RESUMO
Background: Echinochrome A (EchA) is a pigment from sea urchins. EchA is a polyhydroxylated 1,4-naphthoquinone that contains several hydroxyl groups appropriate for free-radical scavenging and preventing redox imbalance. EchA is the most studied molecule of this family and is an active principle approved to be used in humans, usually for cardiopathies and glaucoma. EchA is used as a pharmaceutical drug. Methods: A comprehensive literature and patent search review was undertaken using PubMed, as well as Google Scholar and Espacenet search engines to review these areas. Conclusions: In the bloodstream, EchA can mediate cellular responses, act as a radical scavenger, and activate the glutathione pathway. It decreases ROS imbalance, prevents and limits lipid peroxidation, and enhances mitochondrial functions. Most importantly, EchA contributes to the modulation of the immune system. EchA can regulate the generation of regulatory T cells, inhibit pro-inflammatory IL-1ß and IL-6 cytokine production, while slightly reducing IL-8, TNF-α, INF-α, and NKT, thus correcting immune imbalance. These characteristics suggest that EchA is a candidate drug to alleviate the cytokine storm syndrome (CSS).
Assuntos
Síndrome da Liberação de Citocina/tratamento farmacológico , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Pigmentos Biológicos/farmacologia , Pigmentos Biológicos/uso terapêutico , Ouriços-do-Mar/química , Animais , Síndrome da Liberação de Citocina/metabolismo , Humanos , Imunidade/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
The anticoagulant and antithrombotic properties of three structurally correlated sea urchin-derived 3-linked sulfated α-glycans and their low molecular-weight derivatives were screened comparatively through various in vitro and in vivo methods. These methods include activated partial thromboplastin time, the inhibitory activity of antithrombin over thrombin and factor Xa, venous antithrombosis, the inhibition of platelet aggregation, the activation of factor XII, and bleeding. While the 2-sulfated fucan from Strongylocentrotus franciscanus was observed to be poorly active in most assays, the 4-sulfated fucan from Lytechinus variegatus, the 2-sulfated galactan from Echinometra lucunter and their derivatives showed multiple effects. All marine compounds showed no capacity to activate factor XII and similar low bleeding tendencies regardless of the dose concentrations used to achieve the highest antithrombotic effect observed. The 2-sulfated galactan showed the best combination of results. Our work improves the background about the structure-function relationship of the marine sulfated glycans in anticoagulation and antithrombosis. Besides confirming the negative effect of the 2-sulfated fucose and the positive effect of the 2-sulfated galactose on anticoagulation in vitro, our results also demonstrate the importance of this set of structural requirements on antithrombosis in vivo, and further support the involvement of high-molecular weight and 4-sulfated fucose in both activities.
Assuntos
Anticoagulantes/farmacologia , Fator XII/metabolismo , Fibrinolíticos/farmacologia , Polissacarídeos/farmacologia , Ouriços-do-Mar/química , Trombose Venosa/tratamento farmacológico , Adulto , Animais , Anticoagulantes/química , Anticoagulantes/isolamento & purificação , Anticoagulantes/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fator Xa/metabolismo , Feminino , Fibrinolíticos/química , Fibrinolíticos/isolamento & purificação , Fibrinolíticos/uso terapêutico , Voluntários Saudáveis , Humanos , Masculino , Estrutura Molecular , Peso Molecular , Tempo de Tromboplastina Parcial , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/uso terapêutico , Coelhos , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Sulfatos/química , Tromboplastina/administração & dosagem , Trombose Venosa/induzido quimicamente , Adulto JovemRESUMO
Metastasis is responsible for the majority of cancer-associated deaths, though only a very small number of tumor cells are able to efficiently complete all the steps of that process. Tumor cell survival in the bloodstream is one of the limiting aspects of the metastatic cascade. The formation of tumor cell-platelet complexes that promote tumor cell survival is facilitated by the binding of P-selectin on activated platelets to sialyl Lewis-containing oligosaccharides on the surface of tumor cells. Inhibition of this interaction has been shown to attenuate metastasis. Heparin is a potent selectin inhibitor and is capable to block platelet-tumor cell complex formation, thereby attenuating metastasis. Similarly, other sulfated polysaccharides isolated from marine invertebrates attenuate metastasis by a P-selectin-mediated mechanism. In this work, we investigated the selectin-dependent antimetastatic activity of sea urchin sulfated polysaccharides with slight structural differences: a sulfated fucan from Strongylocentrotus franciscanus; a sulfated fucan from Strongylocentrotus droebachiensis; and a sulfated galactan from Echinometra lucunter. The results demonstrate that these fucans and the galactan have different antiselectin activities despite being very similar molecules. Therefore, they may be interesting tools for studies on the structure-function relationship or even for future treatments.
