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Raghuraman, Arjun. "Designing Non-saccharide Heparin/Heparan Sulfate Mimics." Online version available 8/19/2013, 2008. http://hdl.handle.net/10156/2269.
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Carelli, Guareide [UNESP]. "Associação de doses baixas de heparina não fracionada e de heparina de baixo peso molecular na prevenção de trombose venosa experimental." Universidade Estadual Paulista (UNESP), 2003. http://hdl.handle.net/11449/88962.
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carelli_g_me_botfm.pdf: 357124 bytes, checksum: 5673f0ccb2732bdb65892b407c35e19c (MD5)<br>A heparina é um glicosaminoglicano sulfatado, de cadeia longa, que vem sendo largamente utilizada, desde meados do século passado, no tratamento e profilaxia das tromboses arteriais e venosas e cuja utilização permitiu o desenvolvimento das cirurgias cardíaca e vascular. As heparinas de baixo peso molecular (HBPM) são frações ou fragmentos da heparina separados do complexo polissacarídico por extração com solvente ou por gel filtração, ou por clivagem química ou enzimática aplicada antes dessa separação física. No presente artigo são revistos os diversos aspectos da estrutura, mecanismo de ação, farmacocinética, monitorização laboratorial e aplicações clínicas de ambos os tipos de substâncias, sendo chamada a atenção para as diferenças entre elas. As HBPM tendem a substituir a heparina não fracionada, na maior parte de suas indicações, por serem de mais simples utilização e apresentarem maior eficácia e segurança em algumas indicações, embora sejam de custo mais alto.<br>Heparin is a long sulfated glucosaminoglicane chain has been used in the treatment and prophylaxis of arterial and venous thombosis since the 50’s of last century. Its use also aided the development of cardiac and vascular surgery. Low molecular weight heparins (LMWH) are fractions or fragments of heparin separated from the polysaccharide complex by solvent extraction or gel filtration, or by chemical or enzymatic cleavage, before the extraction. In this article the main aspects of structure, mechanism of action, pharmacokinetics, laboratorial control, and clinical indications of both kinds of substances are reviewed and their main differences emphasized. Despite their high cost, LMWH presently tend to substitute unfractionated heparin in the majority of indications because of its simpler use, high efficacy and security in some cases.
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Noti, Christian. "Synthesis of heparin oligosaccharides and the creation of heparin microarrays /." Zürich : ETH, 2007. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17150.
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Albig, Thomas. "Synthese und Untersuchung von Heparin-Prodrugs auf Glyceridbasis /." [S.l.] : [s.n.], 1986. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=7990.
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Jaime, Rodríguez Juan Carlos. "Unveiling Heparin and Heparan Sulfate Conformations : a Journey into Paramagnetic NMR Analysis." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASF016.
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L'héparine (HP) et les héparane sulfates (HS) sont des polysaccharides sulfatés linéaires qui jouent divers rôles biologiques, notamment dans la croissance cellulaire, l'adhésion, la reconnaissance virale et la métastase du cancer. Leur variété moléculaire et leur motif de sulfatation contribuent à leur polyvalence biologique. Par ailleurs, leur flexibilité conformationnelle a été étudiée par des méthodes telles que la cristallographie aux rayons X et la RMN. Malgré des avancées, interpréter ces caractéristiques reste difficile, surtout pour de longs saccharides. Cette thèse propose l'utilisation de la RMN paramagnétique, notamment des déplacements de pseudo-contacts (PCS), dans l’étude conformationnelle des molécules d’HS. Les résultats obtenus sur un octasaccharide d'HS, montrent une corrélation entre les PCS expérimentales et les simulations de dynamique moléculaire, suggérant des conformations spécifiques des motifs IdoA. Ces découvertes élargissent les applications de la RMN paramagnétique, ouvrant la voie à une analyse approfondie des interactions protéine-polysaccharide<br>Heparin (HP) and heparan sulfates (HS) are linear and sulfated polysaccharides that play various biological roles, including cell growth, adhesion, viral recognition, and cancer metastasis. Their molecular diversity and sulfation pattern contribute to their biological versatility. Furthermore, their conformational flexibility has been studied through methods such as X-ray crystallography and NMR. Despite advancements, interpreting these features remains challenging, especially for long saccharides. This thesis proposes the use of paramagnetic NMR, particularly pseudo-contact shifts (PCS) measurements, in studying the conformation of HS molecules. Results obtained on an HS octasaccharide show a correlation between experimental PCS and molecular dynamics simulations, suggesting specific conformations of IdoA motifs. These findings expand the applications of paramagnetic NMR, paving the way for a thorough analysis of protein-polysaccharide interactions
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Nazir, Ahmad Mohamad Farha. "The role of heparin and heparin-binding growth factors in pre-eclampsia." Thesis, Middlesex University, 2016. http://eprints.mdx.ac.uk/21321/.
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The aims of this study tested the hypothesis that expression of heparin-binding growth factors (HBGFs) in normal placental development was altered in a specific pregnancy disorder preeclampsia. HBGFs bind to heparin, a glycosaminoglycan (GAG) affecting activity. I investigated the role of heparin and HBGFs in pathophysiology of pre-eclampsia. Placental tissue from a cohort study of 87 women was performed following uncomplicated pregnancy at term, but not in labour (TNL, n=26), preterm labour (PTL, n=17), following labour onset (TL, n=21), first trimester (FNL, n=4) and pre-eclampsia (PE, n=19). The HBGFs studied were vascular endothelial growth factor (VEGF), placental growth factor (PLGF), fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), heparin-binding epidermal growth factor (HB-EGF), midkine (MK), pleiotrophin (PTN), and cluster differentiation (CD105). The localisation of HBGFs and receptors VEGFR-1, /(sflt-1), PLGFR-1, VEGFR-2 and FGF2R-1 in placenta were detected. The expression of VEGF, PLGF, FGF2, HGF, PDGF, CD105 was confined to villous trophoblast, endothelial cells except for MK, HB-EGF and PTN was specifically to villous trophoblast. The total RNA production in human placentae samples (n=7) from PE and controls were analysed using qRTPCR. Placental expression of mRNA was extracted for primer assays of PLGF, FGF2, MK, PTN, and endogenous housekeeping gene as Succinate dehydrogenase complex subunit A (SDHA). FGF2 and SDHA mRNA expression was significantly different using Mann-Whitney U test. An in vitro villous trophoblast invasion model was performed with human fibrosarcoma HT1080 invasive cells (positive control), mouse embryonic fibroblast NIH/3T3 non-invasive cells (negative control) and immortalised human primary villous trophoblastic cell lines TCL-1.The greatest stimulation was by FGF2, PDGF-BB, HGF, MK and co-incubation with heparin enhanced these responses, except for PTN using the Mann-Whitney U test. Heparin’s role is indicated in mediating the effects of HBGFs. It’s suggests heparin therapeutic use in the treatment of pre-eclampsia.
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KRISHNASAMY, CHANDRAVEL. "MOLECULAR MODELING STUDIES OF HEPARIN AND HEPARIN MIMETICS BINDING TO COAGULATION PROTEINS." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/18.
Testo completoAbstract (sommario):
Heparin, a glycosaminoglycan (GAG), is a complex biopolymer of varying chain length and consisting of uronic acid and glucosamine residues, which are sulfated at various positions. The interaction of heparin with antithrombin is the basis for anticoagulation therapy. Heparin accelerates the antithrombin mediated inhibition of factor Xa and thrombin by a conformational activation mechansism and bridging mechanism, respectively. The sequence specific pentasaccharide DEFGH in full length heparin is the most important fragment for high affinity and activation of antithrombin, without which the heparin is incapable of binding to antithrombin. Although heparin is a commonly used anticoagulant, it suffers from serious side effects including bleeding complications, heparin-induced thrombocytopenia, and intra- and inter-patient dose response variability. Desai and co-workers have shown that it is possible to replace the GAG skeleton by small, non-saccharide sulfated molecules as antithrombin activators. However, the designed molecules were found to be weak activators of antithrombin due to their binding to the extended heparin-binding site (EHBS), instead of the pentasaccharide-binding site (PBS), of antithrombin. To design better non-saccharide antithrombin activators, a virtual screening-based approach was employed. Combinatorial virtual screening of 24576 molecules based on tetrahydroisoquinoline core scaffold resulted in 92 hits that were predicted to bind preferentially in the PBS of activated antithrombin with good affinity. The work resulted in a predicted pharmacophore consisting of a 5,6-disulfated bicyclic tetrahydroisoquinoline and a 2′,5′-disulfated unicyclic phenyl ring connected by a 4- to 5-carbon linker. The work has led to several hypotheses, which are being tested in the laboratory through synthesis and biochemical evaluation. To understand the mechanism of heparin binding to thrombin in greater detail, structural biology and molecular modeling approaches were used. More specifically, the nature of the heparin binding to thrombin was studied with a special focus on understanding the specificity of recognition. Comparative analysis was performed with heparin–antithrombin interaction to assess similarities and differences between the two heparin binding systems. In antithrombin, three important amino acids are involved in heparin pentasaccharide binding, while in thrombin, at least seven basic amino acids are predicted to be involved. For biological systems, one would expect greater specificity with more interacting points. However, the heparin–thrombin system interestingly displays a lack of specificity. The molecular basis for this lack of specificity is not clear. A study of antithrombin and thrombin crystal structures with regard to surface exposure, flexibility, and geometry of basic amino acids present in the respective heparin binding site provides the basis for the specificity of recognition (or lack thereof) in the two systems. Interestingly, analysis of thrombin exosite-II showed that Arg101, Arg165 and Arg233 are spatially conserved and form a local asymmetric center. Using in-silico docking techniques, selected tetrasaccharide sequences were found to specifically recognize this triad of amino acids indicating the possibility of specific recognition of thrombin. This hypothesis led to the design of a putative lead sequence that is 50% smaller in size and contains 62.5% fewer charges in comparison to the literature reported known exosite II sequence. The design of novel putative ‘specific’ exosite II sequence challenges the idea that the thrombin–heparin interaction is completely non-specific and gives rise to novel opportunities of designing specific thrombin exosite-II ligands.
