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Navegando por Palavras-chave "Heparin"

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Anti-inflammatory properties of a heparin-like glycosaminoglycan with reduced anti-coagulant activity isolated from a marine shrimp
(Elsevier B.V., 2008-11-01) Brito, Adriana S.; Arimateia, Dayse S.; Souza, Lucilla R.; Lima, Marcelo A.; Santos, Vanessa O.; Medeiros, Valquiria P. [UNIFESP]; Ferreira, Paula A.; Silva, Rodrigo A.; Ferreira, Carmen V.; Justo, Giselle Z. [UNIFESP]; Leite, Edda L.; Andrade, Giulianna P. V.; Oliveira, Fernanda W.; Nader, Helena B. [UNIFESP]; Chavante, Suely F.; Univ Fed Rio Grande do Norte; Universidade Federal de São Paulo (UNIFESP); Universidade Estadual de Campinas (UNICAMP)
The anti-inflammatory properties of a heparin-like compound from the shrimp Litopenaeus vannamei are related. Besides reducing significantly (p < 0.001) the influx of inflammatory cells to injury site in a model of acute inflammation, shrimp heparin-like compound was able to reduce the matrix metalloproteinase (MMPs) activity in the peritoneal lavage of inflamed animals. Moreover, this compound also reduced almost 90% the activity of MMP-9 secreted by human activated leukocytes. Negligible anti-coagulant activities in aPPT assay and a poor bleeding potential make this compound a better alternative than mammalian heparin as a possible anti-inflammatory drug. (C) 2008 Elsevier B.V. All rights reserved.
Acesso aberto (Open Access)
Avaliação da profilaxia do tromboembolismo venoso em hospital de grande porte
(Colégio Brasileiro de Cirurgiões, 2010-06-01) Carneiro, João Luiz De Aquino; Targueta, Gabriel Pelegrineti [UNIFESP]; Marino, Lucas Oliveira; Colégio Brasileiro de Cirurgiões; Universidade Federal do Espírito Santo Departamento de Cirurgia; Universidade Federal de São Paulo (UNIFESP); Universidade Federal do Espírito Santo
OBJECTIVE: This study aimed at assessing the adequacy of thromboprophylaxis in a high complexity hospital in Vitória - ES, analysing the possible predictors of inadequate prescriptions and/or procedures. METHODS: A cross-sectional study was carried out through prompt-book analysis. The included patients were hospitalized in 2007 and had their Venous thromboembolism (VTE) risk stratified using the 8th Edition of the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines. The thromboprophylaxis adequacy was determined through a comparison between the adopted prescriptions and/or procedures and the guideline recommendations. EpiInfo 3.4.3 and SPSS 13.0 were the software applications used. RESULTS: In 47% of the patients the thromboprophylaxis was inadequate, being the non-prescription of the indicated medication the major reason (33%). There was no statistically significant difference in inadequate tromboprophylaxis rate between clinical and surgical patients, or ward and Intensive care unit (ICU) ones. An inverse relationship was observed between the inadequate tromboprophylaxis rate and the number of VTE risk factors presented by the patients, as well as their age, and the length of hospital stay (p < 0,05). CONCLUSION: The results show alarming levels of thromboprophylaxis inadequacy, inacceptable in these times of well-established published guidelines. Therefore, a continuing education program should be implanted for all the assistance team.
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The critical interaction of the metallopeptidase PHEX with heparan sulfate proteoglycans
(Elsevier B.V., 2008-01-01) Barros, Nilana M. T. [UNIFESP]; Nascimento, Fabio D. [UNIFESP]; Oliveira, Vitor [UNIFESP]; Juliano, Maria Aparecida [UNIFESP]; Juliano, Luiz [UNIFESP]; Loisel, Thomas; Nader, Helena B. [UNIFESP]; Boileau, Guy; Tersariol, Ivarne L. S.; Carmona, Adriana K. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Enobia Pharma Inc; Univ Montreal; Univ Mogi das Cruzes
The PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome) identified as a mutated gene in patients with X-linked hypophosphatemia (XLH), encodes a protein (PHEX) that shows striking homologies to members of the M13 family of zinc metallopeptidases. in the present work the interaction of glycosaminoglycans with PHEX has been investigated by affinity chromatography, circular dichroism, protein intrinsic fluorescence analysis, hydrolysis of FRET substrates flow cytometry and confocal microscopy. PHEX was eluted from a heparin-Sepharose chromatography column at 0.8 M NaCl showing a strong interaction with heparin. Circular dichroism spectra and intrinsic fluorescence analysis showed that PHEX is protected by glycosaminoglycans against thermal denaturation. Heparin, heparan sulfate and chondroitin sulfate inhibited PHEX catalytic activity, however among them; heparin presented the highest inhibitory activity (K-i = 2.5 +/- 0.2 nM). Flow cytometry analysis showed that PHEX conjugated to Alexa Fluor 488 binds to the cell surface of CHO-K1, but did not bind to glycosaminoglycans defective cells CHO-745. Endogenous PHEX was detected at the cell surface of CHO-K1 colocalized with heparan sulfate proteoglycans, but was not found at the cell surface of glycosaminoglycans defective cells CHO-745. in permeabilized cells, PHEX was detected in endoplasmic reticulum of both cells. in addition, we observed that PHEX colocalizes with heparan sulfate at the cell surface of osteoblasts. This is the first report that the metallopeptidase PHEX is a heparin binding protein and that the interaction with GAGs modulates its enzymatic activity, protein stability and cellular trafficking. (c) 2008 Elsevier B.V. All rights reserved.
