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[PMID]:27777178
[Au] Autor:Pla D; Sanz L; Sasa M; Acevedo ME; Dwyer Q; Durban J; Pérez A; Rodriguez Y; Lomonte B; Calvete JJ
[Ad] Endereço:Structural and Functional Venomics Laboratory, Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
[Ti] Título:Proteomic analysis of venom variability and ontogeny across the arboreal palm-pitvipers (genus Bothriechis).
[So] Source:J Proteomics;152:1-12, 2017 01 30.
[Is] ISSN:1876-7737
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Bothriechis is a genus of eleven currently recognized slender and arboreal venomous snakes, commonly called palm-pitvipers that range from southern Mexico to northern South America. Despite dietary studies suggesting that palm-pitvipers are generalists with an ontogenetic shift toward endothermic prey, venom proteomic analyses have revealed remarkable divergence between the venoms of the Costa Rican species, B. lateralis, B. schlegelii, B. supraciliaris, and B. nigroviridis. To achieve a more complete picture of the venomic landscape across Bothriechis, the venom proteomes of biodiversity of the northern Middle American highland palm-pitvipers, B. thalassinus, B. aurifer, and B. bicolor from Guatemala, B. marchi from Honduras, and neonate Costa Rican B. lateralis and B. schlegelii, were investigated. B. thalassinus and B. aurifer venoms are comprised by similar toxin arsenals dominated by SVMPs (33-39% of the venom proteome), CTLs (11-16%), BPP-like molecules (10-13%), and CRISPs (5-10%), and are characterized by the absence of PLA proteins. Conversely, the predominant (35%) components of B. bicolor are D49-PLA molecules. The venom proteome of B. marchi is similar to B. aurifer and B. thalassinus in that it is rich in SVMPs and BPPs, but also contains appreciable amounts (14.3%) of PLA s. The major toxin family found in the venoms of both neonate B. lateralis and B. schlegelii, is serine proteinase (SVSP), comprising about 20% of their toxin arsenals. The venom of neonate B. schlegelii is the only palm-pitviper venom where relative high amounts of Kunitz-type (6.3%) and γPLA (5.2%) inhibitors have been identified. Despite notable differences between their proteomes, neonate venoms are more similar to each other than to adults of their respective species. However, the ontogenetic changes taking place in the venom of B. lateralis strongly differ from those that occur in the venom of B. schlegelii. Thus, the ontogenetic change in B. lateralis produces a SVMP-rich venom, whereas in B. schlegelii the age-dependent compositional shift generates a PLA -rich venom. Overall, genus-wide venomics illustrate the high evolvability of palm-pitviper venoms. The integration of the pattern of venom variation across Bothriechis into a phylogenetic and biogeographic framework may lay the foundation for assessing, in future studies, the evolutionary path that led to the present-day variability of the venoms of palm-pitvipers. SIGNIFICANCE: Bothriechis represents a monophyletic basal genus of eleven arboreal palm-pitvipers that range from southern Mexico to northern South America. Despite palm-pitvipers' putative status as diet generalists, previous proteomic analyses have revealed remarkable divergence between the venoms of Costa Rican species, B. lateralis, B. schlegelii, B. supraciliaris, and B. nigroviridis. Our current proteomic study of Guatemalan species, B. thalassinus, B. aurifer, and B. bicolor, Honduran B. marchi, and neonate B. lateralis and B. schlegelii from Costa Rica was undertaken to deepen our understanding of the evolutionary pattern of venom proteome diversity across Bothriechis. Ancestral characters are often, but not always, preserved in an organism's development. Venoms of neonate B. lateralis and B. schlegelii are more similar to each other than to adults of their respective species, suggesting that the high evolvability of palm-pitviper venoms may represent an inherent feature of Bothriechis common ancestor. Our genus-wide data identified four nodes of venom phenotype differentiation across the phylogeny of Bothriechis. Integrated into a phylogenetic and biogeographic framework, the pattern of venom variation across Bothriechis may lay the groundwork to establish whether divergence was driven by selection for efficient resource exploitation in arboreal 'islands', thereby contributing to the ecological speciation of the genus.