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Sachchidanand. "Heparin binding to fibronectin." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393457.
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Evans, Dyfed Ll. "The heparin activateable serpins." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385390.
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Freitas, Cristiane Fonseca. "Efeitos do Bay 41-2272 na hipertensão pulmonar experimental em cães anestesiados." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308951.
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Orientador: Edson Antunes<br>Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas<br>Made available in DSpace on 2018-08-09T08:05:23Z (GMT). No. of bitstreams: 1
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Previous issue date: 2007<br>Resumo: Neste estudo, investigamos os efeitos protetores do BAY 41-2272 sobre a hipertensao pulmonar induzida pelo complexo heparina-protamina e hipoxia em cães anestesiados. Os animais foram anestesiados com pentobarbital sodico (Hypnol, 30mg/kg, iv) combinado com citrato de fentanila (0,01 mg/kg/h, i.v.) e diazepam (0,25mg/kg/h, iv). A hipertensao pulmonar pelo complexo heparina-protamina foi induzida com a administracao de 500 UI/kg de heparina, seguida da administracao de protamina (10 mg/kg). A interacao heparina-protamina causou aumento de aproximadamente 350% da pressao media da arteria pulmonar (PMAP), acompanhado de aumento significativo do indice de resistencia vascular pulmonar (IRVP) e da pressao capilar pulmonar (PcP). Este aumento foi significativo 2 min apos a injecao de protamina, mantendo-se significativamente elevado ate aproximadamente 5 minutos apos administracao da mesma. Ao mesmo tempo em que se detectou a hipertensao pulmonar, observamos reducao significativa da pressao arterial media (PAM). Observamos ainda um aumento significativo da frequencia cardiaca (FC) aos 2 minutos apos administracao da protamina com discreta diminuicao do indice cardiaco (IC). O indice de resistencia vascular sistemica (IRVS) nao sofreu alteracoes significativas. A saturacao do oxigenio (SpO2) foi significativamente diminuida apos a formacao do complexo heparina-protamina. Nos animais tratados com BAY 41-2272 (10 /kg/min, i.v.), observamos reducao marcante do aumento da PMAP, do IRVP e da PcP. Por outro lado, este tratamento potencializou a reducao da PAM. Alem disso, o BAY 41-2272 reduziu significantemente o IRVS e aumentou a FC. A diminuicao da SpO2 foi atenuada significativamente pelo BAY 41- 2272. Os niveis plasmaticos de GMPc foram dosados aos 2 min apos a formacao do complexo heparina-protamina, tendo-se mostrado elevados no grupo tratado com o BAY41-2272. O tempo de tromboplastina parcial ativado (TTPA) nao apresentou alteração significativa no tratamento com o BAY 41-2272. O veiculo do BAY 41-2272 (DMSO 30%) nao alterou significativamente os parametros estudados. A hipertensao pulmonar por hipoxia foi induzida com a instalacao de uma baixa tensao de oxigenio (FiO2=12%). Nesta circunstancia, a PMAP elevou-se em aproximadamente 280% aos 5 minutos, mantendo-se significativamente elevada ate 15 minutos apos instalacao da hipoxia. A elevacao da PMAP foi acompanhada de aumentos significativos no IRVP e PcP. A PAM, IRVS, FC e IC nao apresentaram alterações significativas. A SpO2 diminuiu na presenca da hipoxia. O tratamento com BAY 41-2272 (10 /kg/min, i.v.), reduziu significativamente a PMAP, PcP e IRVP. O IRVS foi significativamente potencializado pelo BAY 41-2272. A PAM, FC e IC nao alteraram significativamente. A diminuicao da SpO2 foi atenuada significativamente pelo BAY 41- 2272. Os niveis plasmaticos de GMPc elevaram-se significativamente no grupo tratado com o BAY 41-2272. Em conclusao, o BAY 41-2272 atenuou a acao vasoconstritora pulmonar induzida pelo complexo heparina-protamina e hipoxia levando a uma prevencao da hipertensao pulmonar.<br>Doutorado<br>Farmacologia<br>Doutor em Farmacologia
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Pazzini, Carla. "Preparação e caracterização de nanoparticulas com heparina e sua avaliação em modelo animal de trombose venosa." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310166.
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Orientadores: Joyce Maria Annichino-Bizacchi, Nelci Fenalti Hoher<br>Dissertação (mestrado) - Universidade Estadual de Campinas. Faculdade de Ciencias Medicas<br>Made available in DSpace on 2018-08-15T09:49:31Z (GMT). No. of bitstreams: 1
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Previous issue date: 2010<br>Resumo: A heparina é um anticoagulante amplamente empregado no tratamento e profilaxia da trombose venosa profunda (TVP). Algumas limitações do seu uso são o custo e a via de administração, endovenosa ou subcutânea, às vezes em doses repetidas em 24 horas. Assim, o desenvolvimento de um produto que possa ser administrado por via subcutânea em um menor número de aplicações ou por via oral, torna-se um importante desafio, e de grande aplicabilidade clínica. A utilização de um sistema de liberação sustentada de fármacos pode vir ao encontro desse objetivo, pois permite que o agente seja protegido e liberado gradativamente. Este projeto consistiu na preparação e caracterização de nanopartículas biodegradáveis de poli (e-caprolactona) (PCL) como carreador de heparina de baixo peso molecular, e avaliação de sua atividade anticoagulante e antitrombótica in vivo. As nanopartículas foram preparadas pelo método de dupla emulsão a/o/a e evaporação de solvente. A caracterização das nanopartículas foi realizada por microscopia eletrônica de varredura (MEV), observando-se nanopartículas esféricas e homogêneas. O diâmetro médio das nanopartículas foi de 269 ± 36 nm e o potencial zeta foi de -1,20 ± 1,93 mV, indicando que as mesmas apresentam carga negativa. A eficiência de encapsulação, analisada pelo método Azure II, foi de 80 ± 2,3%. A liberação da heparina in vitro, avaliada pelo método de Azure II, no período de 24 horas foi de 4 ± 1,8%. Após a adição da esterase houve um aumento para 10 ± 1,9% na liberação de heparina, provavelmente pela aceleração da degradação das partículas pela enzima. A liberação in vivo da heparina encapsulada, após aplicação subcutânea em ratos, foi avaliada pela atividade anti-Xa plasmática através do método colorimétrico, e os resultados foram comparados aos obtidos com heparina livre. A dose de heparina encapsulada teve que ser 5 vezes maior que a dose de heparina livre. A heparina encapsulada em nanopartículas apresentou uma liberação sustentada por até 12 horas, por um período significativamente mais prolongado (P<0,01), mas com menor atividade anti-Xa. Esses dados sugerem que as nanopartículas podem permitir que a heparina seja liberada de uma forma mais gradual, e mesmo em dose mais elevada, não parece estar associada a um risco de atividade acima da faixa terapêutica. Quando se comparou a atividade anti-Xa obtida pela injeção subcutânea de nanopartículas com heparina em doses diversas, 800 UI/Kg e 1000 UI/Kg, ficou demonstrado que o efeito e o tempo de ação dependem da dose aplicada. Para avaliação da ação antitrombótica foi padronizado o modelo de TVP por estase em ratos. As doses de nanopartículas empregadas para a avaliação da ação antitrombótica foram calculadas pela atividade anti-Xa semelhante à obtida com a heparina livre, de 0,3 a 0,7 UI/mL. A heparina livre ou encapsulada em nanopartículas foi aplicada em uma única dose, por via subcutânea. Os resultados mostraram que houve diminuição significativa do trombo formado com a utilização de heparina livre, em comparação ao grupo controle (P=0,004). Praticamente não houve a formação de trombose venosa em nenhum dos ratos que receberam a heparina encapsulada em nanopartículas, com uma diferença significativa tanto em relação ao grupo controle (P<0,001) como ao grupo com heparina livre (P<0,001). Em resumo, o método de dupla emulsão a/o/a mostrou-se um método eficiente para o encapsulamento de heparina, proporcionando a obtenção de nanopartículas esféricas e com alta eficiência de encapsulação. Pelos estudos in vivo, a heparina encapsulada não liofilizada mostrou uma liberação sustentada, por um período superior ao obtido com a heparina livre, e com excelente ação antitrombótica. Caso esses resultados se confirmem através da continuidade deste estudo, a utilização de heparina encapsulada em nanopartículas na prática clínica poderá ser uma realidade com grandes vantagens para o paciente.<br>Abstract: Heparin is an anticoagulant widely used in the treatment and prophylaxis of deep vein thrombosis (DVT). Some limitations of its use is the cost and route of administration, intravenous or subcutaneous, sometimes in repeated doses in 24 hours. Thus, the development of a product that can be administered subcutaneously in a smaller number of applications or orally becomes a major challenge, with interesting clinical applications. The use of a system for sustained release of drugs can come to meeting that goal, because it allows the agent to be protected and released gradually. This project consisted of the preparation and characterization of biodegradable nanoparticles of poly (e-caprolactone) (PCL) as a carrier of heparin of low molecular weight, and its evaluation of anticoagulant and antithrombotic activity in vivo. The nanoparticles were prepared by the method of double emulsion w/o/w and evaporation of solvent. The characterization of nanoparticles was performed by scanning electron microscopy (SEM), which showed homogeneous spherical nanoparticles. The average diameter of nanoparticles was 269±36 nm and zeta potential was -1.20±1.93 mV, indicating negative charge. The encapsulation efficiency, assayed by Azure II, was 80±2.3%. The release of heparin in vitro, at the 24-hour period was 4±1.8%. After the addition of esterase the release of heparin was increased to 10±1.9%, probably by accelerating the degradation of particles by the enzyme. The in vivo release of encapsulated heparin after subcutaneous administration in rats, was assessed by anti-Xa plasma activity and the results were compared with free heparin. The dose of heparin encapsulated had to be 5 times the dose of heparin free. Heparin-encapsulated nanoparticles showed a sustained release for up to 12 hours for a period significantly longer (P<0.01), but with lower anti-Xa activity. These data suggest that nanoparticles may allow heparin to be released in a more gradual, but with lower activity. When comparing the anti-Xa activity obtained by subcutaneous injection of nanoparticles with different doses of heparin, 800 IU/kg and 1000 IU/kg, demonstrated that the effect and duration of action depends on the dose applied. To evaluate the antithrombotic action of nanoparticles with heparin a model of DVT by stasis in rats was used. The doses of nanoparticles used for the evaluation of antithrombotic action were calculated by anti-Xa activity similar to that obtained with free heparin, 0.3 to 0.7 IU/mL. Heparin free or encapsulated in nanoparticles was applied in a single dose subcutaneously. The results showed a significant decrease of thrombus formed with the use of free heparin, compared with the control group (P=0.004). There were virtually no formation of venous thrombosis in any of the rats that received heparin encapsulated in nanoparticles, with a significant difference both in the control group (P<0.001) and the group with free heparin (P<0.001). In summary, the method of double emulsion w/o/w proved an efficient method for the encapsulation of heparin, providing spherical homogeneous nanoparticles with high encapsulation efficiency. For in vivo studies, heparin encapsulated showed a sustained release for a period greater than that of free heparin, and with excellent antithrombotic action. If these results are confirmed by the continuity of this study, the use of heparin encapsulated in nanoparticles in clinical practice can be of great benefits for the patient.<br>Mestrado<br>Medicina Experimental<br>Mestre em Fisiopatologia Médica
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Ayerst, Bethanie Imogen. "GDF5 mediated enhancement of chondrocyte phenotype and its modulation by heparin and heparan sulfates." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/gdf5-mediated-enhancement-of-chondrocyte-phenotype-and-its-modulation-by-heparin-and-heparan-sulfates(e835db9b-e63e-4301-8cea-df879b052402).html.
