent conferences on thrombosis and cancer were handsearched for relevant clinical studies. Conclusion: The investigation of anticoagulants as anticancer agents is now an innovative and rapidly growing field. Greater understanding of the interaction between coagulation and cancer will lead to improved patient care.     

舒洛地特研究进展及临床应用

舒洛地特是一种新型天然糖胺聚糖,含有的两个主成分作用原理不同而协同增效,具有抗凝、溶栓、抗心血管疾病、降血脂、保护肾脏等作用,近年来在治疗心血管疾病、周围动脉疾病、静脉炎后综合征、糖尿病并发症,尤其糖尿病肾病等方面的临床应用引起了人们的关注,本文就其化学成分、药代动力学、生物活性、质量控制、作用机制与药理、临床研究与应用,以及近年来的研究进展进行综述。与同类药肝素比,舒洛地特由于可口服,生物利用率高,副作用小,并具有肝素所没有的分解脂肪作用,可以认为应用将更广泛。目前国内只有进口产品,国内厂家正处于研发阶段,相信不久将来会有国产舒洛地特。     

Synthetic anti-lipopolysaccharide peptides and hepatitis C virus infection

Introduction: Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma. Although antiviral therapy has been markedly improved by the licensing of direct-acting antivirals, safety, resistance, high costs and difficult-to-treat patients remain important challenges.

Areas covered: This article focuses and comments on the recent development of synthetic anti-lipopolysaccharide peptides (SALPs) which bind to highly sulfated glycosaminoglycan/heparan sulfate (HS) on cell surface. HS serves as a primary docking site for several viruses to their respective host cells before the viruses interact with their cell surface receptor(s). In vitro studies have shown that SALPs inhibit entry of HCV without cell toxicity.

Expert opinion: SALPs prevent viral infection in cell culture model systems. Treatment studies of established HCV infection in cell culture models as well as proof-of-concept and safety studies in animal models are needed to evaluate their potential for drug development. The mechanism of action of SALPs as entry inhibitors suggests a potential application for HCV-infected patients to prevent reinfection of the liver graft in liver transplantation. Potential limitations may include high doses to obtain an antiviral effect and a target which is widely expressed and has a key function in cell physiology.     

脱硫酸化与多硫酸化肝素衍生物对肥大细胞脱颗粒的影响

目的　研究脱硫酸化与多硫酸化肝素对大鼠肥大细胞 (MC)脱颗粒的影响。方法　采用不同方法制得不同程度硫酸化肝素 :2 O 脱硫酸化肝素 (2DeSH)、N 脱硫酸化 重乙酰化肝素 (NDeSAcH)、6 O 脱硫酸化肝素 (6DeSH)、多硫酸化肝素 (PSH) ,通过大鼠腹腔被动MC脱颗粒实验 ,观察肝素及不同程度硫酸化肝素对卵清蛋白引起MC脱颗粒的影响。结果　与Hank液组比较 ,各样品组均有显著抑制MC脱颗粒的作用 (P <0 0 1 ) ,但 6DeSH组与色苷酸钠组差异有显著性 (P <0 0 1 ) ,显示较弱的抑制活性。结论　肝素抑制MC脱颗粒的活性与肝素结构上的硫酸基位置和多少有关 ,其中6 O 硫酸基对肝素的抑制MC脱颗粒的活性影响较大。     

Capillary electrophoresis: a tool for studying interactions of glycans/proteoglycans with growth factors

Heparan sulfate (HS) and heparin bind to various growth factors and modulate their activities. Interactions of heparin and HS with members of the fibroblast growth factor (FGF) family are prerequisites for binding of FGFs to their high affinity cell receptors. The sulfation patterns of distinct oligosaccharide domains within heparin and HS chains determine their high affinity binding with basic FGF (bFGF). In order to study the structural basis of interactions of HS with bFGF, we developed a capillary electrophoresis (CE) method in order to monitor the ability of HS-derived oligosaccharides to bind this growth factor. HS was degraded to Delta-di- and Delta-oligosaccharides with digestion with heparitinase and the obtained Delta-saccharides were analyzed by capillary zone electrophoresis (CZE), using 50 mM phosphate, pH 3.5, as operating buffer, reversed polarity (30 kV) and detection at 232 nm. Under these conditions all differently sulfated HS Delta-disaccharides and the various Delta-oligosaccharide groups were resolved. Following incubation of the digest with bFGF and re-electrophoresis of the mixture, the bFGF interacting oligosaccharide groups were easily detected and identified. In view of the obtained results, CE is a multipotent analytical tool for determining disaccharide composition in HS, separating the various oligosaccharide groups produced by the action of heparitinase and identifying those interacting with bFGF.