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1.
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。 相似文献
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Decreasing the metastatic potential in cancers--targeting the heparan sulfate proteoglycans 总被引:5,自引:0,他引:5
The heterogeneity of proteoglycans (PG)s contributes to their functional diversity. Many functions depend on their ability to bind and modulate the activity of components of the extracellular matrix (ECM). The ability of PGs to interact with other molecules, such as growth factors, is largely determined by the fine structure of the glycosaminoglycan (GAG) chains. Tumorigenesis is associated with changes in the PG synthesis. Heparan sulfate (HS) PGs are involved in several aspects of cancer biology including tumor progression, angiogenesis, and metastasis. PGs can have both tumor promoting and tumor suppressing activities depending on the protein core, the GAG attached, molecules they associate with, localization, the tumor subtype, stages, and degree of tumor differentiation. Perlecan is an angiogenic factor involved in tumor invasiveness. The C-terminal domain V of perlecan, named endorepellin, has however been shown to inhibit angiogenesis. Another angiogenic factor is endostatin, the COOH-terminal domain of the part-time PG collagen XVIII. Glypicans and syndecans may promote local cancer cell growth in some cancer tissues, but inhibit tissue invasion and metastasis in others. The GAG hyaluronan (HA) promotes cancer growth by providing a loose matrix for migrating tumor cells and mediates adhesion of cancer cells. HSPG degrading enzymes like heparanase, heparitinase, and other enzymes such as hyaluronidase and MMP are also important in tumor metastasis. Several different treatment strategies that target PGs have been developed. They have the potential to be effective in reducing tumor growth and inhibit the formation of metastases. PGs are also valuable tumor markers in several cancers. 相似文献
3.
Breast carcinoma is one of the leading causes of mortality among female cancers globally. Heparan sulfate proteoglycans, found predominantly on cell surfaces and in the extracellular matrix, are known to regulate breast cancer cellular behavior. Many studies have shown that these molecules serve as potential biomarkers for breast cancer. In addition, they have aberrant expression patterns and participate in various molecular signaling pathways in tumor progression. There is substantial interest in targeting heparan sulfate proteoglycans for cancer treatment, which needs to be tailored according to the roles that each proteoglycan plays in cancer biology. Current clinical trials using phosphomannopentaose sulfate, a heparan sulfate mimic, and various forms of heparin have produced promising results in breast cancer patients. Besides heparan sulfate chains, novel therapeutic agents could potentially be developed to regulate the proteoglycan core proteins as well as enzymes that modify heparan sulfation patterns. This review discusses the current use and future prospective applications of heparan sulfate proteoglycans, which have been recently patented, as therapeutic targets in breast cancer treatment. 相似文献
4.
Fügedi P 《Mini reviews in medicinal chemistry》2003,3(7):659-667
Heparin and heparan sulfate have been shown to interact with a large number of biologically important proteins regulating important physiological processes. Specific oligosaccharide structures within the heterogeneous polysaccharide chains are responsible for the binding to individual proteins. Identification of specific protein-binding oligosaccharides provides lead compounds in pharmaceutical development and in one case has already resulted in an approved drug. The chemical and biosynthetic basis of the molecular diversity of heparin and heparan sulfate, its manifestation in heparin-protein interactions, and recent progress for drug development offered by this diversity are reviewed. 相似文献
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Heparan sulfate proteoglycans (HSPGs) are present in several compartments and cell types in blood vessels. Their expression, as well as the activity of their degrading enzyme heparanase, are strongly regulated, with changes in gene expression, protein levels, and activity in response to environmental and metabolic stresses, including diabetes. HSPGs likely play an important role in the development and progression of atherosclerosis. Many functions of HSPGs, such as the promotion of monocyte adhesion, smooth muscle cell proliferation, and low density lipoproteins (LDL) binding, are determined by interactions between cells and specific regions of the HSPG core proteins. Here we review the role of HSPGs expressed in vascular wall in atherosclerotic vascular disease. 相似文献