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Articular cartilage plays a vital role in load-bearing joints, providing an almost frictionless surface to articulating bones. However, the avascular nature and low cell density of the tissue means that following injury, there is limited potential for regeneration and repair. With the ageing population, the prevalence and economic burden associated with osteoarthritis (OA) is increasing rapidly, but as of yet there are no fully effective ways to treat the condition. Research into novel therapies has therefore become a popular avenue of investigation, and human mesenchymal stem/stromal cells (hMSCs) have been highlighted as particularly promising targets. However, current, methods for inducing the chondrogenic differentiation of hMSCs, which typically employ the use of transforming growth factor beta 1 or 3 (TGFβ1/3), result in the production of hypertrophic rather than hyaline tissue, hampering translational progress. Growth differentiation factor 5 (GDF5) belongs to the TGFβ superfamily of proteins and is vital for skeletal formation, however its use in cartilage tissue engineering (TE) strategies has been somewhat neglected. Here we demonstrate that GDF5 significantly increases aggrecan gene expression (a marker of articular cartilage), without affecting collagen type X expression (a marker of chondrocyte hypertrophy), in chondrocyte pellet cultures derived from hMSCs, making it a promising target for the formation of permanent articular cartilage. The therapeutic application of growth factors is, at present, limited due to their expense, susceptibility to proteolytic degradation, and rapid clearance, leading to large quantities being required to get anywhere near the desired outcome. The highly sulfated glycosaminoglycan (GAG), heparin, is already extensively used in the clinic as an anticoagulant, and is also able to bind and potentiate the activity of a wide range of growth factors. As such, researchers are now using it to enhance stem cell expansion/ differentiation protocols, as well as to improve the delivery/ activity of growth factors in TE strategies. Here, we identify GDF5 as a novel heparin/heparan sulfate (HS)-binding protein, and show that endogenous HS proteoglycans (HSPGs) are vital for localizing GDF5 to the cell surface, but are not required for its signalling activity. Importantly, we report that clinically relevant doses of heparin (≥ 10 nM), but not equivalent concentrations of HS, inhibit GDF5’s biological activity, in both hMSC-derived chondrocyte pellet cultures, and in the skeletal cell line ATDC5. We demonstrate that these inhibitory effects are due to heparin (but not HS) inhibiting both GDF5 binding to endogenous HSPGs and GDF5-induced induction of Smad 1/5/8 signalling. This study may therefore explain the variable (and disappointing) results seen with heparin-loaded biomaterials for skeletal TE, and the adverse skeletal effects, such as osteoporosis, that have been reported in the clinic following long-term heparin treatment. Together, our results caution the use of heparin in the clinic and in TE applications, and prompt the transition to using more specific GAGs (e.g. HS derivatives or synthetics), with better-defined structures and fewer off-target effects, if optimal therapy is to be achieved. In the case of GDF5, we have used a variety of developed techniques to begin uncovering important structural and functional information regarding the HS-GDF5 interaction, which are hoped to ultimately pave the way towards achieving this aim. Although further analysis is necessary, our data indicate that relatively long HS sequences are required for binding, and that both ionic and non-ionic interactions play a role in the interaction. In addition we suggest that low- rather than high-affinity HS variants may be key to potentiating the activity of this growth factor.
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Jia, Juan. "Structure and functions of heparan sulfate/heparin - Importance of glucuronyl C5-epimerase and heparanase." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107202.
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Teka, Girma. "NaCl, Heparin, and Heparan Sulphate Affects Binding of Rift Valley Fever Virus to Human Cells." Thesis, Umeå universitet, Biomedicinsk laboratorievetenskap, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-58534.
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Bernstein, Howard. "A system for heparin removal." Thesis, Massachusetts Institute of Technology, 1985. http://hdl.handle.net/1721.1/15291.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1985.<br>MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE.<br>Bibliography: leaves 255-264.<br>by Howard Bernstein.<br>Ph.D.
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Fitton, Hazel Louise. "Modulation of antithrombin by heparin." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624993.
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Bromfield, Stephen M. "Multivalent heparin binding and sensing." Thesis, University of York, 2014. http://etheses.whiterose.ac.uk/7943/.
Testo completoAbstract (sommario):
Heparin therapy involves the clinical use of heparin as an anti-coagulant, for example, during surgery. At the conclusion of treatment, systemic heparin levels must be quantified to allow accurate dosing of a heparin antidote. This thesis details work towards a better sensing methodology and an improved antidote. A synthetically-simple arginine-functionalized dye – Mallard Blue (MalB) – was synthesised and shown able to detect heparin across a clinically relevant concentration range in biological media such as human serum. The heparin binding of MalB is selective over structurally related glycosaminoglycans and is highly tolerant of electrolytic competition. Indeed, the performance of MalB is comparable with the best heparin sensors currently known and makes it the new best-in-class thionine dye. Mallard Blue was developed into a straightforward competition assay able to report on the relative heparin binding efficiencies of candidate molecules in competitive media, including human serum. Using this assay in conjunction with molecular dynamics modelling techniques, fundamental insights into the binding of poly(amidoamine) (PAMAM) dendrimers to heparin were gained. Interestingly, the medium sized (G2-G4) dendrimers achieved the most charge-efficient heparin binding. Comparisons against derivatives modified with poly(phenylenevinylene) cores revealed native PAMAMs to be exponents of adaptive multivalency, in contrast to the more rigid derivatives’ shape-persistent multivalency. The performance of self-assembled multivalent (SAMul) heparin binder C22G1DAPMA was studied in different biological media and shown to be more charge-efficient than the currently used heparin antidote under competitive conditions. Also, C22G1DAPMA was able to reverse anti-coagulation in heparinized human plasma and degrade on a clinically interesting timescale. Structural modifications afforded two new families of SAMul binders, which unveiled fundamental differences in the chiral preferences of heparin and DNA, along with probing the effects of nanoscale morphology on heparin binding ability and aggregate-stability in serum.
18
Kropf, Sabine [Verfasser]. "Heparin-induzierte Thrombozytopenie: Inzidenz von Heparinantikörpern bei Patienten nach orthopädischen Operationen und nachfolgender Thromboseprophylaxe mit unfraktioniertem Heparin im Vergleich zu niedermolekularem Heparin / Sabine Kropf." Greifswald : Universitätsbibliothek Greifswald, 2011. http://d-nb.info/1013341236/34.
Testo completo
19
Dalton, Charlotte. "Chemical synthesis of heparan sulfate oligosaccharides for use in single molecule fluorescence analysis." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/chemical-synthesis-of-heparan-sulfate-oligosaccharides-for-use-in-single-molecule-fluorescence-analysis(a0780c20-6269-4a5c-95d0-376ffa72b3af).html.