[Mh] Termos MeSH primário: Biodiversidade
Venenos de Crotalídeos/química
Proteoma/análise
[Mh] Termos MeSH secundário: Fatores Etários
Animais
Evolução Biológica
Venenos de Crotalídeos/enzimologia
Fosfolipases A2/análise
Filogenia
Proteômica/métodos
Serina Proteases/análise
Toxinas Biológicas/análise
Viperidae
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Crotalid Venoms); 0 (Proteome); 0 (Toxins, Biological); EC 3.1.1.4 (Phospholipases A2); EC 3.4.- (Serine Proteases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


  2 / 3953 MEDLINE  
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[PMID]:29203373
[Au] Autor:Preciado LM; Rey-Suárez P; Henao IC; Pereañez JA
[Ad] Endereço:Programa de Ofidismo/Escorpionismo, Facultad de Ciencias Farmacéuticas y Alimentarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia.
[Ti] Título:Betulinic, oleanolic and ursolic acids inhibit the enzymatic and biological effects induced by a P-I snake venom metalloproteinase.
[So] Source:Chem Biol Interact;279:219-226, 2018 Jan 05.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Betulinic acid (BA), Oleanolic acid (OA) and Ursolic acid (UA), are pentacyclic triterpenoids with widespread occurrence throughout the plant kingdom, these compounds are widely recognized by their pharmacological and biological properties, such as, anti-tumoral, anti-inflammatory, anti-microbial and hepatoprotective activity. In this work we determined the inhibitory ability of these compounds on the enzymatic, hemorrhagic, myotoxic and edema-inducing activities of Batx-I, a P-I metalloproteinase isolated from Bothrops atrox venom. BA, UA and OA inhibited the proteolytic activity of Batx-I on gelatin with IC values of 115.3, 223.0 and 357.3 µM, respectively. Additionally, these compounds showed inhibition of the hemorrhagic activity of Batx-I in skin with IC 345.7, 643.5 and 1077.0 µM for BA, UA and OA in preincubation experiments. In studies with independent-injection, in which Batx-I was injected and then, at the same site, a concentration of 600 µM of each compound were administered at either 0, 5 or 10 min, BA showed a significant reduction of hemorrhage at 0 and 5 min. In addition, these compounds inhibited myotoxicity and edema-forming activity of Batx-I at 600 µM concentration. Molecular docking studies suggested that these compounds could occupy part of the substrate binding cleft of the enzyme affecting its catalytic cycle. In this manner, triterpenic acids are candidates for the development of inhibitors for the prevention of local tissue damage in snakebite envenomation.
[Mh] Termos MeSH primário: Venenos de Crotalídeos/enzimologia
Metaloproteases/metabolismo
Ácido Oleanólico/farmacologia
Triterpenos/farmacologia
[Mh] Termos MeSH secundário: Animais
Bothrops/fisiologia
Edema/induzido quimicamente
Edema/prevenção & controle
Hemorragia/induzido quimicamente
Hemorragia/prevenção & controle
Metaloproteases/genética
Camundongos
Estrutura Molecular
Doenças Musculares/induzido quimicamente
Doenças Musculares/prevenção & controle
Ácido Oleanólico/química
Triterpenos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Crotalid Venoms); 0 (Triterpenes); 4G6A18707N (betulinic acid); 6SMK8R7TGJ (Oleanolic Acid); EC 3.4.- (Metalloproteases); P3M2575F3F (ursolic acid)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180103
[Lr] Data última revisão:
180103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE


  3 / 3953 MEDLINE  
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[PMID]:28867438
[Au] Autor:Cavalcante WLG; Noronha-Matos JB; Timóteo MA; Fontes MRM; Gallacci M; Correia-de-Sá P
[Ad] Endereço:Departamento de Farmacologia, Instituto de Ciências Biológicas, UFMG, Av. Antônio Carlos, 6627 Belo Horizonte, Brazil; Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), R. Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portug
[Ti] Título:Neuromuscular paralysis by the basic phospholipase A subunit of crotoxin from Crotalus durissus terrificus snake venom needs its acid chaperone to concurrently inhibit acetylcholine release and produce muscle blockage.
