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Rio de Janeiro, Brazil

Amaral J.J.,Instituto Oswaldo Cruz | Amaral J.J.,Brazilian National Institute of Technology | Antunes L.M.,University of British Columbia | de Macedo C.S.,Instituto Oswaldo Cruz | And 11 more authors.
PLoS Neglected Tropical Diseases | Year: 2013

Despite considerable efforts over the last decades, our understanding of leprosy pathogenesis remains limited. The complex interplay between pathogens and hosts has profound effects on host metabolism. To explore the metabolic perturbations associated with leprosy, we analyzed the serum metabolome of leprosy patients. Samples collected from lepromatous and tuberculoid patients before and immediately after the conclusion of multidrug therapy (MDT) were subjected to high-throughput metabolic profiling. Our results show marked metabolic alterations during leprosy that subside at the conclusion of MDT. Pathways showing the highest modulation were related to polyunsaturated fatty acid (PUFA) metabolism, with emphasis on anti-inflammatory, pro-resolving omega-3 fatty acids. These results were confirmed by eicosanoid measurements through enzyme-linked immunoassays. Corroborating the repertoire of metabolites altered in sera, metabonomic analysis of skin specimens revealed alterations in the levels of lipids derived from lipase activity, including PUFAs, suggesting a high lipid turnover in highly-infected lesions. Our data suggest that omega-6 and omega-3, PUFA-derived, pro-resolving lipid mediators contribute to reduced tissue damage irrespectively of pathogen burden during leprosy disease. Our results demonstrate the utility of a comprehensive metabonomic approach for identifying potential contributors to disease pathology that may facilitate the development of more targeted treatments for leprosy and other inflammatory diseases. © 2013 Amaral et al.

De Souza Costa M.F.,Laboratorio Of Farmacologia Aplicada | De Souza-Martins R.,Laboratorio Of Farmacologia Aplicada | De Souza M.C.,Laboratorio Of Farmacologia Aplicada | Benjamim C.F.,Federal University of Rio de Janeiro | And 6 more authors.
Journal of Leukocyte Biology | Year: 2010

Herein, we investigated the involvement of the 5-LO-derived lipid mediator LTB4 in γδ T cell migration. When injected into the i.pl. space of C57BL/6 mice, LTB4 triggered γδ T lymphocyte mobilization in vivo, a phenomenon also observed in in vitro chemotaxis assays. The i.pl. injection of Escherichia coli endotoxin (LPS) triggered increased levels of LTB4 in pleural cavities. The in vivo inhibition of LTB4 biosynthesis by the 5-LO inhibitor zileuton or the FLAP inhibitor MK886 attenuated LPS-induced γδ T cell accumulation into pleural cavities. Accordingly, 5-LO KO mice failed to recruit γδ T cells into the inflammatory site after i.pl. LPS. Antagonists of the high-affinity LTB 4 receptor BLT1, CP105,696, and LY292476 also attenuated LPS-induced γδ T cell accumulation in pleural cavities as well as in vitro chemotaxis toward pleural washes obtained from LPS-simulated mice. LTB 4/BLT1 also accounted for γδ T cell migration induced by i.pl. administration of Mycobacterium bovis BCG or antigen in sensitized mice. BLT1 was expressed on naïve, resident as well as LPS-recruited γδ T cells. Isolated γδ T cells were found to undergo F-actin cytoskeleton reorganization when incubated with LTB4 in vitro, confirming that γδ T lymphocytes can respond directly to LTB4. In addition to its direct effect on γδ T cells, LTB4 triggered their accumulation indirectly, via modulation of CCL2 production in mouse pleural cavities. These data show that γδ T cell migration into the pleural cavity of mice during diverse inflammatory responses is dependent on LTB4/BLT1. © Society for Leukocyte Biology.

Conte F.P.,Laboratorio Of Farmacologia Aplicada | Ferraris F.K.,Laboratorio Of Farmacologia Aplicada | Costa T.E.M.M.,Laboratorio Of Farmacologia Aplicada | Pacheco P.,Laboratorio Of Farmacologia Aplicada | And 6 more authors.
Molecules | Year: 2015