Acesso aberto (Open Access)
Dosagem da heparina em cirurgia cardíaca com circulação extracorpórea
(Sociedade Brasileira de Cirurgia Cardiovascular, 1996-09-01) Moraes Neto, Fernando Ribeiro de [UNIFESP]; Nader, Helena Bonciani [UNIFESP]; Dietrich, Carl Peter [UNIFESP]; Buffolo, Enio [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
In order to quantify seric levels of heparin, its attenuation as a time function and its residual value after neutralization with protamine sulfate, blood samples were collected, at pre-set intervals, from 27 patients undergoing myocardial revascularization surgery under extracorporeal circulation. After heparinization (400 Ul/Kg), blood samples were collected at 5, 10, 30 and 60 minutes and subsequently every 30 minutes depending upon the extracorporeal circulation lenght. At each hour after heparinization, a new heparin dose (200 Ul/Kg) was administered. The samples were kept at 4ºC prior to the heparin extract process, which was performed by physical/chemical method. The dosages showed that 5 minutes after heparinization the patients show maximal blood concentration of heparin and after 60 minutes it is aproximately 68% of the concentration at 5 minutes. At 90 minutes time, that is, after re-heparinization, the concentration of heparin is 96% of the one showed on the fifth minute and after the protamine sulfate neutralization (1.5:1), a residual value corresponding to 4% of the one initially observed is still found. It was observed that older patients have a tendency to keep longer seric heparin level, and heparin concentration at a given time could be estimated by the Equation Heparin - Concentration = 104.7 + (-12.85 x minutes (In) + 0.25 x age).
Acesso aberto (Open Access)
Efeito da heparinização sistêmica em fígado e rim de suínos submetidos a choque hipovolêmico, clampeamento aórtico e reperfusão
(Universidade Federal de São Paulo (UNIFESP), 2019-11-28) Silva, Seleno Glauber De Jesus [UNIFESP]; Fagundes, Djalma Jose [UNIFESP]; Simões, Manuel de Jesus [UNIFESP]; http://lattes.cnpq.br/5987164343458678; http://lattes.cnpq.br/8694381071456316; http://lattes.cnpq.br/5512997237332989; Universidade Federal de São Paulo (UNIFESP)
Objectives: To develop a model of hemorrhagic shock (HS), aortic clamping (AC) and ischemia-reperfusion (IR) in pigs, and to study functional, morphological and immunohistochemical (IHC) effects in the liver and kidneys of these animals when submitted to systemic heparinization. Methods: Twenty-one swines (Sus scrofa, Large White breed) were distributed into three groups: CC (n = 8), underwent general anesthesia, invasive monitoring, laparotomy and supraceliac aortic isolation, HS for 30 min, AC for 1 h and visceral reperfusion for 3 h; CCH (n = 8), submitted to the same procedures plus to systemic heparinization with 200 IU/kg in bolus, with activated clotting time maintained > 200 s during AC; and Simulated (n = 5), submitted only to surgical manipulation, without HS or AC. Vital signs and blood samples for biochemical study were collected at various stages of the experiment. Euthanasia occurred at the end of the reperfusion period, when liver and kidney fragments were withdrawn and processed for hematoxylin-eosin and IHC staining by caspase-3 and submitted to semi-quantitative analysis. Results: the proposed IR model caused a severe cardiocirculatory disturbance, observed by increased carotid-femoral pressure gradients (p <0.001) and lactate (p = 0.001) and decreased serum pH (p = 0.013) in the CC and CCH groups in relation to the Simulated. An increase in the alanine aminotransferase of CC and CCH groups was observed in relation to the Simulated (p = 0.009) at the end of the experiment, but there was no significant change in the values of aspartate aminotransferase, urea or creatinine. The mean values of the histological lesion score did not show significant differences among Simulated, CC and CCH Groups, for both liver (0.8, 1.0 and 3.3 points, respectively; p = 0.23) and for kidneys (1.4, 2.9 and 3.1; p = 0.41). However, caspase-3 score decreased in CCH related to CC in both samples of liver (119.6 ± 6.67 vs 187.5 ± 4.12; p < 0.0001) and the kidneys (117.4 ± 6.10 vs 163.5 ± 9.92; p < 0.0001). Conclusions: The proposed HS, AC and IR model was effective in producing a severe cardiocirculatory disturbance. Although no significant physiological or histological changes were observed in liver and kidney, attenuation of cellular apoptosis was observed in the animals submitted to systemic heparinization.