Assuntos
Antineoplásicos/uso terapêutico , Galactanos/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Polissacarídeos/uso terapêutico , Selectinas/metabolismo , Animais , Antineoplásicos/farmacologia , Plaquetas/efeitos dos fármacos , Linhagem Celular Tumoral , Galactanos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Neoplasias Experimentais/patologia , Polissacarídeos/farmacologia , Ligação Proteica , Ouriços-do-Mar/químicaRESUMO
An L-rhamnose-binding lectin named ELEL was isolated from eggs of the rock boring sea urchin Echinometra lucunter by affinity chromatography on lactosyl-agarose. ELEL is a homodimer linked by a disulfide bond with subunits of 11 kDa each. The new lectin was inhibited by saccharides possessing the same configuration of hydroxyl groups at C-2 and C-4, such as L-rhamnose, melibiose, galactose and lactose. The amino acid sequence of ELEL was determined by tandem mass spectrometry. The ELEL subunit has 103 amino acids, including nine cysteine residues involved in four conserved intrachain disulfide bonds and one interchain disulfide bond. The full sequence of ELEL presents conserved motifs commonly found in rhamnose-binding lectins, including YGR, DPC and KYL. A three-dimensional model of ELEL was created, and molecular docking revealed favorable binding energies for interactions between ELEL and rhamnose, melibiose and Gb3 (Galα1-4Galß1-4Glcß1-Cer). Furthermore, ELEL was able to agglutinate Gram-positive bacterial cells, suggesting its ability to recognize pathogens.
Assuntos
Lectinas/química , Óvulo/química , Ouriços-do-Mar/química , Sequência de Aminoácidos , Animais , Cátions Bivalentes , Concentração de Íons de Hidrogênio , Lectinas/isolamento & purificação , Lectinas/metabolismo , Modelos Moleculares , Conformação Molecular , Dados de Sequência Molecular , Peso Molecular , Ligação Proteica , Ramnose/química , Ramnose/metabolismo , Alinhamento de Sequência , TemperaturaRESUMO
Cardiovascular diseases (CDs) are the principal cause of death in the world. Anticoagulation is the commonest therapeutic strategy for treatments of CDs in clinical settings. Although possessed of numerous downsides, heparin is the main clinical anticoagulant/antithrombotic agent used so far. Novel sulfated polysaccharides like the marine dermatan sulfate, sulfated fucans and galactans are also able to block clot and thrombus formation. These relatively new marine glycans call special attention mostly due to their unique structures and distinct mechanisms of action. This structural uniqueness is seen by the peculiar aspect of these polysaccharides being made of clear and regular sulfation patterns. The structures have been reported only in polysaccharides from marine invertebrates like sea urchins and cucumbers. This report intends to prove the promising combination of the triad sea-carbohydrates-clotting in drug discovery of the cardiovascular field.
Assuntos
Anticoagulantes/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Dermatan Sulfato/uso terapêutico , Fibrinolíticos/uso terapêutico , Galactanos/uso terapêutico , Polissacarídeos/uso terapêutico , Animais , Anticoagulantes/química , Anticoagulantes/isolamento & purificação , Coagulação Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Dermatan Sulfato/química , Dermatan Sulfato/isolamento & purificação , Descoberta de Drogas , Fibrinolíticos/química , Fibrinolíticos/isolamento & purificação , Galactanos/química , Galactanos/isolamento & purificação , Heparina/química , Heparina/uso terapêutico , Humanos , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Pepinos-do-Mar/química , Ouriços-do-Mar/químicaRESUMO
Several studies have reported that molecules extracted from invertebrates have activity against different viruses, even against those that do not infect these organisms in their environment. One of the main mechanisms against pathogens in these organisms is the production of antimicrobial peptides. The objective of this study was to determine whether the coelomic fluid (CF) of the sea urchin Tripneustes depressus has activity against Suid herpesvirus type 1 (SHV-1) and/or rabies virus (RV). We tested the antiviral activity of CF in neutralizing assays and observed 50% inhibition against SHV-1 lytic plaque formation using 33 µg of CF, whereas 21 µg CF was sufficient to obtain more than 90% inhibition for RV. Cytotoxicity to MDBK and BHK-21 cells was found with whole CF yet was eliminated by heating at 56 or 72 °C (even when using 50 µg of heat-inactivated CF supernatant [SN or thermostable fraction]), and SN retained the antiviral effect. In both cases, the antiviral effect was direct and thermostable (SN 56 and 72 °C), and the best inhibition was observed when CF + virus was incubated prior to the addition of the cells. Therefore, the coelomic fluid of T. depressus has antiviral activity against SHV-1 and RV that is direct and stable at 72 °C. We suggest that further assays should be performed using more accurate methods to characterize new molecules with antiviral activity that may result in new drugs.