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Shriver Z Capila I Venkataraman G Sasisekharan R 《Handbook of experimental pharmacology》2012,(207):159-176
The structural microheterogeneity of heparin and heparan sulfate is one of the major reasons for the multifunctionality exhibited by this class of molecules. In a physiological context, these molecules primarily exert their effects extracellularly by mediating key processes of cellular cross-talk and signaling leading to the modulation of a number of different biological activities including development, cell proliferation, and inflammation. This structural diversity is biosynthetically imprinted in a nontemplate-driven manner and may also be dynamically remodeled as cellular function changes. Understanding the structural information encoded in these molecules forms the basis for attempting to understand the complex biology they mediate. This chapter provides an overview of the origin of the structural microheterogeneity observed in heparin and heparan sulfate, and the orthogonal analytical methodologies that are required to help decipher this information. 相似文献
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The sulfated oligosaccharide PI-88 is a potent antiangiogenic, antitumor and anti-metastatic agent derived from yeast. It is primarily composed of sulfated phosphomannopentaose and phosphomannotetraose oligosaccharide units and is presently under evaluation in Phase II clinical trials for anticancer efficacy. PI-88 inhibits the heparan sulfate-degrading enzyme heparanase, exhibits antiangiogenic activity and has anticoagulant properties mediated by heparin cofactor II. It also inhibits vascular smooth muscle cell proliferation, kinase signalling and arterial intimal thickening following balloon injury. Many heparan sulfate-binding growth factors require heparan sulfate as a co-receptor in order to effectively deliver growth signals to cells. Thus, the antiangiogenic and antirestenotic activity of PI-88 may be at least partially due to this highly sulfated oligosaccharide competing with the interaction of growth factors, such as FGF-2 and VEGF, with cell surface heparan sulfate. This heparan sulfate mimetic has, therefore, multiple functions and therapeutic potential in a variety of vascular disorders. 相似文献
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Said Charef Michel Tulliez Liliane Esmilaire José Courty Dulce Papy-Garcia 《Food and chemical toxicology》2010
Heparan sulfate mimetic polymers promotes tissue repair when injected locally in doses of 1–2 mg/kg by various routes. These biopolymers, have been extensively studied for their diverse biological activities. However, there is no detailed report investigating the toxicity of OTR4120. In this study, the acute and subchronic (30 days) toxicity of varying levels of OTR4120 was investigated in mice after intraperitoneal administration. 相似文献
11.
Ishii T Ishimori H Mori K Uto T Fukuda K Urashima T Nishimura M 《Journal of pharmacological sciences》2007,104(4):366-373
Bovine lactoferrin (bLf) is an iron-binding secretory protein present in breast milk, mucosal secretions, and the secondary granules of neutrophils. Although bLf has multiple functions, including antimicrobial and immunomodulatory activities, its effect on neuronal cells is not fully understood. We report that bLf prevents cell adhesion of PC12 cells and allows them to be cultivated in suspension. PC12 cells normally adhere well to plastic culture plates and show anchorage-dependent cell growth, but we found that soon after adding bLf, they detach from culture plates and begin to grow in suspension. When bLf was removed from the medium, the cells began to re-adhere to the plates. Thus, bLf inhibits cell adhesion and stimulates anchorage-independent growth in PC12 cells. On the other hand, bLf-induced cell suspension growth was not observed when cells were grown on a laminin matrix, suggesting that bLf does not affect integrin-mediated cell adhesion on a laminin matrix. Treatment of cells with heparin or chondroitin sulfate A or C inhibited bLf-induced growth in cell suspension. Furthermore, pretreatment of cells with heparinase and/or chondroitinase prevented direct binding of bLf to the cell membrane. These results suggest that bLf binds to the membrane of PC12 cells via membrane-associated proteoglycans and leads to anchorage-independent growth. 相似文献