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Estabilidade do cloridrato de vancomicina empregado na técnica de selo com antimicrobianos para descontaminação de cateteres intravenosos centrais
(Universidade Federal de São Paulo (UNIFESP), 2019-08-29) Barros, Daniele Porto [UNIFESP]; Peterlini, Maria Angelica Sorgini [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
Introduction: Bloodstream infection related to central lines catheter is a frequent complication in children undergoing bone marrow transplantation, and the use of an antimicrobial lock technique, such as vancomycin hydrochloride in combination with sodium heparin is recommended as an adjunct to treatment. However, there is little evidence of the stability of the drugs used. Objectives: To verify the concentration and stability of vancomycin hydrochloride and sodium heparin solutions similar to those used in the antimicrobial lock technique, according to the influence of time and temperature. Methods: Experimental research developed under controlled environmental conditions. The hydrogen potential (pH), the osmolality and the concentration of vancomycin hydrochloride (500 mg), saline solution and sodium heparin (5,000 U.I.) were analized separately and in association, resulting in 282 analyzes. The concentration was verified by means of high performance liquid chromatography, the method being validated following the recommended guidelines for selectivity, linearity, precision and accuracy parameters. Vancomycin hydrochloride was reconstituted in distilled water (AD), diluted in saline solution and associated with sodium heparin, resulting in a concentration of 5 mg/mL of the antimicrobial and 100 U.I./mL of the anticoagulant. The solutions were conditioned in bottles of amber glass, at temperatures of 22° C and 37° C and the analyzes performed at the initial moment (T0), three (T3), eight (T8) and 24 hours (T24) after preparation. The data were analyzed according to mean and standard deviation, and one-way ANOVA, Kolmogorov-Smirnov, with Bonferroni correction (p≤0.05) was used. Results: Descriptive analysis of pH and osmolality of the solutions evidenced variation without statistically significant difference, except for osmolality of SF (p=0.022). The pH values of dilute vancomycin hydrochloride solutions, as well as in combination with sodium heparin at 22° C, showed statistically significant variation (p<0.001). The diluted antimicrobial solutions at 37° C resulted in a pH of 3,73 (± 0.02) in T0 at 3,68 (± 0.02) in T24 (p=0.004), and in the association 3,80 (±0.02) in T0 at 3,78 (±0.01) in T24 (p=0.389). The concentration of the diluted vancomycin hydrochloride at 22° C resulted in 5,10 (±0,08) in T0 at 5,12 (±0,07) mg/mL in T24 (p<0.001); and associated heparin sodium from 5,09 (±0.19) in T0 to 4,82 (±0.08) mg/mL in T24 (p<0.001). The diluted antimicrobial solutions at 37° C resulted in a concentration of 4,89 (±0.03) in T0 at 4,92 (±0.14) in T24 (p<0.001); the association of the drugs in 4,75 (±0.09) in T0 at 4,85 (±0.06) mg/mL in T24 (p=0.001). By analyzing the physical aspect of the solutions containing vancomycin hydrochloride and sodium heparin, precipitate formation was observed in T3, both at 22º C and 37º C. Conclusion: Vancomycin hydrochloride presented significant changes in the experimental situations studied, however. , the concentration variation was less than 10% in all experimental situations. The association of the antimicrobial with the anticoagulant resulted in pharmaceutical stability, but with physical incompatibility.