Testo completoAbstract (sommario):
Heparan sulfate (HS) is a cell-surface sulfated polysaccharide that binds to multiple proteins and has been implicated in cancer, viral infection and Alzheimer's disease. Due to the heterogeneity of HS, the structural requirements for protein binding are ill- defined. Chemical synthesis of structurally-defined HS oligosaccharides, which are tunable in terms of length, order of monosaccharides and sulfation pattern, is required for the investigation of HS-protein binding. Single molecule methods have been utilised in biophysics to study dynamic processes and can allow observation of rare events which would be 'averaged out' in ensemble measurements. Access to fluorescently labelled HS oligosaccharides should allow investigation of interactions with proteins at the single molecule level using methods such as single molecule FRET, providing a method complementary to NMR studies (ensemble) and X-ray crystallography (non-dynamic).This thesis presents the development of a method for the fluorescent labelling of a chemically synthesised HS disaccharide utilising a reducing-end amine tag. Analysis of the fluorescence properties of the labelled disaccharide at ensemble and single molecule level indicated no perturbation of the fluorophore when attached to the sugar. Fluorescence correlation spectroscopy measurements of the fluorescent HS disaccharide with the protein FGF-1 showed no binding, which is attributed to the low concentration (1 nM) of disaccharide required in the experiment. Additional work is presented in this thesis on the development of a method for atom-specific 13C labelling of HS oligosaccharides, which has been initiated by synthesis of a 13C labelled L-iduronate monosaccharide and a 13C labelled disaccharide. New strategies for the synthesis of HS oligosaccharides based on orthogonal thioglycoside-based glycosylations employing S-benzoxazolyl and S-thiazolyl donors have been investigated. Development of a chemoselective glycosylation strategy for HS oligosaccharide synthesis utilising a 'super-disarmed' [2.2.2] L-iduronic lactone is presented.
20
Johnson, Wyatt. "Metalloglycomics: Investigating the Interactions of Metal Complexes with Heparan Mimetics." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5672.
Testo completoAbstract (sommario):
Proteoglycans containing Heparan Sulfate (HS), a sulfated glycosaminoglycan (GAG), play a major role in the cell signaling process, interacting with many different proteins. HS is over expressed on the surface of many cancer cells. Enzymatic cleavage of HS-GAGs by heparanase causes release of angiogenic growth factors leading to tumor cell migration. Heparanase is also over-expressed in tumors with significant correlation between metastatic potential and heparanase activity. Proteoglycans and their associated enzymes are thus significant drug targets of high biological relevance.
A functional consequence of strong PPC-HS binding has been shown in proof-of-concept studies confirming inhibition of the model pentasaccharide, Fondaparinux, by bacterial Heparinase. Such metalloshielding by PPCs may also protect HS from enzymatic cleavage by the mammalian heparanase; preventing growth factors from binding to HS and/or preventing release of bound growth factors and thus inhibiting the metastatic response in the cancer cells. HS-GAGs are also receptors for cellular accumulation of cationic Polynuclear Platinum Complexes (PPCs) through high-affinity binding to the highly anionic HS. PPCs competitively inhibit uptake of TAMRA-R9, a fluorescent nona-arginine derivative, in CHO cells.
The previously reported series of Pt(II) complexes were investigated as DNA binders, initiating the apoptotic cascade. The result of PPC-DNA binding produces long range inter and intra-strand cross-links, that produce structural and conformational changes. Hydrogen bonding between phosphate oxygens and square planar Pt(II) nitrogen results in bidentate complexes by either backbone tracking or groove spanning of DNA. This complex forms a clamp like structure, called a phosphate clamp, similar to that of the arginine fork. Understanding this clamp allows us to investigate the structurally similar sulfate binding between metal complexes and target HSPG. HSPGs may allow significant research into both a novel cellular internalization of principal metals and “metalloshielding” of heparin by these compounds.
Previous studies have shown that a wide range of metal ions have high affinity to heparin. The trend of metal/heparin affinity is believed to be dependent on parameters consisting of the metal’s overall size, spatial orientation of the ligands attached to each metal, the net charge and oxidation state of these metals, and number of binding sites. Studies have shown relative affinities of sulfate and carboxylate groups for the metal ions. These metal cations play an important role in the affinity, specificity, and stability of many protein/heparin interactions. The study of simple coordination compounds, like Pt, Mn, V, Ru and Co, will allow preliminary results which will extend into the PPCs mode of binding.
This thesis focuses on the concept of metalloglycomics and reviews the interactions of various metal complexes with heparin. The covalent and non-covalent interactions of metal complexes with heparin resulting in strong bonding are explained through spectroscopy and calorimetry. The cleavage inhibition of heparanase by metal complexes is also described. Sulfate cluster anchoring shields the sulfates from loss as seen in mass spectrometry. The study of metalloglycomics offers potential understanding into the relevance of metal-heparin interactions and possibilities into the development of new compounds as therapeutic agents.
21
Brito, Adriana da Silva. "Potencial terap?utico de um heparin?ide isolado do invertebrado marinho Litopenaeus vannamei." Universidade Federal do Rio Grande do Norte, 2008. http://repositorio.ufrn.br:8080/jspui/handle/123456789/12521.
Testo completoAbstract (sommario):
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Previous issue date: 2008-06-13<br>Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior<br>The occurrence of bioactive compounds in marine organisms comes awaking the interest of the pharmaceutical industry. Heparin, a sulfated polysaccharide which presence was already identified in several marine invertebrates, is very attractive due its remarkable functional versatility. Besides to intervene in blood coagulation, this molecule has a great anti-inflammatory potential. However, its strong anticoagulant
activity difficult the clinical exploitation of its anti-inflammatory properties. Thus, the aims of this work were to evaluate the effect of a heparin-like compound (heparinoid),
isolated from the cephalotorax of the Litopenaeus vannamei shrimp, on the inflammatory response, hemostasia and synthesis of antithrombotic heparan sulfate by endothelial cells, besides studying some aspects concerning its structure. The purified heparinoid was structurally characterized following an analytical boarding, involving electrophoresis and chromatography. The structural analysis have shown
that this compound possess a high content of glucuronic acid residues and disulfated disaccharide units. In contrast to mammalian heparin, the heparinoid was incapable to stimulate the synthesis of heparan sulfate by endothelial cells in the tested concentrations, beyond to show reduced anticoagulant activity and hemorrhagic effect. In a model of acute inflammation, the compound isolated from the shrimp
reduced more than 50% of the cellular infiltration. Besides reduce the activity of MMP-9 and proMMP-2 of the peritoneal lavage of inflamed animals, the heparinoid also reduced the activity of MMP-9 secreted by activated human leukocytes. These results demonstrate the potential of heparinoid from L. vannamei to intervene in the inflammatory response. For possessing reduced anticoagulant activity and
hemorrhagic effect, this compound can serve as a structural model to direct the development of more specific therapeutical agents to the treatment of inflammatory
diseases<br>A ocorr?ncia de compostos bioativos em representantes da biodiversidade marinha vem despertando o interesse da ind?stria farmac?utica. Heparina, um polissacar?deo
sulfatado cuja presen?a j? foi identificada em v?rios invertebrados marinhos, destaca-se por sua extraordin?ria versatilidade funcional. Al?m de interferir na coagula??o sangu?nea, essa mol?cula possui grande potencial antiinflamat?rio. No entanto, sua forte atividade anticoagulante dificulta o aproveitamento cl?nico de sua
propriedade antiinflamat?ria, o que estimula a pesquisa por an?logos de heparina com efeitos colaterais reduzidos. Diante disso, este trabalho teve por objetivos avaliar o efeito de um composto semelhante ? heparina (heparin?ide), isolado do
cefalot?rax do camar?o Litopenaeus vannamei, sobre a resposta inflamat?ria, hemostasia e s?ntese de heparam sulfato antitromb?tico pelas c?lulas endoteliais, al?m de estudar alguns aspectos relevantes a cerca de sua estrutura. O heparin?ide purificado foi estruturalmente caracterizado seguindo uma abordagem anal?tica, envolvendo eletroforeses e cromatografias. As an?lises estruturais mostraram que esse composto possui um elevado conte?do de res?duos de ?cido glucur?nico e de dissacar?deos dissulfatados. Ao contr?rio da
heparina de mam?feros, o heparin?ide foi incapaz de estimular a s?ntese de heparam sulfato pelas c?lulas endoteliais nas concentra??es testadas, al?m de apresentar atividade anticoagulante in vitro e efeito hemorr?gico reduzidos. Em
um modelo de inflama??o aguda, o composto isolado do camar?o reduziu mais de 50% da infiltra??o celular. Al?m de reduzir a atividade de MMP-9 e proMMP-2 no lavado peritoneal dos animais submetidos ao modelo de inflama??o, o
heparin?ide tamb?m reduziu a atividade de MMP-9 secretada por leuc?citos humanos ativados. Esses resultados demonstram o potencial do heparin?ide de L. vannamei em interferir em v?rios eventos da resposta inflamat?ria. Por possuir atividade anticoagulante e efeito hemorr?gico reduzidos, esse composto pode servir como um modelo estrutural para direcionar o desenvolvimento de agentes
terap?uticos mais espec?ficos para o tratamento de doen?as inflamat?rias
22
Glushka, John. "The synthesis of disaccharides related to heparin /." Thesis, McGill University, 1986. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=72844.
Testo completo
23
Hasan, Jurjees. "Heparin oligosaccharides inhibit angiogenesis in vivo." Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488657.