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G B Gervasi C Bartoli C Farina R Catalani G Carpita N Pistelli 《Arzneimittel-Forschung》1991,41(4):410-413
A low molecular weight heparan sulfate derivative, alpha-idosane was separated from a mixture of glycosaminoglycans extracted from porcine mucosa. Its molecular weight, sulfur, uronic acid and hexosamine contents, C-NMR spectrum and electrophoretic properties are reported in this paper. The pharmacological effects of a-idosane were investigated "ex vivo" in dogs and rats. At doses of 10-50 mg/kg p.o., a-idosane shows fibrinolytic activity but it is devoid of anticoagulant action. At the dose of 100 mg/kg p.o. a-idosane exertes a significant anti-inflammatory effect but is unable to protect the rats against arachidonate-induced sudden death. 相似文献
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Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprotein (LDL) receptor family which has been linked to Alzheimer's disease (AD) by biochemical and genetic evidence. Levels of neurotoxic amyloid beta-peptide (Abeta) in the brain are elevated in AD contributing to the disease process and neuropathology. Faulty Abeta clearance from the brain appears to mediate focal Abeta accumulations in AD. Central and peripheral production of Abeta from Abeta-precursor protein (APP), transport of peripheral Abeta into the brain across the blood-brain barrier (BBB) via receptor for advanced glycation end products (RAGE), enzymatic Abeta degradation, Abeta oligomerization and aggregation, neuroinflammatory changes and microglia activation, and Abeta elimination from brain across the BBB by cell surface LRP; all may control brain Abeta levels. Recently, we have shown that a soluble form of LRP (sLRP) binds 70 to 90 % of plasma Abeta, preventing its access to the brain. In AD individuals, the levels of LRP at the BBB are reduced, as are levels of Abeta binding to sLRP in plasma. This, in turn, may increase Abeta brain levels through a decreased efflux of brain Abeta at the BBB and/or reduced sequestration of plasma Abeta associated with re-entry of free Abeta into the brain via RAGE. Thus, therapies which increase LRP expression at the BBB and/or enhance the peripheral Abeta "sink" activity of sLRP, hold potential to control brain Abeta accumulations, neuroinflammation and cerebral blood flow reductions in AD. 相似文献
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Ohkawara S Yamamoto C Fujiwara Y Sakamoto M Kaji T 《Environmental toxicology and pharmacology》1997,3(3):187-194
The purpose of the present study is to clarify whether or not cadmium-induced production of heparan sulfate in vascular endothelial cells includes: (1) an increase in the number of heparan sulfate proteoglycan (HSPG) molecules; (2) a formation of longer chains of heparan sulfate; and (3) a binding of more heparan sulfate chains to core proteins. Bovine aortic endothelial cells were cultured and metabolically labeled with [(3)H]glucosamine and [(35)S]sulfate in the presence of cadmium chloride. Radiolabeled HSPGs were separated from more highly charged chondroitin or dermatan sulfate proteoglycans by ion-exchange chromatography and hydrodynamic size of HSPGs was characterized by gel filtration. Heparan sulfate chains were characterized by gel filtration after digestion with either papain or heparitinase. It was found that cadmium increases the incorporation of radioactive precursors into the high molecular weight subclass of HSPGs without a marked change of molecular weight of heparan sulfate chains (approximately 45 kDa). A sodium dodecyl sulfate-polyacrylamide gel electrophoresis of [(35)S]methionine-labeled proteins after heparitinase digestion revealed that the endothelial cells actively produce a HSPG core with a high molecular weight (~400 kDa), probably a perlecan core and the accumulation was increased by cadmium. HSPGs produced by cadmium-treated endothelial cells enhanced the [(3)H]thymidine incorporation in vascular smooth muscle cells cultured in the presence of basic fibroblast growth factor. It was therefore suggested that vascular endothelial cells after exposure to cadmium produce more perlecan molecules and this alteration may contribute to the antithrombogenic property of vascular wall and the formation of atherosclerosis after exposure to the metal through increase in anticoagulant heparan sulfate chains and stimulation of vascular smooth muscle proliferation, respectively. 相似文献
16.