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F-19 labelled glycosaminoglycan probes for solution NMR and non-linear (CARS) microscopy
(Springer, 2017) Lima, Marcelo A. [UNIFESP]; Cavalheiro, Renan P. [UNIFESP]; Viana, Gustavo M. [UNIFESP]; Meneghetti, Maria C. Z. [UNIFESP]; Rudd, Timothy R.; Skidmore, Mark A.; Powell, Andrew K.; Yates, Edwin A. [UNIFESP]
Studying polysaccharide-protein interactions under physiological conditions by conventional techniques is challenging. Ideally, macromolecules could be followed by both in vitro spectroscopy experiments as well as in tissues using microscopy, to enable a proper comparison of results over these different scales but, often, this is not feasible. The cell surface and extracellular matrix polysaccharides, glycosaminoglycans (GAGs) lack groups that can be detected selectively in the biological milieu. The introduction of F-19 labels into GAG polysaccharides is explored and the interaction of a labelled GAG with the heparin-binding protein, antithrombin, employing F-19 NMR spectroscopy is followed. Furthermore, the ability of F-19 labelled GAGs to be imaged using CARS microscopy is demonstrated. F-19 labelled GAGs enable both F-19 NMR protein-GAG binding studies in solution at the molecular level and non-linear microscopy at a microscopic scale to be conducted on the same material, essentially free of background signals.
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Fret Studies of Conformational Changes in Heparin-Binding Peptides
(Springer, 2014-05-01) Souza, Eduardo Sergio de; Katagiri, Alberto H.; Juliano, Luiz [UNIFESP]; Juliano, Maria Aparecida [UNIFESP]; Pimenta, Daniel Carvalho; Ito, Amando Siuiti; Universidade Federal de Goiás (UFG); Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP); Inst Butantan
FRET (Forster Resonance Energy Transfer) was applied to study structural properties of heparin-binding peptides containing the sequence XBBBXXBX where 'X' represents hydropathic or uncharged and 'B' represents basic amino acids. Internally quenched fluorogenic peptides were synthesized containing the fluorescent donor oaminobenzoic acid (o-Abz) and the acceptor dinitrophenyl ethylenediamine (Eddnp) group. Using the CONTIN computational package, distance distributions were recovered from time resolved fluorescence data, associated to end-to-end distances of the peptides. the peptides containing three or four repeat units have random structure in aqueous medium, and the interaction with low molecular weight heparin stabilized short end-to end distances. Experiments in water/trifluoroethanol (TFE) mixtures showed changes in distance distributions compatible with compact conformations stabilized above 40 % volume content of TFE in the mixture. Similar changes in distance distributions were also observed for the peptides in interaction with SDS micelles in aqueous suspensions and circular dichroism data revealed alpha-helix formation in the peptides in interaction with heparin, SDS micelles or the co-solvent TFE. the process is dependent on electrostatic and hydrogen bond interactions and the end-to-end distances obtained are smaller than expected for the peptides in linear alpha-helix conformation, indicating the occurrence of structural arrangements leading to additional decrease in the distances.
Acesso aberto (Open Access)
Heparin modulates the expression of genes encoding pro and anti-apoptotic proteins in endothelial cells exposed to intestinal ischemia and reperfusion in rats
(Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia, 2014-07-01) Taha, Murched Omar [UNIFESP]; Miranda-Ferreira, Regiane [UNIFESP]; Taha, Nabiha Saadi Abrahão [UNIFESP]; Monteiro, Hugo Pequeno [UNIFESP]; Caricati-Neto, Afonso [UNIFESP]; Fagundes, Djalma José [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
PURPOSE: To investigate if expression of genes encoding pro and anti-apoptotic proteins in the rat enteric endothelial cells stimulated by intestinal ischemia followed by reperfusion (IR) can be modified by treatment with heparin (HP).METHODS: Eighteen adult Wistar rats were divided in three groups: sham group submitted to laparotomy only (SG), ischemia followed by reperfusion group (IRG); ischemia followed by reperfusion plus pretreatment with HP 100 mg.kg-1 (IRG+HP). Ischemia was performed by clamping of the superior mesenteric artery. After 60 min of ischemia, metal clamps were removed for reperfusion for 120 min. Gene expression of encoding pro (Casp1, Casp6, Casp3, Cflar, Fas and Pgl) and anti-apoptotic (Bcl2, Bcl2l1 and Naip2) proteins in rat enteric endothelial cells was evaluated by PCR microarray method.RESULTS: Compared to rat endothelial cells of SG, the expression of pro-apoptotic genes was up-regulated in IRG while anti-apoptotic genes were down-regulated. In contrast, the expression of anti-apoptotic genes in IRG+HP was up-regulated while pro-apoptotic genes was down-regulated compared to SG.CONCLUSION: The attenuation by heparin of intestinal ischemia-reperfusion previously demonstrated in rodents could be related with ability of this drug to stimulate and reduce gene expression of encoding anti and pro-apoptotic proteins, respectively.