Testo completoAbstract (sommario):
The prototypic heparan sulfate (HS)-dependent angiogenic cytokine is FGF-2. Here we present the first in vivo study of size fractionated heparin oligosaccharides in 3 models of angiogenesis that are progressively less dependent on FGF-2. We developed the modified hollow fibre assay, a novel model for quantifying angiogenesis in vivo. We tested the ability of size defined oligosaccharides (dp 6-14) to inhibit FGF-2 in a sponge model of angiogenesis, where the process can be driven by a defined angiogenic molecule. Sponges were implanted subcutaneously and injected with FGF2 100 ng/day and oligosaccharides (20 mglkg/day). After 14 days the sponges were excised and the microvessel density (MVD) measured. Octasaccharides were the most potent species, reducing MVD to levels below those observed in saline treated implants. In a second experiment HEC-FGF2 human endometrial cancer cells that over-express FGF-2 were implanted in a hollow fibre placed subcutaneously in vivo. Oligosaccharides were administered at 20 mglkg/day for 2 weeks and the data again showed that octasaccharides significantly reduced MVD around the fiber. In a more complex model, where angiogenesis was induced by a broad spectrum of growth factors including VEGF, we implanted H460 lung carcinoma cells in hollow fibers and treated the animals with oligosaccharides at 20mglkg/day over three weeks. The data showed that octasaccharides were able to reduce the microvessel density to the level of angiogenesis present in empty hollow fibres. Preliminary investigation of 6-0-desulfated heparins showed that these also had anti-angiogenic activity. In summary, we have shown that heparin octasaccharides have antiangiogenic activity in vivo in several models of variable dependence on FGF-2. We have now embarked on a synthetic programme to produce and investigate oligosaccharides with predefined sulfation patterns and cytokine specificities as FGF inhibitors.
24
Jin, L. "Antithrombin structures and the heparin pentasaccharide." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.605606.
Testo completoAbstract (sommario):
Antithrombin, the major inhibitor of blood coagulation, is relatively inactive until it binds to, and is achieved by the heparan sidechains that line the microvasculature. The binding specifically occurs to a core pentasaccharide, present both in the heparans and in their therapeutic derivative heparin. This specific binding can cause antithrombin's conformational change which is required for activation. The crystal structure of a dimer of inhibitory(I) and latent(I) antithrombin, each in complex with the high-affinity pentasaccharide, was solved at 2.9A resolution. To achieve this, a new approach to the effective crystallisation of antithrombin was developed involving equal-molar mixing of inhibitory and latent antithrombin, in this case, in the additional presence of the heparin pentasaccharide. The structure elucidated, for the first time, the binding details and accompanying conformational change of antithrombin which is fundamental for activation. The pentasaccharide binds to antithrombin by hydrogen-bonding or salt-bridging of its sulphates and carboxylates to Arg129 and Lys125 on the D-helix, to Asn45, Arg46 and Arg47 on the A-helix, to Lys114 and Glu113 on the new induced P-helix and to LKys11 and Arg13 in a cleft formed by the amino-terminus. Inhibitory activation results from a shift in the main β-sheet of the molecule(the A-sheet) from a partially six-stranded to a five-stranded form with extrusion of the reactive loop to give a more exposed orientation. There is a tilting and elongation of the D-helix with the formation of a new 2-turn P-helix between the C and D helices. Comparing the concomitant conformational changes at the heparin binding site of the I and L molecules also explains structurally both the initial tight binding of antithrombin to the heparans and the subsequent release of the antithrombin/protease complex into the circulation. The clear definition of the binding site and interaction details has given a new insight into the molecular pathology of antithrombin deficiency and provides a structural basis for developing heparin analogues which are more specific towards their intended target, antithrombin, and therefore less likely to exhibit side-effects.
25
Christey, Peter B. "Heparin binding and activation of antithrombin." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315820.
Testo completo
26
Spinelli, Frances Josephine. "Characterization of heparin-based hydrogel networks." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 102 p, 2009. http://proquest.umi.com/pqdweb?did=1663116581&sid=6&Fmt=2&clientId=8331&RQT=309&VName=PQD.
Testo completo
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LUNA, Rayana Leal de Almeida. "Influência de citocinas e fatores de crescimento em modelos murinos de pré- eclampisia de perda gestacional: alvos-terapêuticas alternativos na prevenção do aborto e na má-formação vascular fetal." Universidade Federal de Pernambuco, 2016. https://repositorio.ufpe.br/handle/123456789/17879.
Testo completoAbstract (sommario):
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Previous issue date: 2016-06-15<br>FACEPE<br>O desenvolvimento de uma gestação saudável depende de uma adequada circulação
uteroplacentária. Abortos recorrentes (AR), óbito fetal, partos prematuros, pré-eclâmpsia (PE) e
trombofilia materna (TM) são algumas das patologias que interferem nessa rede vascular. São
muitos os fatores que podem influenciar na tênue interface entre o parto de um feto saudável, um
parto prematuro ou até mesmo um aborto. Uma variedade de moléculas como citocinas,
proteínas de adesão e fatores de crescimento podem ter um papel importante durante o
desenvolvimento fetal assim como em todo processo gestacional. Desta forma, desequilíbrio
entre vias de sinalização assim como as vias inflamatórias têm sido relacionadas com o
desencadeamento do processo abortivo. O fator de crescimento placentário (PGF) é um marcador
importante para identificar deficiência placentária que pode ser ligada a PE. Mulheres com PE
tendem a ter níveis inferiores de PGF circulantes quando comparadas a mulheres com gestações
saudáveis. A inflamação aguda é comumente associada com injúria fetal assim como a
inflamação crônica tem sido associada com a morte fetal e aborto. Estudos epigenéticos e
epidemiológicos têm demostrado que indivíduos nascidos de mães que tiveram complicações
durante a gravidez possuem maior risco de desenvolverem patologias diversas na vida adulta
como acidente vascular cerebral, cardiopatias, obesidade e infertilidade. O Sildenafil, um
inibidor de fosfodiesterase tipo-5 com características vasodilatadoras tem ajudado na terapia de
restrição de crescimento fetal (RCF). Recentemente Sildenafil, tem sido demostrado por
apresentar-se como anti-inflamatório em diversos modelos animais de patologias humanas como
esclerose múltipla, hiperplasia prostática, doenças cardiovasculares, pulmonares entre outras. Por
outro lado a Heparina de baixo peso molecular tem sido utilizada como tratamento para casos de
AR quando o diagnóstico é associado ou não com TM, apesar deste tipo de esquema terapêutico
não ser considerado eficaz em muitos casos. O presente estudo se propôs a investigar alvosterapêuticos
em modelos animais de AR e PE, através da avaliação do tratamento com Sidenafil
ou/com Heparina para a prevenção do processo abortivo assim como a investigação da influência
da sinalização via-PGF na formação da vascularização cerebral fetal. Tratamento com Sildenafil
sozinho ou tratamento conjunto com Heparina protegeu contra a mortalidade fetal, diminuiu a
sinalização inflamatória na placenta assim como melhorou a saúde dos fetos de camundongo
expostos a altas doses de Lipopolissacarídeos (LPS) como modelo para perda gestacional. PGF
foi identificado em áreas importantes do cérebro de fetos geneticamente normais, no período de
gestação média assim como também foram identificados níveis compatíveis do receptor 1 para
fator de crescimento vascular endotelial (VEGF): Flt-1. A via que envolve o PGF mostrou-se
essencial para o desenvolvimento vascular cerebral saudável. A proteção placentária e por
consequência manutenção da saúde do feto é de suma importância para que a gestação chegue a
termo e resulte no parto de um indivíduo saudável e sem riscos à saúde da mãe. Esse trabalho
traz informações detalhadas de como acontece a modulação durante a vascularização cerebral
durante o desenvolvimento em animais geneticamente normais assim como em camundongos
PGF-/-. Adicionalmente, demostra como a terapia utilizando Sildenafil isoladamente ou em
combinação com Heparina pode diminuir o perfil inflamatório e/ou trombótico do sistema
fisiológico gravídico e desta forma prevenir o processo abortivo, mantendo a saúde fetal.<br>The development of a healthy pregnancy depends on proper uteroplacental circulation.
Recurrent miscarriages (RM), fetal death, pre-term labour, preeclampsia (PE) and maternal
thrombophilia (MT) are some of the pathologies that may affect with arrangements of this
circulation network. There are many factors that can influence the maternal-fetal interface and
aberrant gene expression at the site of this interface can result in premature birth or even
miscarriage. A variety of molecules including a variety of cytokines, adhesion proteins and
growth factors play an important role during fetal development as well as throughout gestation.