[So] Source:Toxicol Appl Pharmacol;334:8-17, 2017 Nov 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: Crotoxin (CTX), a heterodimeric phospholipase A (PLA ) neurotoxin from Crotalus durissus terrificus snake venom, promotes irreversible blockade of neuromuscular transmission. Indirect electrophysiological evidence suggests that CTX exerts a primary inhibitory action on transmitter exocytosis, yet contribution of a postsynaptic action of the toxin resulting from nicotinic receptor desensitization cannot be excluded. Here, we examined the blocking effect of CTX on nerve-evoked transmitter release measured directly using radioisotope neurochemistry and video microscopy with the FM4-64 fluorescent dye. EXPERIMENTAL APPROACH: Experiments were conducted using mice phrenic-diaphragm preparations. Real-time fluorescence video microscopy and liquid scintillation spectrometry techniques were used to detect transmitter exocytosis and nerve-evoked [ H]-acetylcholine ([ H]ACh) release, respectively. Nerve-evoked myographic recordings were also carried out for comparison purposes. KEY RESULTS: Both CTX (5µg/mL) and its basic PLA subunit (CB, 20µg/mL) had biphasic effects on nerve-evoked transmitter exocytosis characterized by a transient initial facilitation followed by a sustained decay. CTX and CB reduced nerve-evoked [ H]ACh release by 60% and 69%, respectively, but only the heterodimer, CTX, decreased the amplitude of nerve-evoked muscle twitches. CONCLUSION AND IMPLICATIONS: Data show that CTX exerts a presynaptic inhibitory action on ACh release that is highly dependent on its intrinsic PLA activity. Given the high safety margin of the neuromuscular transmission, one may argue that the presynaptic block caused by the toxin is not enough to produce muscle paralysis unless a concurrent postsynaptic inhibitory action is also exerted by the CTX heterodimer.
[Mh] Termos MeSH primário: Acetilcolina/antagonistas & inibidores
Venenos de Crotalídeos/toxicidade
Crotalus/fisiologia
Crotoxina/toxicidade
Chaperonas Moleculares/metabolismo
Bloqueio Neuromuscular
[Mh] Termos MeSH secundário: Acetilcolina/metabolismo
Animais
Venenos de Crotalídeos/química
Crotoxina/química
Feminino
Masculino
Camundongos
Chaperonas Moleculares/química
Músculos/efeitos dos fármacos
Neurotoxinas/toxicidade
Fosfolipases A2
Subunidades Proteicas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Crotalid Venoms); 0 (Molecular Chaperones); 0 (Neurotoxins); 0 (Protein Subunits); 9007-40-3 (Crotoxin); EC 3.1.1.4 (Phospholipases A2); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


  4 / 3953 MEDLINE  
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[PMID]:28787445
[Au] Autor:Madrigal M; Pla D; Sanz L; Barboza E; Arroyo-Portilla C; Corrêa-Netto C; Gutiérrez JM; Alape-Girón A; Flores-Díaz M; Calvete JJ
[Ad] Endereço:Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
[Ti] Título:Cross-reactivity, antivenomics, and neutralization of toxic activities of Lachesis venoms by polyspecific and monospecific antivenoms.
[So] Source:PLoS Negl Trop Dis;11(8):e0005793, 2017 Aug.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Bothrops, Crotalus and Lachesis represent the most medically relevant genera of pitvipers in Central and South America. Similarity in venom phenotype and physiopathological profile of envenomings caused by the four nominal Lachesis species led us to hypothesize that an antivenom prepared against venom from any of them may exhibit paraspecificity against all the other congeneric taxa. METHODS: To assess this hypothesis, in this work we have applied antivenomics and immunochemical methods to investigate the immunoreactivity of three monovalent antivenoms and two polyvalent antivenoms towards the venoms from different geographic populations of three different Lachesis species. The ability of the antivenoms to neutralize the proteolytic, hemorrhagic, coagulant, and lethal activities of the seven Lachesis venoms was also investigated. RESULTS: A conspicuous pattern of immunorecognition and cross-neutralization for all effects was evident by the polyspecific antivenoms, indicating large immunoreactive epitope conservation across the genus during more than 10 million years since the Central and South American bushmasters diverged. CONCLUSIONS: Despite the broad geographic distribution of Lachesis, antivenoms against venoms of different species are effective in the neutralization of congeneric venoms not used in the immunization mixture, indicating that they can be used equivalently for the clinical treatment of any lachesic envenoming. GENERAL SIGNIFICANCE: This study demonstrates that antivenoms raised against venom of different Lachesis species are indistinctly effective in the neutralization of congeneric venoms not used in the immunization mixture, indicating that antivenoms against conspecific venoms may be used equivalently for the clinical treatment of envenomings caused by any bushmaster species.