Gedunin, a natural limonoid from Meliaceae species, has been previously described as an antiinflammatory compound in experimental models of allergic inflammation. Here, we report the antiinflammatory and antinociceptive effects of gedunin in an acute model of articular inflammation induced by zymosan (500 μg/cavity; intra-articular) in C57BL/6 mice. Intraperitoneal (i.p.) pretreatment with gedunin (0.005-5 mg/kg) impaired zymosan-induced edema formation, neutrophil accumulation and hypernociception in mouse knee joints, due to decreased expression of preproET-1 mRNA and production of LTB4, PGE2, TNF-α and IL-6. Mouse post-treatment with gedunin (0.05 mg/kg; i.p.) 1 and 6 h after stimulation also impaired articular inflammation, by reverting edema formation, neutrophil accumulation and the production of lipid mediators, cytokines and endothelin. In addition, gedunin directly modulated the functions of neutrophils and macrophages in vitro. The pre-incubation of neutrophil with gedunin (100 μM) impaired shape change, adhesion to endothelial cells, chemotaxis and lipid body formation triggered by different stimuli. Macrophage pretreatment with gedunin impaired intracellular calcium mobilization, nitric oxide production, inducible nitric oxide synthase expression and induced the expression of the antiinflammatory chaperone heat shock protein 70. Our results demonstrate that gedunin presents remarkable antiinflammatory and anti-nociceptive effects on zymosan-induced inflamed knee joints, modulating different cell populations. © 2015 by the authors; licensee MDPI.

Ferraris F.K.,Laboratorio Of Farmacologia Aplicada | Ferraris F.K.,Oswaldo Cruz Institute | Rodrigues R.,Laboratorio Of Quimica Of Produtos Naturais | Rodrigues R.,State University of Norte Fluminense | And 4 more authors.
International Immunopharmacology | Year: 2011

We have previously described the anti-allergic activities of a pooled fraction of tetranortriterpenoids (TNTPs) containing 6α-acetoxygedunin, 7-deacetoxy-7-oxogedunin, andirobin and methyl angolensate isolated from the seeds of Carapa guianensis. In the present study, we performed in vitro studies in order to elucidate the mechanisms by which TNTPs present their anti-allergic effects and to identify the bioactive compound(s) present in such fraction. Here, we show that in vitro incubation of eosinophils with the pooled TNTP fraction, as well as with each one of the five isolated tetranortriterpenoids, impaired the adhesion of eosinophils to tumor necrosis factor-α (TNF-α)-primed tEND.1 endothelial cells. Furthermore, the individual or pooled TNTPs impaired CCL11/eotaxin-mediated chemotaxis. By contrast, pooled TNTPs failed to inhibit adhesion and chemotaxis of T lymphocytes. However, TNTPs were able to impair anti-CD3 monoclonal antibody-induced T cell proliferation and the expression of CD25 and CD69. These data suggest that TNTPs prevent T cell activation. Pretreatment of splenocytes with the pooled TNTP fraction, as well as with each one of the five isolated TNTPs, inhibited ovalbumin (OVA)-induced in vitro production of interleukin-2, chemokine (C-C motif) ligand 11 (CCL11) and regulated on activation normal T cell expressed and secreted (RANTES, also known as CCL5). TNTPs (except 6α-acetoxygedunin) also impaired nuclear factor-κB (NFκB) nuclear translocation in OVA-challenged splenocytes. Taken together, these results demonstrate that the anti-allergic effects of TNTPs isolated from C. guianensis might rely on their ability to inhibit eosinophil migration, as well as the activation of T lymphocytes, which is shared by the five isolated TNTPs. © 2010 Elsevier B.V. All rights reserved.

Farias J.A.C.,Federal University of Alagoas | Ferro J.N.S.,Federal University of Alagoas | Silva J.P.,Federal University of Alagoas | Agra I.K.R.,Federal University of Alagoas | And 7 more authors.
Inflammation | Year: 2012

The present study was carried out to investigate the anti-inflammatory effect of the hexane extract of the leaves from Clusia nemorosa G. Mey, called HECn, using carrageenan-induced mice pleurisy and cotton pellet-induced mice granuloma. Additionally, the ability of HECn to affect both neutrophil migration as viability was investigated by use of the Boyden chamber assay and flow cytometry, respectively. The HECn significantly inhibited exudation, total leukocytes and neutrophils influx, as well as TNFα levels in carrageenan-induced pleurisy. However, the extract not suppressed the granulomatous tissue formation in the cotton pellet-induced granuloma test. Experiments performed in vitro revealed that HECn on human neutrophils inhibited a dose-dependent manner the CXCL1-induced neutrophil chemotaxis. Furthermore, HECn also inhibited the chemoattraction of human neutrophils induced by formyl-methionyl-leucyl-phenylalanine (fMLP), leukotriene B4 (LTB4) and platelet activating factor (PAF) in a Boyden chamber. However, this same treatment not was able to induce apoptosis. The results obtained in this study showed that the extract from leaves of C. nemorosa possess a potent inhibitory activity in acute model of inflammation, being the effects mediated, in part, by inhibition of neutrophil responsiveness. These results indicate that C. nemorosa could be a good source for anti-inflammatory compounds. © 2011 Springer Science+Business Media, LLC.

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