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101.
Max Seidy Saito André Luiz Lourenço Luiza Rosaria Sousa Dias Antônio Carlos Carreira Freitas Maíra Ingrid Vitorino Magaly Girão Albuquerque 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1591-1601
Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N′-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3?h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE2 and TXB2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases. 相似文献
102.
Beno?t Grellier Beno?t Grellier Fabrice Le Pogam Fabrice Le Pogam Marc Vitorino Marc Vitorino Jean-Philippe Starck Jean-Philippe Starck Michel Geist Michel Geist Vanessa Duong Vanessa Duong Hélène Haegel Hélène Haegel Thierry Menguy Thierry Menguy Jean-Yves Bonnefoy Jean-Yves Bonnefoy Jean-Baptiste Marchand Jean-Baptiste Marchand Philippe Ancian Philippe Ancian 《MABS-AUSTIN》2014,6(2):533-546
The humanized monoclonal antibody H27K15 specifically targets human CD115, a type III tyrosine kinase receptor involved in multiple cancers and inflammatory diseases. Binding of H27K15 to hCD115 expressing cells inhibits the functional effect of colony-stimulating factor-1 (CSF-1), in a non-competitive manner. Both homology modeling and docking programs were used here to model the human CD115 extracellular domains, the H27K15 variable region and their interaction. The resulting predicted H27K15 epitope includes mainly the D1 domain in the N-terminal extracellular region of CD115 and some residues of the D2 domain. Sequence alignment with the non-binding murine CD115, enzyme-linked immunosorbent assay, nuclear magnetic resonance spectroscopy and affinity measurements by quartz crystal microbalance revealed critical residues of this epitope that are essential for H27K15 binding. A combination of computational simulations and biochemical experiments led to the design of a chimeric CD115 carrying the human epitope of H27K15 in a murine CD115 backbone that is able to bind both H27K15 as well as the murine ligands CSF-1 and IL-34. These results provide new possibilities to minutely study the functional effects of H27K15 in a transgenic mouse that would express this chimeric molecule. 相似文献
103.
João Pinto da Costa Rui Oliveira-Silva Ana Luísa Daniel-da-Silva Rui Vitorino 《Biotechnology advances》2014
Formed as an interdisciplinary domain on the basis of Human Genome Project, Proteomics aims at the large-scale study of proteins. The enthusiasm that resulted from obtaining the complete human genetic information has, however, been chastened by the realization that this information contributes little to the comprehension and knowledge of the expressed proteins. In the wake of this realization, the Human Proteome Project (HUPO) was founded, which is a global, collaborative initiative, aiming at the complete characterization of the proteins of all protein-coding genes. Nonetheless, the rapid detection of these molecules in complex biological samples under conditions considered to be of clinical relevance is extremely difficult, requiring the development of very sensitive, robust, reproducible and high throughput platforms. Nanoproteomics has emerged as a feasible, promising option, offering short assay times, low sample consumption, ultralow detection and high throughput capacity. Additionally, the successful synthesis of biomolecules and nanoparticle hybrids yields systems which often exhibit new or improved features. Herein, we overview the recent advances in bioconjugation at the nanolevel and, specifically, their application in Proteomics, discussing not only the merits and prospects of Proteomics, but also present day limitations. 相似文献
104.
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106.
Padrão AI Ferreira RM Vitorino R Alves RM Neuparth MJ Duarte JA Amado F 《Biochimica et biophysica acta》2011,1807(9):1106-1113
In cardiac tissue two mitochondria subpopulations, the subsarcolemmal and the intermyofibrillar mitochondria, present different functional emphasis, although limited information exists about the underlying molecular mechanisms. Our study evidenced higher OXPHOS activity of intermyofibrillar compared to subsarcolemmal mitochondria, paralleled by distinct membrane proteins susceptibility to oxidative damage and not to quantitative differences of OXPHOS composition. Indeed, subsarcolemmal subunits of respiratory chain complexes were more prone to carbonylation while intermyofibrillar mitochondria were more susceptible to nitration. Among membrane protein targets to posttranslational modifications, ATP synthase subunits alpha and beta were notoriously more carbonylated in both subpopulations, although more intensely in subsarcolemmal mitochondria. Our data highlight a localization dependence of cardiac mitochondria OXPHOS activity and susceptibility to posttranslational modifications. 相似文献
107.