[Mh] Termos MeSH primário: Antivenenos/farmacologia
Reações Cruzadas
Venenos de Crotalídeos/antagonistas & inibidores
Fatores Imunológicos/farmacologia
[Mh] Termos MeSH secundário: Testes de Neutralização
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antivenins); 0 (Crotalid Venoms); 0 (Immunologic Factors); 0 (Lachesis venom)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005793


  5 / 3953 MEDLINE  
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[PMID]:28708892
[Au] Autor:Engmark M; Lomonte B; Gutiérrez JM; Laustsen AH; De Masi F; Andersen MR; Lund O
[Ad] Endereço:Department of Bio and Health Informatics, Technical University of Denmark, Kgs. Lyngby, Denmark.
[Ti] Título:Cross-recognition of a pit viper (Crotalinae) polyspecific antivenom explored through high-density peptide microarray epitope mapping.
[So] Source:PLoS Negl Trop Dis;11(7):e0005768, 2017 Jul.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Snakebite antivenom is a 120 years old invention based on polyclonal mixtures of antibodies purified from the blood of hyper-immunized animals. Knowledge on antibody recognition sites (epitopes) on snake venom proteins is limited, but may be used to provide molecular level explanations for antivenom cross-reactivity. In turn, this may help guide antivenom development by elucidating immunological biases in existing antivenoms. In this study, we have identified and characterized linear elements of B-cell epitopes from 870 pit viper venom protein sequences by employing a high-throughput methodology based on custom designed high-density peptide microarrays. By combining data on antibody-peptide interactions with multiple sequence alignments of homologous toxin sequences and protein modelling, we have determined linear elements of antibody binding sites for snake venom metalloproteases (SVMPs), phospholipases A2s (PLA2s), and snake venom serine proteases (SVSPs). The studied antivenom antibodies were found to recognize linear elements in each of the three enzymatic toxin families. In contrast to a similar study of elapid (non-enzymatic) neurotoxins, these enzymatic toxins were generally not recognized at the catalytic active site responsible for toxicity, but instead at other sites, of which some are known for allosteric inhibition or for interaction with the tissue target. Antibody recognition was found to be preserved for several minor variations in the protein sequences, although the antibody-toxin interactions could often be eliminated completely by substitution of a single residue. This finding is likely to have large implications for the cross-reactivity of the antivenom and indicate that multiple different antibodies are likely to be needed for targeting an entire group of toxins in these recognized sites.
[Mh] Termos MeSH primário: Antivenenos/imunologia
Venenos de Crotalídeos/imunologia
Mapeamento de Epitopos
Epitopos de Linfócito B/imunologia
Metaloproteases/imunologia
Fosfolipases A2/imunologia
[Mh] Termos MeSH secundário: Animais
Antivenenos/uso terapêutico
Reações Cruzadas
Seres Humanos
Análise em Microsséries
Alinhamento de Sequência
Mordeduras de Serpentes/terapia
Homologia Estrutural de Proteína
Viperidae
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antivenins); 0 (Crotalid Venoms); 0 (Epitopes, B-Lymphocyte); EC 3.1.1.4 (Phospholipases A2); EC 3.4.- (Metalloproteases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005768


  6 / 3953 MEDLINE  
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[PMID]:28704364
[Au] Autor:Eble JA; McDougall M; Orriss GL; Niland S; Johanningmeier B; Pohlentz G; Meier M; Karrasch S; Estevão-Costa MI; Martins Lima A; Stetefeld J
[Ad] Endereço:Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
[Ti] Título:Dramatic and concerted conformational changes enable rhodocetin to block α2ß1 integrin selectively.