Indeed, an imbalance of signaling and inflammatory signaling pathways have been associated
with the initiation of the abortive process, regardless of the origin of this event. Placental
growth factor (PGF) is an important marker to identify placental defects that can be linked to
PE. Women with PE tend to have lower levels of circulating PGF when compared to women
with healthy pregnancies. Acute inflammation is often associated with fetal injury and chronic
inflammation has been associated with abortion and fetal death. Additionally, epigenetic and
epidemiological studies have shown that individuals born to mothers who have complications
during pregnancy have a higher risk of developing various diseases in adulthood such as:
stroke, heart disease, obesity and infertility. Sildenafil, a phosphodiesterase type-5 inhibitor
with vasodilating characteristics has proved beneficial in fetal growth restriction (FGR)
pathologies. Recent studies have shown that Sildenafil plays an anti-inflammatory agent in a
wide range of pathologies in animal models of human diseases such as: multiple sclerosis,
prostatic hyperplasia, cardiovascular, and pulmonary diseases among others. Low molecular
weight heparin (LMWH) has been used as a treatment for RM cases when diagnosis is
associated or not with MT. Despite these facts, recently published meta-analyses have
demonstrated that treatments using LMWH are not superior. This study proposed to investigate
new therapeutic approaches in animal models of RM and PE. This was accomplished by
evaluation of the effectiveness of Sildenafil and/or Heparin in the prevention of fetal
mortality/abortion as well as the investigation of the influence of PGF signaling pathway in the
formation of fetal brain vasculature. Treatment with sildenafil; alone or in combination with
heparin protected against fetal mortality and decreased inflammatory signaling in the placenta,
as well as improved the health of the mouse fetuses exposed to high doses of
lipopolysaccharide (LPS). PGF was detected in important areas of the brain in genetically
normal fetuses and the average period of gestation was also identified as compatible to vascular
endothelial growth factor (VEGF) receptor: Flt-1. The pathway involving PGF was found to be
essential for healthy vascular development in the brain. Therefore, early placental protection
and therefore maintaining the fetus' health is of paramount importance if the pregnancy comes
to term and results in the birth of a healthy individual and without risks to health of the mother.
This work provides detailed information into critical events that occur during the development
of the cerebral vasculature both in genetically normal as well as in PGF -/- mice. Additionally,
this work demonstrates how therapies with sildenafil alone or in combination with heparin can
reduce the inflammatory status and/or thrombotic physiological systems of pregnancy and
thereby prevent fetal mortality, thus maintaining fetal health.
28
Vecchietti, D. G. "Low Molecular Weight Heparins : in depth structural characterization to understand their different biological properties." Doctoral thesis, Università degli Studi di Milano, 2008. http://hdl.handle.net/2434/59669.
Testo completoAbstract (sommario):
Heparin is a linear, heterogeneous, highly sulfated polysaccharide belonging to the family of glycosaminoglycans, endowed with anticoagulant and antithrombotic properties. Its linear chains are made up of 15-200 disaccharide units of N-sulfated or N-acetylated D-glucosamine linked to hexuronic (glucuronic or iduronic) acid.
Low molecular weight heparins (LMWHs), developed to circumvent some unwanted side effect of unfractionated heparins (UFH), are obtained from UFH by diverse chemical and enzymatic depolymerisation processes. Fragments generated by cleavage of heparin may therefore structurally differ from each other more than the original chains because of the modification induced by the depolymerisation methods and the heterogeneity of the UFH. Only about one-third of heparin chains contains a unique pentasaccharide sequence (AGA*IA), which specifically binds antithrombin (AT) thus promoting the inhibition of certain proteases of the coagulation cascade. Such a sequence, characterized by a central trisulfated glucosamine (A*), is believed to survive the depolymerising procedures used for the preparation of LMWHs.
Functional assays performed in vitro, evaluating plasma protein binding and antiprotease activity AT mediated, showed wide variations among the commercially available LMWHs, indicating that their compositional differences have an important impact on function.
With the aim of contributing to the elucidation of structure-activity relationship of LMWHs, the present work is focusing on the in depth study of the oligosaccharide composition of different LMWH preparations. Three of the most popular commercial preparations Enoxaparin, Dalteparin and Tinzaparin were analysed.
Their compositional differences were determined by analyzing their oligosaccharidic populations by gel permeation chromatography, a very characteristic fingerprint for each sample was revealed.
Affinity chromatography on AT-Sepharose was performed to separate and quantify the high affinity fraction,. Structural characterization of all samples was obtained by 1D and 2D NMR spectroscopy and all molecular weight parameters were evaluated through HP-SEC/TDA. All the HA fractions exhibited a considerably higher molecular weight and a reduced polydispersity with respect to NA fractions.
To deepen the characterization of HA components, HA heparin chains of each LMWH were further fractionated into three subfractions with graded affinity toward AT HA1>HA2>HA3.
All the above fractions were analysed via NMR evaluating the average content of all the monosaccharide components and, in particular, the percentage of A* (N-glucosamine tri-sulfated) and G-A* (disaccharide composed by glucuronic acid and A*) both regarded as markers of heparin active site for AT (AGA*IA).
Selected oligomeric fractions and the HA1, HA2, HA3 fractions were analysed via ESI-TOF (as detector after a SEC chromatography). The molecular weight of all HA subfractions were estimated by two different methods: HP-SEC/ESI-MS and NMR.
The results suggest that neither the molecular weight nor the sulfation degree calculated via NMR exhibited any correlation with the degree of affinity for AT.
By combining information obtained by NMR (G-A* content) and the chain length (calculated by Mw evaluation)the AGA*IA content per chain was approximately calculated pointing out the presence of some chains containing more than an active pentasaccharide (HA1 of enoxaparin and dalteparin).
Preliminary data on biological activity in vitro indicated that the different anti-Xa activities were directly related to the degree of AT affinity and the overall structural considerations.
The present work represents the first insight into the detailed and comparative structural characterization of three commercial LMWHs differing in manufacturing process. Important and characteristic structural parameters were defined, including the precise oligomeric composition, the relative content of AT interacting species, and their molecular weight, together with the relative content of variously substituted monosaccharide components. Further studies are required to unravel the correlation of structural features with LMWH functional properties.
29
Matthíasson, Stefán E. "Low molecular weight heparin and dextran in thromboprophylaxis human and experimental studies /." Malmö : Dept. of Surgery, Lund University, Malmö General Hospital, 1994. http://books.google.com/books?id=9OxsAAAAMAAJ.
Testo completo
30
Gandara, Esteban. "Is an Intermediate Dose of LMWH Effective for Secondary Prevention of Recurrent Venous Thromboembolism in Pregnant Patients Diagnosed with Deep Vein Thrombosis or Pulmonary Embolism? Design of a Pilot Study." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23388.
Testo completoAbstract (sommario):
Statement of the problem The primary objective of this thesis was to determine the best study design to evaluate the safety and effectiveness of an intermediate dose of low molecular weight heparin for secondary prevention of pregnancy associated VTE (PAVTE). An RCT was deemed unfeasible,so the use of a single arm study with prior evaluation of feasibility with a pilot study is proposed. // Methods - A systematic review was conducted to evaluate the efficacy of current strategies used for secondary prevention of PAVTE.A survey was used to elicit the non-inferiority margin. // Results - The pooled proportion of recurrent VTE in patients treated with full dose LMWH was 0.012(95% CI 0.006 to 0.02) and the rate of major bleeding was 0.025(95% CI=0.01 to 0.041). The non-inferiority margin was elicited at 2.5%. // Conclusions - Although a randomized controlled trial should be conducted whenever possible, in certain scenarios they are unfeasible. Therefore, an alternative study design should perhaps be used to evaluate the safety and efficacy of therapeutic strategies.
31
Raiber, Eun-Ang. "Design, synthesis and biological evaluation of heparin/heparan sulfate analogues as inhibitors of GAG-growth factor interaction." Thesis, University of Salford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490260.
Testo completoAbstract (sommario):
Control of cell proliferation is of fundamental importance to cancer chemotherapy. One of the key signalling events leading to cellular activities (i.e. cell division, proliferation, migration) involves Growth Factors such as Hepatocyte Growth Factor/Scatter Factor (HGF/SF) and Fibroblast Growth Factors (FGFs). They bind to specific transmembrane tyrosine kinase receptors at the cell surface. This can only take place in the presence of heparin and heparan sulfate proteoglycans. The literature in this area is reviewed.
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Eldridge, Stacie Liane. "Development of analytical methods for trace impurity analysis and structure determination of heparin/heparan sulfate-derived oligosaccharides." Diss., [Riverside, Calif.] : University of California, Riverside, 2009. http://proquest.umi.com/pqdweb?index=0&did=1899476621&SrchMode=2&sid=2&Fmt=2&VInst=PROD&VType=PQD&RQT=309&VName=PQD&TS=1269284173&clientId=48051.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--University of California, Riverside, 2009.<br>Includes abstract. Available via ProQuest Digital Dissertations. Title from first page of PDF file (viewed March 10, 2010). Includes bibliographical references. Also issued in print.
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Powell, Andrew Keith. "Characterisation of the interaction of fibroblast growth factor receptors with heparan sulphate." Thesis, University of Birmingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288866.
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Douglas, Michael Stephen. "Endothelial inflammation : examination of the role of glycosaminoglycans." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244556.
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35
Brack, Michael John. "Heparin and restenosis following angioplasty : a study of the effect of subcutaneous heparin on angiographic recurrence following angioplasty." Thesis, University of Leicester, 1994. http://hdl.handle.net/2381/34223.
Testo completoAbstract (sommario):
Restenosis following percutaneous transluminal coronary angioplasty (PTCA) continues to be the major limitation of the procedure with an incidence of 30-50%. The restenotic process is characterised by myointimal hyperplasia, initiated by smooth muscle cell migration and proliferation. Work in animal models of vascular injury suggests that heparin may reduce myointimal hyperplasia and hence restenosis. I therefore evaluated the effects of unfractionated heparin, 12 500 IU, twice daily, for 4 months, on angiographic and clinical restenosis following PTCA. 339 patients were randomised to receive no heparin (n=172) or 12 500 IU of heparin twice daily (n=167), with angiographic follow-up at 4 months. Blinded quantitative angiographic analysis was undertaken to determine the minimal luminal diameter (mid) pre PTCA, post PTCA and at follow-up. 40 patients defaulted, and 39 patients underwent "early" cardiac catheterisation. A total of 260 patients underwent elective cardiac catheter (n=136 in the no heparin group, n=124 in the heparin group). The mean difference between the mld at follow-up and immediately post PTCA was -0.49 mm(0.57) in the no heparin group, and -0.41mm(0.57) in the heparin group. The treatment effect, 0.08mm, was not significant (p=0.22). The restenosis rate in the no heparin group was 48% and 39% in the heparin group (p=0.32). For early and elective patients combined, the mean difference in mld at follow-up and post PTCA was -0.55 mm(0.58) for the no heparin group, and -0.43 mm(0.59) for the heparin group. The overall treatment effect was 0.12mm, (p=0.06), restenosis rate, 51% in the no heparin group and 41% in the heparin group (p=0.09). At elective follow-up 33% of patients in the no heparin group and 32% of the patients in the heparin group complained of angina. Unfractionated heparin at a dose of 12 500IU twice daily for 4 months does not significantly reduce angiographic or clinical restenosis rates following PTCA.