Assuntos
Herpesviridae/crescimento & desenvolvimento , Proteínas/farmacologia , Vírus da Raiva/crescimento & desenvolvimento , Ouriços-do-Mar/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Testes de Neutralização , Replicação Viral/efeitos dos fármacosRESUMO
The sea urchin eggs are surrounded by a jelly coat, which contains sulfated polysaccharides with unique structures. These molecules are responsible for inducing the species-specific acrosome reaction, an obligatory event for the binding of sperm and fusion with the egg. The mechanism of biosynthesis of these sulfated polysaccharides is virtually unknown. The egg jelly of the sea urchin Echinometra lucunter contains a simple 2-sulfated, 3-linked alpha-L-galactan. Here, we pulse labeled the sea urchin ovary in vitro with (35)S-sulfate to follow the biosynthesis of the sulfated alpha-L-galactan. We found that the ovary contains a 2,6-disulfated, 3-linked alpha-L-galactan, which incorporates (35)S-sulfate more avidly than the 2-sulfated isoform. The 2,6-disulfated alpha-L-galactan was purified by anion exchange chromatography, analyzed by electrophoresis and characterized by 1D and 2D nuclear magnetic resonance spectra. We also investigated the location of the sulfated polysaccharides on the oocytes using histochemical procedures. The stain revealed high amounts of sulfated polysaccharide in mature oocytes and accessory cells. The amount of intracellular sulfated polysaccharides decreased as oocytes are spawned. We speculate that 2,6-disulfated galactan is initially synthesized in the ovary and that 6-sulfate ester is removed when the polysaccharide is secreted into the egg jelly. Similar events related to remodeling of sulfated polysaccharides have been reported in other biological systems.
Assuntos
Galactanos/química , Ovário/química , Óvulo/fisiologia , Ouriços-do-Mar/química , Sulfatos/química , Animais , Feminino , Óvulo/química , Radioisótopos de EnxofreRESUMO
Functional evidence indicates that voltage-dependent Ca2+ (Cav) channels participate in sea urchin sperm motility and the acrosome reaction (AR), however, their molecular identity remains unknown. We have identified transcripts for two Ca2+ channel alpha1 subunits in sea urchin testis similar in sequence to Cav1.2 and Cav2.3. Antibodies against rat Cav1.2 and Cav2.3 channels differentially label proteins in the flagella and acrosome of mature sea urchin sperm. The Cav channel antagonists nifedipine and nimodipine, which inhibit the AR, diminish the intracellular Ca2+ elevation induced by a K+-induced depolarization in valinomycin-treated sperm. These findings reveal that Cav1.2 and Cav2.3 channels could participate in motility and/or the AR in sea urchin sperm.
Assuntos
Canais de Cálcio/análise , Ouriços-do-Mar/química , Espermatozoides/química , Acrossomo/química , Reação Acrossômica , Sequência de Aminoácidos , Animais , Canais de Cálcio/genética , Canais de Cálcio/fisiologia , Movimento Celular , Flagelos/química , Masculino , Filogenia , RNA Mensageiro/análise , Ouriços-do-Mar/citologiaRESUMO
A linear sulfated fucan with a regular repeating sequence of [3)-alpha-L-Fucp-(2SO4)-(1-->3)-alpha-L-Fucp-(4SO4)-(1-->3)-alpha-L-Fucp-(2,4SO4)-(1-->3)-alpha-L-Fucp-(2SO4)-(1-->]n is an anticoagulant polysaccharide mainly due to thrombin inhibition mediated by heparin cofactor II. No specific enzymatic or chemical method is available for the preparation of tailored oligosaccharides from sulfated fucans. We employ an apparently nonspecific approach to cleave this polysaccharide based on mild hydrolysis with acid. Surprisingly, the linear sulfated fucan was cleaved by mild acid hydrolysis on an ordered sequence. Initially a 2-sulfate ester of the first fucose unit is selectively removed. Thereafter the glycosidic linkage between the nonsulfated fucose residue and the subsequent 4-sulfated residue is preferentially cleaved by acid hydrolysis, forming oligosaccharides with well-defined size. The low-molecular-weight derivatives obtained from the sulfated fucan were employed to determine the requirement for interaction of this polysaccharide with heparin cofactor II and to achieve complete thrombin inhibition. The linear sulfated fucan requires significantly longer chains than mammalian glycosaminoglycans to achieve anticoagulant activity. A slight decrease in the molecular size of the sulfated fucan dramatically reduces its effect on thrombin inactivation mediated by heparin cofactor II. Sulfated fucan with approximately 45 tetrasaccharide repeating units binds to heparin cofactor II but is unable to link efficiently the plasma inhibitor and thrombin. This last effect requires chains with approximately 100 or more tetrasaccharide repeating units. We speculate that the template mechanism may predominate over the allosteric effect in the case of the linear sulfated fucan inactivation of thrombin in the presence of heparin cofactor II.
Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Laminaria/química , Polissacarídeos/farmacologia , Ouriços-do-Mar/química , Animais , Anticoagulantes/química , Anticoagulantes/isolamento & purificação , Cofator II da Heparina/química , Cofator II da Heparina/metabolismo , Hidrólise , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Ésteres do Ácido Sulfúrico/químicaRESUMO
Histones from the parasitic platyhelminthes, Echinococcus granulosus and Fasciola hepatica, were systematically characterized. Core histones H2A, H2B, H3 and H4, which were identified on the basis of amino acid sequencing and mass spectrometry data, showed conserved electrophoretic patterns. Histones H1, identified on the basis of physicochemical properties, amino acid composition and amino acid sequencing, showed divergence, both in their number and electrophoretic mobilities, between the two species and among other organisms. According to these data, core histones but not H1 histones, would be stabilized during evolution at the level of platyhelminthes.