[So] Source:PLoS Biol;15(7):e2001492, 2017 Jul.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The collagen binding integrin α2ß1 plays a crucial role in hemostasis, fibrosis, and cancer progression amongst others. It is specifically inhibited by rhodocetin (RC), a C-type lectin-related protein (CLRP) found in Malayan pit viper (Calloselasma rhodostoma) venom. The structure of RC alone reveals a heterotetramer arranged as an αß and γδ subunit in a cruciform shape. RC specifically binds to the collagen binding A-domain of the integrin α2 subunit, thereby blocking collagen-induced platelet aggregation. However, until now, the molecular basis for this interaction has remained unclear. Here, we present the molecular structure of the RCγδ-α2A complex solved to 3.0 Å resolution. Our findings show that RC undergoes a dramatic structural reorganization upon binding to α2ß1 integrin. Besides the release of the nonbinding RCαß tandem, the RCγ subunit interacts with loop 2 of the α2A domain as result of a dramatic conformational change. The RCδ subunit contacts the integrin α2A domain in the "closed" conformation through its helix C. Combined with epitope-mapped antibodies, conformationally locked α2A domain mutants, point mutations within the α2A loop 2, and chemical modifications of the purified toxin protein, this molecular structure of RCγδ-α2A complex explains the inhibitory mechanism and specificity of RC for α2ß1 integrin.
[Mh] Termos MeSH primário: Venenos de Crotalídeos/química
Integrina alfa2beta1/química
[Mh] Termos MeSH secundário: Venenos de Crotalídeos/farmacologia
Cristalografia por Raios X
Integrina alfa2beta1/antagonistas & inibidores
Modelos Moleculares
Ligação Proteica
Estrutura Terciária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Crotalid Venoms); 0 (Integrin alpha2beta1); 0 (rhodocetin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2001492


  7 / 3953 MEDLINE  
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[PMID]:28663253
[Au] Autor:Choo HJ; Kholmukhamedov A; Zhou C; Jobe S
[Ad] Endereço:From the BloodCenter of Wisconsin, Milwaukee (A.K., S.J.); Emory University School of Medicine, Department of Pediatrics and Children's Healthcare of Atlanta, GA (H.-J.C., C.Z., S.J.); Emory University, School of Medicine, Department of Cell Biology, Atlanta, GA (H.-J.C.); and Medical College of Wis
[Ti] Título:Inner Mitochondrial Membrane Disruption Links Apoptotic and Agonist-Initiated Phosphatidylserine Externalization in Platelets.
[So] Source:Arterioscler Thromb Vasc Biol;37(8):1503-1512, 2017 Aug.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Phosphatidylserine exposure mediates platelet procoagulant function and regulates platelet life span. Apoptotic, necrotic, and integrin-mediated mechanisms have been implicated as intracellular determinants of platelet phosphatidylserine exposure. Here, we investigate (1) the role of mitochondrial events in platelet phosphatidylserine exposure initiated by these distinct stimuli and (2) the cellular interactions of the procoagulant platelet in vitro and in vivo. APPROACH AND RESULTS: Key mitochondrial events were examined, including cytochrome c release and inner mitochondrial membrane (IMM) disruption. In both ABT-737 (apoptotic) and agonist (necrotic)-treated platelets, phosphatidylserine externalization was temporally correlated with IMM disruption. Agonist stimulation resulted in rapid cyclophilin D-dependent IMM disruption that coincided with phosphatidylserine exposure. ABT-737 treatment caused rapid cytochrome c release, eventually followed by caspase-dependent IMM disruption that again closely coincided with phosphatidylserine exposure. A nonmitochondrial and integrin-mediated mechanism has been implicated in the formation of a novel phosphatidylserine-externalizing platelet subpopulation. Using image cytometry, this subpopulation is demonstrated to be the result of the interaction of an aggregatory platelet and a procoagulant platelet rather than indicative of a novel intracellular mechanism regulating platelet phosphatidylserine externalization. Using electron microscopy, similar interactions between aggregatory and procoagulant platelets are demonstrated in vitro and in vivo within a mesenteric vein hemostatic thrombus. CONCLUSIONS: Platelet phosphatidylserine externalization is closely associated with the mitochondrial event of IMM disruption identifying a common pathway in phosphatidylserine-externalizing platelets. The limited interaction of procoagulant platelets and integrin-active aggregatory platelets identifies a potential mechanism for procoagulant platelet retention within the hemostatic thrombus.