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。 相似文献
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Robertson RT Baratta JL Haynes SM Longmuir KJ 《Journal of pharmaceutical sciences》2008,97(8):3257-3273
Previous studies demonstrated that intravenously administered liposomes, incorporating a peptide from the Plasmodium circumsporozoite protein, accumulate rapidly and selectively in mouse liver. The present investigation was designed to determine the molecular components in liver responsible for liposome targeting. Studies of liver tissue slices demonstrated that immunoreactivity for heparan sulfate proteoglycan (HSPG), but not other tested proteoglycans, was distributed along sinusoidal borders of liver; this immunoreactivity appeared associated with nonparenchymal cells of the sinusoids and with the basolateral portion of hepatocytes. Peptide-containing liposomes bound to liver tissue in a pattern similar to the distribution of heparan sulfate immunoreactivity, either after intravenous injection of liposomes in vivo or after incubation of liposomes with liver slices in vitro. Control liposomes, without the peptide, displayed very light binding without a pattern. Pretreatment of liver slices with heparinase, but not chondroitinase or hyaluronidase, eliminated peptide-containing liposome binding, but did not affect binding of control liposomes. Coincubation of peptide-containing liposomes with heparin, but not with other glycosaminoglycans, markedly inhibited liposome binding to liver slices. N-desulfated and O-desulfated heparins individually were less effective inhibitors of liposome binding than was heparin. These results indicate that liposomes containing a peptide from Plasmodium target liver tissue by binding to HSPGs in the extracellular matrix. 相似文献
18.
Arylsulfotransferase activity was found in the feces of human (14.74 +/- 2.674) and rat (7.37 +/- 1.126 mumol/hr/g wet feces). In the case of the rat, arylsulfotransferase activity was markedly and rapidly decreased by the treatment with antibiotics mixture, but restored to the original activity 3 weeks after stopping the administration of antibiotics. The excretion of the sulfate esters derived from p-nitrophenylsulfate was enhanced by the administration of acetaminophen but not by the treatment with antibiotics. Furthermore, in rats treated with antibiotics, inorganic sulfate excretion was severely decreased. When only acetaminophen was administered, the excretion of acetaminophen-O-sulfate showed a 10-15% decrease in rats treated with antibiotics compared with conventional rat. 相似文献
19.
硫酸乙酰肝素蛋白聚糖对C_3H小鼠乳腺癌移植瘤的抑制作用及其机制 总被引:1,自引:3,他引:1
目的观察硫酸乙酰肝素蛋白聚糖(HSPG)对C3H小鼠乳腺癌移植瘤的抑制作用及其机制。方法建立肿瘤模型并随机分为5组:生理盐水组、HSPG组(5、10、50mg.kg-1)及阳性对照组,各组动物自模型建立d2开始腹腔注射给药治疗22d并观察记录肿瘤体积。d24处死动物,称量肿瘤重量,计算胸腺指数及脾指数,使用原位凋亡检测法(TUNEL)检测HSPG对肿瘤细胞凋亡的影响,免疫组化检测血管内皮生长因子(VEGF)的表达。结果HSPG可明显抑制肿瘤生长,而不降低胸腺指数和脾指数。TUNEL结果HSPG组肿瘤组织中出现大量蓝黑色凋亡细胞,且明显多于生理盐水组,HSPG组肿瘤组织的VEGF的表达明显降低。结论HSPG对C3H小鼠移植性乳腺癌生长具有明显的抑制作用,其机制可能与诱导肿瘤细胞凋亡及抑制VEGF表达有关。 相似文献
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Antiviral effect of the heparan sulfate mimetic, PI-88, against dengue and encephalitic flaviviruses
Many viruses, including flaviviruses, display affinity for cell surface heparan sulfate (HS) proteoglycans with biological relevance in virus attachment/entry. This raises the possibility of the application of HS mimetics in antiviral therapy. We have evaluated the antiviral effect of the sulfated polysaccharides, suramin, pentosan polysulfate (PPS) and PI-88, which are currently approved or in trial for clinical use, against dengue virus (DEN) and the encephalitic flaviviruses, Japanese encephalitis virus, West Nile virus, and Murray Valley encephalitis virus. A flow cytometry-based method for the measurement of inhibition of virus infectivity was developed, which showed the in vitro antiviral activity of the three compounds, albeit with differences in efficiency which were virus-dependent. The 50% effective concentration (EC(50)) values for DEN inhibition were in the order: PPS相似文献