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Heparin prevents Zika virus induced-cytopathic effects in human neural progenitor cells
(Elsevier Science Bv, 2017) Ghezzi, Silvia; Cooper, Lynsay; Rubio, Alicia; Pagani, Isabel; Capobianchi, Maria Rosaria; Ippolito, Giuseppe; Pelletier, Julien; Meneghetti, Maria Cecilia Z. [UNIFESP]; Lima, Marcelo A. [UNIFESP]; Skidmore, Mark A.; Broccoli, Vania; Yates, Edwin A. [UNIFESP]; Vicenzi, Elisa
The recent Zika virus (ZIKV) outbreak, which mainly affected Brazil and neighbouring states, demonstrated the paucity of information concerning the epidemiology of several flaviruses, but also highlighted the lack of available agents with which to treat such emerging diseases. Here, we show that heparin, a widely used anticoagulant, while exerting a modest inhibitory effect on Zika Virus replication, fully prevents virus-induced cell death of human neural progenitor cells (NPCs). (C) 2017 Elsevier B.V. All rights reserved.
Acesso aberto (Open Access)
A heparin-like compound isolated from a marine crab rich in glucuronic acid 2-O-sulfate presents low anticoagulant activity
(Elsevier B.V., 2013-04-15) Andrade, Giuliana Paiva Viana de; Lima, Marcelo Andrade de [UNIFESP]; Souza Junior, Airton Araujo de [UNIFESP]; Fareed, Jawed; Hoppensteadt, Debra A.; Santos, Elizeu Antunes dos; Chavante, Suely Ferreira; Oliveira, Fernanda Wanderley de; Rocha, Hugo Alexandre de Oliveira; Nader, Helena Bonciani [UNIFESP]; Univ Fed Rio Grande do Norte; Universidade Federal de São Paulo (UNIFESP); Univ Liverpool; Inst Fed Rio Grande Norte; Loyola Med Sch
A natural heparin-like compound isolated from the crab Goniopsis cruentata was structurally characterized and its anticoagulant and hemorrhagic activities were determined. Enzymatic and nuclear magnetic resonance analysis revealed that its structure is rich in disulfated disaccharides, possessing significant amounts of 2-O-sulfated-beta-D-glucuronic acid units. Furthermore, low amounts of trisulfated disaccharide units containing 2-O-sulfated-alpha-L-iduronic acid were detected, when compared to mammalian heparin. in addition, this heparin-like structure showed negligible in vitro anticoagulant activity and low bleeding potency, facts that make it a suitable candidate for the development of structure-driven, heparin based therapeutic agents with fewer undesirable effects. (C) 2013 Elsevier B.V. All rights reserved.
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A heparin-like glycosaminoglycan from shrimp containing high levels of 3-O-sulfated D-glucosamine groups in an unusual trisaccharide sequence
(Elsevier B.V., 2014-05-22) Chavante, Suely F.; Brito, Adriana S.; Lima, Marcelo [UNIFESP]; Yates, Edwin [UNIFESP]; Nader, Helena [UNIFESP]; Guerrini, Marco; Torri, Giangiacomo; Bisio, Antonella; Univ Fed Rio Grande do Norte; Universidade Federal de São Paulo (UNIFESP); Univ Liverpool; Ist Ric Chim & Biochim G Ronzoni
The detailed characterization of a novel heparin-like glycosaminoglycan purified from the viscera (heads) of the shrimp Litopenaeus vannamei is reported. Structural analysis performed by mono-and two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed it to be rich in both glucuronic acid and N, 6-sulfated glucosamine residues. the key peculiarities were its high 3-O-sulfated glucosamine content compared to mammalian heparins; a residue which is usually associated with the antithrombin (AT) binding site, and the location of these residues within 2-O-sulfated iduronate and glucuronate-containing sequences (I(2S-)A*-G), a situation not found in mammalian heparin. It also exhibited higher molecular weight (similar to 36 kDa) than conventional heparin (similar to 16 kDa) but, negligible anticoagulant activity (similar to 5 IU/mg compared to heparin similar to 190 IU/mg) and stabilization of AT, which has been linked directly to anticoagulation activity. A high affinity fraction, eluting at a similar salt concentration (0.75-1.5 M NaCl) from an antithrombin affinity column, to the high affinity fraction of heparin, also showed only weak thermal stabilization of AT (+ similar to 2 degrees C). These structural peculiarities may help elucidate more clearly the relationship between structure and function of sulfated polysaccharides, and provide useful model compounds with which to better understand interactions of biological significance. (C) 2014 Published by Elsevier B.V.