[Mh] Termos MeSH primário: Apoptose
Plaquetas/metabolismo
Mitocôndrias/metabolismo
Membranas Mitocondriais/metabolismo
Fosfatidilserinas/sangue
Agregação Plaquetária
Trombose Venosa/sangue
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Compostos de Bifenilo/farmacologia
Coagulação Sanguínea/efeitos dos fármacos
Plaquetas/efeitos dos fármacos
Plaquetas/ultraestrutura
Caspases/sangue
Venenos de Crotalídeos/farmacologia
Ciclofilinas/sangue
Ciclofilinas/genética
Citocromos c/sangue
Modelos Animais de Doenças
Genótipo
Integrinas/sangue
Cinética
Lectinas Tipo C
Camundongos Knockout
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/ultraestrutura
Membranas Mitocondriais/efeitos dos fármacos
Necrose
Nitrofenóis/farmacologia
Fenótipo
Piperazinas/farmacologia
Agregação Plaquetária/efeitos dos fármacos
Transdução de Sinais
Sulfonamidas/farmacologia
Trombina/farmacologia
Trombose Venosa/genética
Trombose Venosa/patologia
Proteína Killer-Antagonista Homóloga a bcl-2/sangue
Proteína Killer-Antagonista Homóloga a bcl-2/genética
Proteína X Associada a bcl-2/sangue
Proteína X Associada a bcl-2/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABT-737); 0 (Bak1 protein, mouse); 0 (Bax protein, mouse); 0 (Biphenyl Compounds); 0 (Crotalid Venoms); 0 (Integrins); 0 (Lectins, C-Type); 0 (Nitrophenols); 0 (Phosphatidylserines); 0 (Piperazines); 0 (Sulfonamides); 0 (bcl-2 Homologous Antagonist-Killer Protein); 0 (bcl-2-Associated X Protein); 37206-04-5 (convulxin); 9007-43-6 (Cytochromes c); EC 3.4.21.5 (Thrombin); EC 3.4.22.- (Caspases); EC 5.2.1.- (Cyclophilins); EC 5.2.1.8 (cyclophilin D)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170819
[Lr] Data última revisão:
170819
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309473


  8 / 3953 MEDLINE  
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[PMID]:28601268
[Au] Autor:Gerardo CJ; Quackenbush E; Lewis B; Rose SR; Greene S; Toschlog EA; Charlton NP; Mullins ME; Schwartz R; Denning D; Sharma K; Kleinschmidt K; Bush SP; Ryan S; Gasior M; Anderson VE; Lavonas EJ
[Ad] Endereço:Division of Emergency Medicine, Duke University School of Medicine, Durham, NC. Electronic address: Charles.gerardo@duke.edu.
[Ti] Título:The Efficacy of Crotalidae Polyvalent Immune Fab (Ovine) Antivenom Versus Placebo Plus Optional Rescue Therapy on Recovery From Copperhead Snake Envenomation: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial.
[So] Source:Ann Emerg Med;70(2):233-244.e3, 2017 Aug.
[Is] ISSN:1097-6760
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:STUDY OBJECTIVE: Copperhead snake (Agkistrodon contortrix) envenomation causes limb injury resulting in pain and disability. It is not known whether antivenom administration improves limb function. We determine whether administration of antivenom improves recovery from limb injury in patients envenomated by copperhead snakes. METHODS: From August 2013 through November 2015, we performed a multicenter, randomized, double-blind, placebo-controlled, clinical trial to evaluate the effect of ovine Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) antivenom therapy on recovery of limb function in patients with copperhead snake envenomation at 14 days postenvenomation. The study setting was 18 emergency departments in regions of the United States where copperhead snakes are endemic. Consecutive patients aged 12 years or older with mild- to moderate-severity envenomation received either FabAV or placebo. The primary outcome was limb function 14 days after envenomation, measured by the Patient-Specific Functional Scale. Additional outcomes included the Patient-Specific Functional Scale at other points; the Disorders of the Arm, Shoulder, and Hand, Lower Extremity Functional Scale, and Patient's Global Impression of Change instruments; grip strength; walking speed; quality of life (Patient-Reported Outcomes Measurement Information System Physical Fucntion-10); pain; and analgesic use. RESULTS: Seventy-four patients received study drug (45 FabAV, 29 placebo). Mean age was 43 years (range 12 to 86 years). Fifty-three percent were men, 62% had lower extremity envenomation, and 88% had mild initial severity. The primary outcome, the least square mean Patient-Specific Functional Scale score at 14 days postenvenomation, was 8.6 for FabAV-treated subjects and 7.4 for placebo recipients (difference 1.2; 95% confidence interval 0.1 to 2.3; P=.04). Additional outcome assessments generally favored FabAV. More FabAV-treated subjects experienced treatment-emergent adverse events (56% versus 28%), but few were serious (1 in each group). CONCLUSION: Treatment with FabAV reduces limb disability measured by the Patient-Specific Functional Scale 14 days after copperhead envenomation.