Aileen?G?RowanEmail author Koichiro?Suemori Hiroshi?Fujiwara Masaki?Yasukawa Yuetsu?Tanaka Graham?P?Taylor Charles?RM?Bangham 《Retrovirology》2014,11(1):116
Background
Immunogenetic evidence indicates that cytotoxic T lymphocytes (CTLs) specific for the weak CTL antigen HBZ limit HTLV-1 proviral load in vivo, whereas there is no clear relationship between the proviral load and the frequency of CTLs specific for the immunodominant antigen Tax. In vivo, circulating HTLV-1-infected cells express HBZ mRNA in contrast, Tax expression is typically low or undetectable. To elucidate the virus-suppressing potential of CTLs targeting HBZ, we compared the ability of HBZ- and Tax-specific CTLs to lyse naturally-infected cells, by co-incubating HBZ- and Tax-specific CTL clones with primary CD4+ T cells from HLA-matched HTLV-1-infected donors. We quantified lysis of infected cells, and tested whether specific virus-induced host cell surface molecules determine the susceptibility of infected cells to CTL-mediated lysis.Results
Primary infected cells upregulated HLA-A*02, ICAM-1, Fas and TRAIL-R1/2 in concert with Tax expression, forming efficient targets for both HTLV-1-specific CTLs and CTLs specific for an unrelated virus. We detected expression of HBZ mRNA (spliced isoform) in both Tax-expressing and non-expressing infected cells, and the HBZ26–34 epitope was processed and presented by cells transfected with an HBZ expression plasmid. However, when coincubated with primary cells, a high-avidity HBZ-specific CTL clone killed significantly fewer infected cells than were killed by a Tax-specific CTL clone. Finally, incubation with Tax- or HBZ-specific CTLs resulted in a significant decrease in the frequency of cells expressing high levels of HLA-A*02.Conclusions
HTLV-1 gene expression in primary CD4+ T cells non-specifically increases susceptibility to CTL lysis. Despite the presence of HBZ spliced-isoform mRNA, HBZ epitope presentation by primary cells is significantly less efficient than that of Tax.108.
Mehanna A Vitorino DC Panis C Blanco EE Pinge-Filho P Martins-Pinge MC 《Life sciences》2007,81(16):1301-1308
Sepsis is characterized by systemic hypotension, hyporeactiveness to vasoconstrictors, impaired tissue perfusion, and multiple organ failure. During exercise training (ET), dynamic cardiovascular adjustments take place to maintain proper blood pressure and adjust blood supply to different vascular beds. The aim of this study was to investigate whether ET protects against the cardiovascular abnormalities induced by LPS, a model of experimental endotoxemia, and to evaluate the role of nitric oxide (NO) in pulmonary edema. Wistar rats were subjected to swimming training (up to 1 h/day, 5 days/week for 4 weeks) after which their femoral artery and vein were catheterized. LPS (5 mg/kg, i.v.), injected in control (C) and trained animals (ET), promoted 3 distinct phases in mean arterial pressure (MAP) and heart rate (HR). After ET the alterations in MAP were attenuated. The ET animals showed a lower pulmonary edema index (PEI) after LPS (C=0.65+/-0.01; ET=0.60+/-0.02), which was attenuated after treatment with aminoguanidine in both groups (C=0.53+/-0.02; ET=0.53+/-0.02, p<0.05). After l-NAME, PEI was enhanced numerically in the C and was statistically higher in the ET group (C=0.73+/-0.05; ET=1.30+/-0.3, p<0.05). 7-nitroindazole did not promote any alteration in either group. The adaptations promoted by ET seem to be beneficial, counteracting the cardiovascular abnormalities and pulmonary edema seen in septicemia induced by LPS. The results suggest that iNOS aggravates and cNOS protects against this pulmonary edema. 相似文献
109.
I. D. Paterson P. A. Muskett L. A. Mdodana M. D. Vitorino 《Biocontrol Science and Technology》2019,29(7):715-719
The stem-mining weevil, Pereskiophaga brasiliensis, was a candidate biological control agent for the invasive cactus Pereskia aculeata in South Africa. In host specificity trials, it developed on two indigenous test plant species under choice and no-choice conditions. Pereskiophaga brasiliensis is therefore not suitably host specific for release in South Africa. 相似文献
110.
Ana Cristina Sarmento Henrique Lopes Cláudia S. Oliveira Rui Vitorino Bart Samyn Kjell Sergeant Griet Debyser Jozef Van Beeumen Pedro Domingues Francisco Amado Euclides Pires M. Rosário M. Domingues Marlene T. Barros 《Planta》2009,230(2):429-439
Aspartic proteinases (AP) play major roles in physiologic and pathologic scenarios in a wide range of organisms from vertebrates
to plants or viruses. The present work deals with the purification and characterisation of four new APs from the cardoon Cynara cardunculus L., bringing the number of APs that have been isolated, purified and biochemically characterised from this organism to nine.
This is, to our knowledge, one of the highest number of APs purified from a single organism, consistent with a specific and
important biological function of these protein within C. cardunculus. These enzymes, cardosins E, F, G and H, are dimeric, glycosylated, pepstatin-sensitive APs, active at acidic pH, with a
maximum activity around pH 4.3. Their primary structures were partially determined by N- and C-terminal sequence analysis,
peptide mass fingerprint analysis on a MALDI-TOF/TOF instrument and by LC–MS/MS analysis on a Q-TRAP instrument. All four
enzymes are present on C. cardunculus L. pistils, along with cyprosins and cardosins A and B. Their micro-heterogeneity was detected by 2D-electrophoresis and
mass spectrometry. The enzymes resemble cardosin A more than they resemble cardosin B or cyprosin, with cardosin E and cardosin
G being more active than cardosin A, towards the synthetic peptide KPAEFF(NO2)AL. The specificity of these enzymes was investigated and it is shown that cardosin E, although closely related to cardosin
A, exhibits different specificity.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献