Acesso aberto (Open Access)
Heparina de alto peso molecular. Uma alternativa nas operações com circulação extracorpórea: estudo experimental
(Sociedade Brasileira de Cirurgia Cardiovascular, 2001-06-01) Catani, Roberto [UNIFESP]; Bertini Jr., Ayrton [UNIFESP]; Pessa, Clodualdo J. N. [UNIFESP]; Gomes, Walter José [UNIFESP]; Lourenco, Dayse Maria [UNIFESP]; Nader, Helena Bonciani [UNIFESP]; Dietrich, Carl Peter [UNIFESP]; Branco, João Nelson Rodrigues [UNIFESP]; Buffolo, Enio [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
Introduction: In surgical procedures, with cardiopulmonary bypass, hemorrhagic syndromes during and after pump constitute a major concern and in a great number of cases they are heparin-related, a substance still without substitute. Most authors point out the anticoagulant action of heparin as the main problem in bleeding situations and research is developing on antifibrinolytic or platelet-like- drugs to try to substitute for usual heparin. Experience with low-molecular weight heparin, without anticoagulant properties, in cardiopulmonary bypass, was disastrous. High dosage was accompanied by high tube drainage suggesting that postoperative bleeding does not happen just because of the anticoagulant effect of heparin. Material and Methods: Believing in the vascular component of hemostasis and that low-molecular weight heparin non-neutralized by protamin is responsible for the paralysis of small vessels during and after cardiopulmonary bypass surgery, we isolated a high-molecular weight heparin ( modal weight of 25.000 Daltons) to be tested in vitro and in vivo. Results: Its specific anticoagulant activity, by mass, was superior to usual heparin ( modal weight of 15.000 Daltons) in vitro (273 ui/mg against 181 ui/mg, respectively) as in vivo, in dogs, utilizing cardiopulmonary bypass and measuring its activity by activated clotting time, APTT and heparin blood levels. In the experimental laboratory the half-life of usual heparin was of 60 minutes, while for high-molecular weight heparin was above 90 minutes. Conclusion: We believe that this unprecedented experience will lead to its future use in anima nobile to further test its neutralization by protamin as well as to confirm the decreased prevalence of bleeding phenomena with its use.
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Heparina: interação com a matriz células endoteliais e atividade antitrombótica
(Universidade Federal de São Paulo (UNIFESP), 2000) Trindade, Edvaldo da Silva [UNIFESP]; Nader, Helena Bonciani [UNIFESP]
Heparina e drogas antitromboticas em geral estimulam, de forma especifica, a sintese do proteoglicano de heparam sulfato (PGHS) em celulas endoteliais. O efeito e composto e celula especificos. Ensaios cineticos com heparina mo que o estimulo e tempo e dose dependentes, e que esta se liga na superficie celular, sugerindo a existencia de possiveis receptores. Pelo presente trabalho, desenvolveu-se uma heparina marcada com biotina com o intuito de estudar a interacao com celulas endoteliais. A reacao de biotinilacao resultou num composto contendo uma biotina para cada residuo de acido urom'co. Essa heparina apresentou menor atividade anticoagulante (38U.I./mg), desprezivel atividade hemorragica, maior peso molecular (l8,6kDa), quando comparados com a heparina padrao, que possui 166U.I./mg, potente acao hemorragica e peso molecular de l3kDa. Essa heparina ainda, deixou de ser substrato para a heparinase e heparitinase H, porem manteve a capacidade de interacao com a Antitrombina III e a Fibronectina Os dados mostraram tambem que esta heparina e capaz de estimular a sintese de PGHS, como a heparina padrao. O(s) sitio(s) de ligacao para a heparina, nas celulas endoteliais, foram investigados utilizando-se como modelo, a heparina biotinilada em tecnicas de deteccao citoquimica e analise em microscopia confocal. Alem desta heparina, foram utilizados lectina WGA, que interage com a superficie celular e anticorpos especificos tanto para a superficie celular (anti-sindecam 4), como para a matriz extracelular (anti-fibronectina). Esses compostos foram ensaiados empregando-se tanto celulas recem-plaqueadas, sub-confluentes e confluentes, como em suspensao. Ainda a matriz extracelular livre de celulas foi investigada. Todos estes experimentos, revelaram que a ligacao da heparina biotinilada ocorreu somente nos componentes da matriz extracelular. Experimentos mantendo-se as celulas em presenca de heparina biotinilada por 22 horas, mostraram que ocorre o processo de internalizacao da mesma. Este conjunto de resultados sugere que o estimulo da sintese de PGHS, causado pela heparina possa ser independente da sua interacao com a superficie celular
Acesso aberto (Open Access)