[Mh] Termos MeSH primário: Agkistrodon
Antivenenos/uso terapêutico
Venenos de Crotalídeos/envenenamento
Fragmentos Fab das Imunoglobulinas/uso terapêutico
Extremidade Inferior/lesões
Mordeduras de Serpentes/tratamento farmacológico
Extremidade Superior/lesões
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Criança
Método Duplo-Cego
Feminino
Seguimentos
Seres Humanos
Extremidade Inferior/fisiopatologia
Masculino
Meia-Idade
Avaliação de Resultados da Assistência ao Paciente
Recuperação de Função Fisiológica
Mordeduras de Serpentes/fisiopatologia
Mordeduras de Serpentes/reabilitação
Estados Unidos
Extremidade Superior/fisiopatologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antivenins); 0 (Crotalid Venoms); 0 (Crotalidae Polyvalent immune Fab); 0 (Immunoglobulin Fab Fragments)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170612
[St] Status:MEDLINE


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[PMID]:28596377
[Au] Autor:Chang CH; Chung CH; Tu YS; Tsai CC; Hsu CC; Peng HC; Tseng YJ; Huang TF
[Ad] Endereço:From the Graduate Institute of Pharmacology, College of Medicine (C.-H.C., C.-C.H., H.-C.P., T.-F.H.), Graduate Institute of Biomedical Electronics and Bioinformatics (Y.-S.T., C.-C.T., Y.J.T.), and Department of Computational Science and Information Engineering (Y.J.T.), National Taiwan University,
[Ti] Título:Trowaglerix Venom Polypeptides As a Novel Antithrombotic Agent by Targeting Immunoglobulin-Like Domains of Glycoprotein VI in Platelet.
[So] Source:Arterioscler Thromb Vasc Biol;37(7):1307-1314, 2017 Jul.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Currently prescribed antiplatelet drugs have 1 common side effect-an increased risk of hemorrhage and thrombocytopenia. On the contrary, bleeding defects associated with glycoprotein VI (GPVI) expression deficiency are usually slightly prolonged bleeding times. However, GPVI antagonists are lacking in clinic. APPROACH AND RESULTS: Using reverse-phase high-performance liquid chromatography and sequencing, we revealed the partial sequence of trowaglerix α subunit, a potent specific GPVI-targeting snaclec (snake venom C-type lectin protein). Hexapeptide (Troα6 [trowaglerix a chain hexapeptide, CKWMNV]) and decapeptide (Troα10) derived from trowaglerix specifically inhibited collagen-induced platelet aggregation through blocking platelet GPVI receptor. Computational peptide design helped to design a series of Troα6/Troα10 peptides. Protein docking studies on these decapeptides and GPVI suggest that Troα10 was bound at the lower surface of D1 domain and outer surface of D2 domain, which was at the different place of the collagen-binding site and the scFv (single-chain variable fragment) D2-binding site. The newly discovered site was confirmed by inhibitory effects of polyclonal antibodies on collagen-induced platelet aggregation. This indicates that D2 domain of GPVI is a novel and important binding epitope on GPVI-mediated platelet aggregation. Troα6/Troα10 displayed prominent inhibitory effect of thrombus formation in fluorescein sodium-induced platelet thrombus formation of mesenteric venules and ferric chloride-induced carotid artery injury thrombosis model without prolonging the in vivo bleeding time. CONCLUSIONS: We develop a novel antithrombotic peptides derived from trowaglerix that acts through GPVI antagonism with greater safety-no severe bleeding. The binding epitope of polypeptides on GPVI is novel and important. These hexa/decapeptides have therapeutic potential for developing ideal small-mass GPVI antagonists for arterial thrombogenic diseases.