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Newman, Peter Michael Pathology UNSW. "Antibody and Antigen in Heparin-Induced Thrombocytopenia." Awarded by:University of New South Wales. Pathology, 2000. http://handle.unsw.edu.au/1959.4/17485.
Testo completoAbstract (sommario):
Immune heparin-induced thrombocytopenia (HIT) is a potentially serious complication of heparin therapy and is associated with antibodies directed against a complex of platelet factor 4 (PF4) and heparin. Early diagnosis of HIT is important to reduce morbidity and mortality. I developed an enzyme immunoassay that detects the binding of HIT IgG to PF4-heparin in the fluid phase. This required techniques to purify and biotinylate PF4. The fluid phase assay produces consistently low background and can detect low levels of anti-PF4-heparin. It is suited to testing alternative anticoagulants because, unlike in an ELISA, a clearly defined amount of antigen is available for antibody binding. I was able to detect anti-PF4-heparin IgG in 93% of HIT patients. I also investigated cross-reactivity of anti-PF4-heparin antibodies with PF4 complexed to alternative heparin-like anticoagulants. Low molecular weight heparins cross-reacted with 88% of the sera from HIT patients while half of the HIT sera weakly cross-reacted with PF4-danaparoid (Orgaran). The thrombocytopenia and thrombosis of most of these patients resolved during danaparoid therapy, indicating that detection of low affinity antibodies to PF4-danaparoid by immunoassay may not be an absolute contraindication for danaparoid administration. While HIT patients possess antibodies to PF4-heparin, I observed that HIT antibodies will also bind to PF4 alone adsorbed on polystyrene ELISA wells but not to soluble PF4 in the absence of heparin. Having developed a technique to affinity-purify anti-PF4-heparin HIT IgG, I provide the first estimates of the avidity of HIT IgG. HIT IgG displayed relatively high functional affinity for both PF4-heparin (Kd=7-30nM) and polystyrene adsorbed PF4 alone (Kd=20-70nM). Furthermore, agarose beads coated with PF4 alone were almost as effective as beads coated with PF4 plus heparin in depleting HIT plasmas of anti-PF4-heparin antibodies. I conclude that the HIT antibodies which bind to polystyrene adsorbed PF4 without heparin are largely the same IgG molecules that bind PF4-heparin and thus most HIT antibodies bind epitope(s) on PF4 and not epitope(s) formed by part of a PF4 molecule and part of a heparin molecule. Binding of PF4 to heparin (optimal) or polystyrene/agarose (sub-optimal) promotes recognition of this epitope. Under conditions that are more physiological and sensitive than previous studies, I observed that affinity-purified HIT IgG will cause platelet aggregation upon the addition of heparin. Platelets activated with HIT IgG increased their release and surface expression of PF4. I quantitated the binding of affinity-purified HIT 125I-IgG to platelets as they activate in a plasma milieu. Binding of the HIT IgG was dependent upon heparin and some degree of platelet activation. Blocking the platelet Fc??? receptor-II with the monoclonal antibody IV.3 did not prevent HIT IgG binding to activated platelets. I conclude that anti-PF4-heparin IgG is the only component specific to HIT plasma that is required to induce platelet aggregation. The Fab region of HIT IgG binds to PF4-heparin that is on the surface of activated platelets. I propose that only then does the Fc portion of the bound IgG activate other platelets via the Fc receptor. My data support a dynamic model of platelet activation where released PF4 enhances further antibody binding and more release.
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Chen, Iris Ye Wu. "The interactions between human antithrombin and heparin." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0005/NQ42731.pdf.
Testo completo
38
Brigstock, David Roger. "Heparin-binding growth factors from porcine uterus." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.279306.
Testo completo
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Lietha, Daniel. "Structure and function of NK1-heparin complexes." Thesis, Birkbeck (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407953.
Testo completo
40
Kesby, Gregory John. "Heparin and cranial neurulation in the rat." Thesis, University of Cambridge, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259732.
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Belzar, Klara Jane. "The allosteric activation of antithrombin by heparin." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621213.
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42
Bergmann, Carl W. "Studies on the anticoagulant determinants of heparin /." The Ohio State University, 1986. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487268021748443.
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43
Xu, Ruoyan. "Analysis of fibroblast growth factor-heparin interactions." Thesis, University of Liverpool, 2012. http://livrepository.liverpool.ac.uk/8833/.
Testo completoAbstract (sommario):
The functions of a large number (> 435) of extracellular regulatory proteins are controlled by their interactions with heparan sulfate (HS). In the case of fibroblast growth factors (FGFs), HS binding controls their transport between cells and is required for the assembly of a high affinity signaling complex with the cognate FGF receptor. However, the specificity of the interaction of FGFs with HS is still debated. In this thesis, a panel of FGFs (FGF-1, FGF-2, FGF-7, FGF-9, FGF-18 and FGF-21) spanning five FGF sub-families were used to probe their specificities for HS/heparin at different levels: recombinant FGF proteins were expressed and purified and their biological activities tested in a DNA synthesis assay. Then, the proteins were tested for their heparin binding specificity using a variety of complementary approaches: 1. Measurement of the binding parameters of FGFs and a model heparin sugar in an optical biosensor or by microscale thermophoresis; 2. Identification of the heparin binding site (HBS) in the proteins using a Protect and Label strategy; 3. Determination of stability changes in FGFs when bound to different heparin sugars and related glycosaminoglycans employing differential scanning flurometry; 4. Measurement of the conformational changes in FGFs when binding to a variety of molar ratios of heparin and chemically modified heparins using synchrotron radiation circular dichroism (SRCD); 5. Measure directly the binding of FGF-2 to cellular HS using nanoparticles (NPs) to label the FGF-2 and transmission electron microscopy. For interaction with heparin, the FGFs have KDs varying between 38 nM (FGF-18) and 620 nM (FGF-9) and association rate constants spanning over 20-fold (FGF-1, 2,900,000 M-1s-1, FGF-9, 130,000 M-1s-1). The canonical HBS in FGF-1, FGF-2, FGF-7, FGF-9 and FGF-18 differs in its size and these FGFs have a different complement of secondary HBS, ranging from none (FGF-9) to two (FGF-1). Differential scanning fluorimetry identified clear preferences in these FGFs for distinct structural features in the polysaccharide. SRCD revealed conformational changes in FGFs induced by binding to heparin and the changes were distinct at different heparin concentrations. Moreover, there was evidence that the conformational changes of FGFs differed with chemically modified heparins, indicating that the conformational change caused by binding to heparin is related to the sulfation pattern. At the cellular level, FGF-2 labeled with nanoparticles allowed the distribution of FGF-2 to be determined in the pericellular matrix of Rama 27 fibroblasts. The results showed that the FGF-2-NPs were specifically bound to cellular HS and were clustered. Taken together, these data suggest that the differences in heparin binding sites in both the protein and the sugar are greatest between FGF sub-families and may be more restricted within a FGF sub-family in accord with the known conservation of function within FGF sub-families, which supports the idea that heparin binding of these proteins is specific, but in terms of consensus sites on the GAG chain, rather than precisely defined chemical structures.
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Hadfield, Lynsay Claire. "Heparin and heparin-like molecules inhibit the Alzheimer's β-secretase (BACE1) : considerations for biological assay and future therapeutic development". Thesis, Keele University, 2018. http://eprints.keele.ac.uk/4998/.
Testo completoAbstract (sommario):
The biologically and medically important heparan sulphate and heparin polysaccharides have previously been shown to modulate the activity of an aspartyl protease, β-secretase (BACE1), implicated in the aetiology of Alzheimer’s disease. Research groups investigating the activity of heparin with BACE1 have demonstrated both inhibitory and stimulatory effects of this glycosaminoglycan, and other analogues. In an attempt to understand this relationship, a review of the available recombinant BACE1 products was conducted to determine if protein purification tag had an effect on the heparin/heparan sulphate interaction with BACE1. FLAG-tagged BACE1 was identified as a suitable proxy for native, untagged BACE1 for activity studies. In this study, the common purification tag, IgG Fc region, has been shown to interact with heparin and other glycosaminoglycans at acid pH (pH 4.0 and pH 5.0) with heparin affinity of > 800 mM. Further investigation, first of whole immunoglobulin (IgG & IgM) and then with Fab and F(ab’)2 antibody fragments, identified heparin binding at acid pH in all fragments tested. Thermal stability studies were conducted to identify heparin/HS structural requirements for this novel interaction, which suggest sulphate is necessary but not sufficient for activity. Finally, a library of chemically sulphated non-heparin polysaccharides were utilised to identify ‘hit’ BACE1 inhibitors with beneficial BACE1 therapeutic attributes such as low molecular weight, minimal charge and attenuated off-target effects, such as anti-coagulant activity. Differential scanning fluorimetry was identified as a potential high-throughput screening assay to replace fluorescence resonant energy transfer, during the initial nonheparin polysaccharide library BACE1 inhibitor screening.