Heparinas e a Covid-19 – um estudo de revisão bibliográfica sobre as heparinas de baixo peso molecular e o tratamento para SARS-CoV-2
(Universidade Federal de São Paulo, 2021-07-07) Gama, Gabriella dos Santos [UNIFESP]; Ceridório, Lucinéia Ferreira [UNIFESP]; http://lattes.cnpq.br/1469862511079434; http://lattes.cnpq.br/0631413069505609
A COVID-19 é uma doença causada pelo vírus SARS-Cov-2 o qual caracterizou-se em 2020 como uma pandemia devido o alto grau de transmissibilidade entre os indivíduos. Apresenta sintomas respiratórios e quadros clínicos com grande variedade, sendo as complicações cardiovasculares comuns decorrentes da infecção por SARS-Cov-2. Considerando que as heparinas de baixo peso molecular são indicadas para a prevenção dos eventos cardíacos e vasculares, principalmente em pacientes hospitalizados este estudo foi direcionado à análise das propriedades químicas da heparina e a discussão sobre o seu uso no tratamento de COVID-19. Assim, o estudo objetivou desenvolver uma pesquisa de natureza explotratória, revisão biliográfica, a respeito do uso de heparinas no tratamento de coagulação em casos de contaminação pelo SARS-Cov-2. Para a revisão biliográfica foi utilizado artigos públicados em periódicos indexados pela busca em base de dados como Web of Science, PubMed, Scfinder entre outras com descritores heparin, covid-19, hypercoagulibity publicados entre novembro de 2019 a dezembro de 2020. A metodologia de trabalho seguiu as etapas: i) busca direcionada, ii) leitura flutuante, iii) seleção dos documentos, iv) leitura exploratória com análise do conteúdo, v) sistematização das informações e vi) revisão. Uma síntese da relacão entre a coagulação e a Covid-19, das propriedades das heparinas e o uso das heparinas de baixo peso molecular (HBPM) para inibir a coagulação é apresentada. A análise assinala os mecanismos e os casos avaliados respeito das HBPM inibirem a atividade de heparanase e atuarem na inibição da coagulação ao ativar a antitrombina III, inibindo a hipercoagulação. A exploração da revisão biliogafica também revelou o uso das heparinas para além de sua ação anticoagulante, com eficácia ao efeito antiinflamatório antiarrítmico, impedido a entrada do vírus no corpo do hospedeiro que atua como protetor endotelial, evitando que o endotélio sofra injúria endotelial causada pelas histonas. O conjunto de conhecimento desse trabalho deve contribuir a compreender o uso das HBPM e a Covid-19 no contexto de divulgação científica e ensino na área de Química, Bioquímica e Ciencias da Saúde.
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Heparins and heparinoids: Occurrence, structure and mechanism of antithrombotic and hemorrhagic activities
(Bentham Science Publ Ltd, 2004-01-01) Nader, Helena Bonciani [UNIFESP]; Lopes, Carla Cristina [UNIFESP]; Rocha, Hugo Alexandre de Oliveira [UNIFESP]; Santos, Elizeu Antunes dos [UNIFESP]; Dietrich, Carl Peter [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
The correlation between structure, anticloting, antithrombotic and hemorrhagic activities of heparin, heparan sulfate, low molecular weight heparins and heparin-like compounds from various sources that are in used in clinical practice or under development is briefly reviewed. Heparin-like molecules composed exclusively of iduronic acid 2-O-sulfate residues have weak anticloting activities, whereas molecules that contain both iduronic acid 2-O sulfate, iduronic acid and small amounts or glucuronic acid, such as heparin, or mixed amounts of glucuronic and iduronic acids (mollusk heparins) possess high anticloting and anti-Xa activities. These results also suggest that a proper combination of these elements might produce a strong antithrombotic agent. Heparin isolated from shrimp mimics the pharmacological activities of low molecular weight heparins. A heparan sulfate derived from bovine pancreas and a sulfated fucan from brown algae have a potent antithrombotic activity in arterial and venous thrombosis model in vivo with a negligible activity upon the serine-proteases of the coagulation cascade in vitro. These and other results led to the hypothesis that antithrombotic activity of heparin and other antithrombotic agents is due at least in part by their action on endothelial cells stimulating the synthesis of an antithrombotic heparan sulfate. All the antithrombotic agents derived from heparin and other heparinoids have hemorrhagic activity. Exceptions to this are a heparan sulfate from bovine pancreas and a sulfated fucan derived from brown algae, which have no hemorrhagic activity but have high antithrombotic activities in vivo. Once the structure of these compounds are totally defined it will be possible to design an ideal antithrombotic.