[Mh] Termos MeSH primário: Plaquetas/efeitos dos fármacos
Lesões das Artérias Carótidas/tratamento farmacológico
Venenos de Crotalídeos/farmacologia
Fibrinolíticos/farmacologia
Fragmentos de Peptídeos/farmacologia
Inibidores da Agregação de Plaquetas/farmacologia
Agregação Plaquetária/efeitos dos fármacos
Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores
Trombose/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Plaquetas/metabolismo
Lesões das Artérias Carótidas/sangue
Lesões das Artérias Carótidas/induzido quimicamente
Cloretos
Projeto Auxiliado por Computador
Venenos de Crotalídeos/metabolismo
Venenos de Crotalídeos/toxicidade
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Desenho de Drogas
Compostos Férricos
Fibrinolíticos/metabolismo
Fibrinolíticos/toxicidade
Fluoresceína
Hemorragia/induzido quimicamente
Seres Humanos
Lectinas Tipo C/metabolismo
Masculino
Camundongos Endogâmicos ICR
Simulação de Acoplamento Molecular
Fragmentos de Peptídeos/metabolismo
Fragmentos de Peptídeos/toxicidade
Inibidores da Agregação de Plaquetas/metabolismo
Inibidores da Agregação de Plaquetas/toxicidade
Glicoproteínas da Membrana de Plaquetas/metabolismo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Transdução de Sinais/efeitos dos fármacos
Trombose/sangue
Trombose/induzido quimicamente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chlorides); 0 (Crotalid Venoms); 0 (Ferric Compounds); 0 (Fibrinolytic Agents); 0 (Lectins, C-Type); 0 (Peptide Fragments); 0 (Platelet Aggregation Inhibitors); 0 (Platelet Membrane Glycoproteins); 0 (platelet membrane glycoprotein VI); 0 (trowaglerix protein, Tropidolaemus wagleri); TPY09G7XIR (Fluorescein); U38V3ZVV3V (ferric chloride)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170610
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.116.308604


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[PMID]:28579355
[Au] Autor:Sun K; Huang C; Yu F; Zhu S; Xu S; He Y; Xu W; Xu L; Feng Y; Wu H; Li X; Fang L; Hu Q
[Ad] Endereço:Department of Cell Biology and Genetics, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, 530021, PR China.
[Ti] Título:Expression, purification and characterization of a novel recombinant SVTLE, r-agkihpin-2, from Gloydius halys Pallas venom gland in Escherichia coli.
[So] Source:Protein Expr Purif;136:7-13, 2017 Aug.
[Is] ISSN:1096-0279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In our previous work, a thrombin-like enzyme (TLE), agkihpin, was successfully isolated, purified, cloned and named from the venom of Gloydius halys Pallas, having fibrinolytic, fibrinogenolytic and thrombosis-reduced activities, attenuating migration of liver cancer cell, and without bleeding risk. To explore the possibility of agkihpin as a thrombolytic and/or anti-metastasis agent in the future, in this study recombinant agkihpin was expressed and purified in Escherichia coli, and its biological activities investigated. Thus, r-agkihpin-2 was successfully expressed and purified and confirmed by Western blot and peptide mass fingerprinting. After purification and renaturation, 46 mg (399 U) of active r-agkihpin-2 was obtained from 1 L bacterial culture. The results of the arginine esterase activity assay, fibrin plate test fibrinogenolytic activity assay, thrombin-induced venous thrombosis assay, Scratch-Wound assay and bleeding assay showed that active r-agkihpin-2 had slightly lower TAME hydrolytic, fibrinolytic, fibrinogenolytic, thrombus-reduced and migration-attenuated activities than those of native agkihpin, and had no bleeding risk. These findings confirmed that, active r-agkihpin-2 could be further investigated for thrombolytic and/or anti-metastasis drug discovery in the future.
[Mh] Termos MeSH primário: Hidrolases de Éster Carboxílico
Venenos de Crotalídeos
Viperidae/genética
[Mh] Termos MeSH secundário: Animais
Hidrolases de Éster Carboxílico/biossíntese
Hidrolases de Éster Carboxílico/classificação
Hidrolases de Éster Carboxílico/genética
Hidrolases de Éster Carboxílico/isolamento & purificação
Venenos de Crotalídeos/biossíntese
Venenos de Crotalídeos/química
Venenos de Crotalídeos/genética
Venenos de Crotalídeos/isolamento & purificação
Escherichia coli/genética
Escherichia coli/metabolismo
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Crotalid Venoms); 0 (Recombinant Proteins); EC 3.1.- (agkihpin protein, Gloydius halys); EC 3.1.1.- (Carboxylic Ester Hydrolases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170606
[St] Status:MEDLINE



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