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Kimmerle, Sabine. "Rapid determination of Anti-Heparin/Platelet factor 4 antibody titers in the diagnosis of Heparin-induced Thrombocytopenia$cSabine Kimmerle." Bern : [s.n.], 2003. http://www.stub.unibe.ch/html/haupt/datenbanken/diss/bestell.html.
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McClarence, David. "An investigation into the location of the heparan sulphate/heparin-binding site of human bone morphogenetic protein-7." Thesis, Royal Holloway, University of London, 2011. http://repository.royalholloway.ac.uk/items/77a3aece-4752-648b-2480-49a0f059ffc2/10/.
Testo completoAbstract (sommario):
The bone morphogenetic proteins (BMPs) are small cystine-knot-containing cytokines that serve pivotal functions during the development of a wide range of tissues. Consisting of approximately twenty structurally and functionally related proteins, the BMP family makes up the largest branch of the transforming growth factor beta (TGF-β) superfamily. At least three of the BMPs have the ability to bind to heparan sulphate (HS) and heparin, which are highly sulphated, complex polysaccharides that are found in abundance on cell surfaces and in the extracellular matrix. The functional significance of these interactions remains unclear, but it has been demonstrated that BMPs -2 and -4 bind to HS/heparin via a small cluster of basic amino acids in their N-terminal regions. BMP-7 has also been shown to interact with HS and heparin. However, it belongs to a different BMP sub-group to BMPs -2 and -4, and it differs from them considerably in this key N-terminal region. This raises the question as to where the HS/heparin-binding site of BMP-7 is situated. The aim of this study was to answer this question using a combination of predictive computational molecular docking calculations, site-directed mutagenesis techniques and heparin-affinity chromatography. The findings from a series of predictive docking calculations suggested that BMP-7 binds to HS/heparin through three basic residues close to the C-terminal ends of each of its constituent monomers. However, experimental studies have shown that this is unlikely, as removing two of these three basic residues from each monomer had no affect on the heparin-binding affinity of BMP-7. The same was true when two of seven basic residues were removed from the N-terminal regions of each BMP-7 monomer, both alone and in combination with the C-terminal mutations. Further investigation is therefore required in order to resolve this matter.
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Coelho, Luciana de Figueir?do. "Efeito anti-inflamat?rio do heparin?ide isolado do camar?o Litopenaeus vannamei sobre a peritonite aguda." Universidade Federal do Rio Grande do Norte, 2013. http://repositorio.ufrn.br:8080/jspui/handle/123456789/12611.
Testo completoAbstract (sommario):
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Previous issue date: 2013-03-04<br>Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior<br>In recent years the heparin has been the subject of several studies that aim to expand its use as a therapeutic agent, due to its ability to modulate the activity of various proteins that play important roles in the regulation of pathophysiological processes. In several experiments and preclinical trials, heparin has demonstrated an anti-inflammatory role. However, its clinical use is limited, due to its strong anticoagulant activity and hemorrhagic complications. For this reason, considerable efforts have been employed in discovery of heparin analogous (heparinoid) with reduced side effects, that retain the anti-inflammatory properties of heparin. In this context, a heparinoid obtained from the head of Litopenaeus vannamei shrimp, which presents a structural similarity to heparin, showed, in previous studies, anti-inflammatory activity in a model of acute peritonitis with reduced anticoagulant effect in vitro and low hemorrhagic activity. Thus, the present work had as objective to evaluate the effect the heparinoid of the cephalothorax of gray shrimp on the acute inflammatory response in different times (3 or 6 hours after the induction of inflammatory stimulus), using the model of acute peritonitis induced in mice. It was also analyzed the HL effect over the activity of elastase, an enzyme involved in leukocyte recruitment. Furthermore to check if the different doses of heparin and heparinoid change the hemostatic balance in vivo, was assessed the effect of these compounds on the plasma clotting time in animals submitted to inflammation. The results show that in 3 hours, all doses of heparinoid were able to prevent efficiently in the acute inflammatory process without any anticoagulant effects, unlike the extrapolation dose of heparin, which has induced a large hemorrhage due its high anticoagulant activity. However, 6 hours after induction of inflammation, only the dosages of 0.1 and 1.0 μg/Kg of heparin and 1.0 μg/Kg of heparinoid kept anti-migratory effect, without changing of the hemostatic balance. These results indicate that the anti-migratory effect of theses compounds depends on the dosage and time of inflammatory stimulus. The HL and heparin were also able to inhibit the activity of the enzyme elastase. The discovery of this bioactive compound in the cephalothorax of shrimps can arouse great interest in biotechnology, since this compound could be useful as a structural model interesting for the development of new therapeutic agents for peritonitis<br>Nos ?ltimos anos a heparina tem sido alvo de diversos estudos que visam ampliar seu uso como agente terap?utico, devido ? sua habilidade de modular a atividade de v?rias prote?nas que desempenham pap?is importantes na regula??o de processos fisiopatol?gicos. Em diversos experimentos e ensaios pr?-cl?nicos, a heparina tem demonstrado papel anti-inflamat?rio. Entretanto, seu uso cl?nico ? limitado, devido ? sua forte atividade anticoagulante e complica??es hemorr?gicas. Por essa raz?o, consider?vel esfor?o tem sido empregado na descoberta de an?logos da heparina (heparin?ide) com reduzidos efeitos colaterais, que retenham as propriedades anti-inflamat?rias da heparina. Nesse contexto, um heparin?ide (HL) obtido da cabe?a do camar?o Litopenaeus vannamei, de semelhan?a estrutural ? heparina, apresentou em estudos pr?vios atividade anti-inflamat?ria em modelo de peritonite aguda, com reduzido efeito anticoagulante in vitro e baixa atividade hemorr?gica. Assim, o presente trabalho teve como objetivo avaliar o efeito deste heparin?ide sobre a resposta inflamat?ria aguda em diferentes tempos (3 ou 6 horas ap?s a indu??o do est?mulo inflamat?rio), utilizando o modelo de peritonite aguda induzida em camundongos. Foi analisado tamb?m o efeito do HL sobre a atividade da elastase, uma enzima envolvida no recrutamento de leuc?citos. Al?m disso, para verificar se as diferentes doses do heparin?ide e da heparina alteram o equil?brio hemost?tico in vivo, foi avaliado o efeito desses compostos sobre o tempo de coagula??o do plasma nos animais submetidos ? inflama??o. Os resultados revelam que em 3 horas, todas as doses do heparin?ide foram capazes de interferir de forma eficiente no processo inflamat?rio agudo sem apresentar efeito anticoagulante e interfer?ncia no equil?brio hemost?tico, ao contr?rio da dose de extrapola??o da heparina que induziu forte hemorragia, al?m de apresentar alta atividade anticoagulante. Entretanto, no tempo de 6 horas ap?s a indu??o da inflama??o, apenas as doses de 0,1 e 1,0 μg/Kg da heparina e 1,0 μg/Kg do heparin?ide mantiveram o efeito antimigrat?rio, sem alterar o equil?brio hemost?tico. Esses resultados indicam que o efeito antimigrat?rio depende do tempo e da dose administrada. O HL e a heparina tamb?m foram capazes de inibir a atividade da enzima elastase. A descoberta desse composto bioativo no cefalot?rax do camar?o poder? despertar grande interesse biotecnol?gico, pois este composto poderia servir como um modelo estrutural interessante para o desenvolvimento de novos agentes terap?uticos espec?ficos para a peritonite
48
Chan, Harriet S. C. "Duration of subcutaneous heparin injections : effect on bruising and pain." Thesis, Curtin University, 2000. http://hdl.handle.net/20.500.11937/460.
Testo completoAbstract (sommario):
Injection site-pain and bruising are common side effects of subcutaneous heparin injections. These adverse outcomes are problematic for both the patient and the nurse. Specifically, site-pain causes the patient discomfort and bruising limits possible sites for subsequent injections. It is important that nurses use an injection technique that minimises the incidence of adverse outcomes when administering subcutaneous heparin injections. This study examines the effect of duration of subcutaneous heparin injection on site-pain intensity and bruise size experienced by a group of patients being treated with heparin for ischaemic stroke or transient ischaemic attacks.A quasiexperimental design with subjects serving as their own control was used to address the study objectives. The independent variable was the duration of the injection and the dependent variables were site-pain and bruise size. A convenience sample of 34 subjects receiving 5000 units of a subcutaneous Fragmin injection twice a day were recruited from a large teaching hospital. Subjects rated the level of perceived site-pain intensity during injection using the vertical Visual Analogue Scale. Injection-site bruising was measured at 48 and 60 hours after injection. Data were analysed using the Wilcoxon Sign-Rank test. Results indicated that injection technique B (30-second injection duration) resulted in significantly less intense site-pain during administering the injection and fewer and smaller bruises.The findings of this study indicate that injecting subcutaneous heparin over a longer duration may reduce injection site-pain and bruising.
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Witte, Andreas. "Darstellung und Reinigung von Chondroitinsulfat-Tetrasacchariden NMR-Studien zur Bindung von Chondroitinsulfat und Heparin an Proteine /." [S.l. : s.n.], 1999. http://deposit.ddb.de/cgi-bin/dokserv?idn=958880050.
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Yeung, Man-nga, and 楊文雅. "Functional roles of heparanase in endochondral ossification." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43224027.
Testo completo