Acesso aberto (Open Access)
INVESTIGAÇÃO DO USO DE HEPARINIZAÇÃO REGIONAL DURANTE ISQUEMIA ARTERIAL TEMPORÁRIA EM COELHOS
(Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia, 1999-04-01) Moreschi Junior, Dorival; Nigro, Amaury José Teixeira [UNIFESP]; Bandeira, César Orlando Peralta; Seidel, Amélia Cristina [UNIFESP]; Tormena, Eloísa de Brida; Universidade Estadual de Maringá (UEM); Universidade Federal de São Paulo (UNIFESP); UEM
The purpose of this study is to evaluate the effect of the regional heparinization during temporary arterial ischemia performed in rabbits. The evaluated parameters served for measuring were activated partial thromboplastin times (aPTT) as well as the presence or absence of thrombi or endothelial edema in the analyzed vessels. Forty New Zealand rabbits were utilized. They were distributed into two groups of twenty animals. After dissection and repair of the left illiac artery, an arteriotomy was carried out and then a polyethylene catheter was fitted in so that heparin solution could be injected into the experimental group and physiological serum into the control group. The aPTT was measured at the beginning of the experiment and after ninety minutes of ischemia. There were no significant differences found from the initial values to the end of the experiment. Throughout microscopic evaluation the presence of thrombi in the vessels of the animals from both groups was not found. Intimal thickening as well as disruption of the middle layer regarded as endothelial edema ocurred in only one animal from the control group, however it was not considered a significant data. It was concluded that the injection of heparin (60 UI/kg weight) did not provoke significant alterations in the systemic coagulation of the rabbit. Furthermore, in the absence of endothelial lesion thrombosis of the analyzed vessels did not occur, neither with nor without the utilization of heparin.
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Investigating the relationship between temperature, conformation and calcium binding in heparin model oligosaccharides
(Elsevier Sci Ltd, 2017) Hughes, Ashley; Meneghetti, Maria [UNIFESP]; Huang, Teng-Yi; Hung, Shang-Cheng; Elli, Stefano; Guerrini, Marco; Rudd, Timothy; Lima, Marcelo [UNIFESP]; Yates, Edwin [UNIFESP]
Glycosaminoglycans such as heparan sulfate (HS) are major components of the cell surface and extra cellular matrix (ECM) of all multicellular animals, connecting cells to each other as well as to their environment. The ECM must, therefore, both sense and accommodate changes to external conditions. Heparin, a model compound for HS, responds to increased temperatures, involving changes in the populations of conformational states with implications for the binding of HS to proteins, cations and, potentially, for its activity. A fully(13)C and N-15 labelled model octasasccharide
Somente Metadadados
A Kunitz-type FXa inhibitor affects tumor progression, hypercoagulable state and triggers apoptosis
(Elsevier B.V., 2013-04-01) Ventura, Janaina Souza [UNIFESP]; Faria, Fernanda; Correia Batista, Isabel Fatima; Simons, Simone Michaela [UNIFESP]; Lourenco Oliveira, Daniella Gorete [UNIFESP]; Morais, Katia L. P. [UNIFESP]; Chudzinski-Tavassi, Ana Marisa [UNIFESP]; Inst Butantan; Universidade Federal de São Paulo (UNIFESP)
Cancer is linked to hypercoagulability, and many studies have shown that anticoagulant drugs affect tumor progression. in this study was demonstrated that the Amblyomin-X (which is a recombinant protein that exerts similarity to the Kunitz-type inhibitors and shows pro-apoptotic effects in different tumor cell lines) and heparin (a classic anticoagulant) have similar effects on cancer progression and on normalization of the hypercoagulable state. However, Amblyomin-X showed a distinct mechanism in triggering its effects in vitro, because it exerted a cytotoxic effect in cancer cells by inducing apoptosis and promoting cell cycle arrest. (C) 2013 Elsevier Masson SAS. All rights reserved.
Acesso aberto (Open Access)
Lepstospira interrogans shotgun phage display identified LigB as a heparin-binding protein
(Elsevier B.V., 2012-11-02) Ching Ching, Ana Tung; Favaro, Regiane Degan; Lima, Swiany Silveira; Muniz Chaves, Agtha de Alencar; Lima, Marcelo Andrade de [UNIFESP]; Nader, Helena Bonciani [UNIFESP]; Estima Abreu, Patricia A.; Ho, Paulo Lee; Inst Butantan; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)
LigB is an adhesin from pathogenic Leptospira that is able to bind to extracellular matrix and is considered a virulence factor. A shotgun phage display genomic library was constructed and used for panning against Heparan Sulfate Proteoglycan (HSPG). A phage clone encoding part of LigB protein was selected in panning experiments and showed specific binding to heparin. To validate the selected clone, fragments of LigB were produced as recombinant proteins and showed affinity to heparin and to mammalian cells. Heparin was also able to reduce the binding of rLB-Ct to mammalian cells. Our data suggests that the glycosaminoglycan moiety of the HSPG is responsible for its binding and could mediate the attachment of the recombinant protein rLB-Ct. Thus, heparin may act as a receptor for Leptospira to colonize and to invade the host tissue. (C) 2012 Elsevier Inc. All rights reserved.

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