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Search Results: 1 - 10 of 380614 matches for " Célio Geraldo Freire-de-Lima "
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Inhibitory Effects of Trypanosoma cruzi Sialoglycoproteins on CD4+ T Cells Are Associated with Increased Susceptibility to Infection
Marise Pinheiro Nunes, Bárbara Fortes, Jo?o Luiz Silva-Filho, Eugênia Terra-Granado, Leonardo Santos, Luciana Conde, Isadora de Araújo Oliveira, Leonardo Freire-de-Lima, Marina Vieira Martins, Ana Acacia Sá Pinheiro, Christina Maeda Takyia, Célio Geraldo Freire-de-Lima, Adriane Regina Todeschini, George Alexandre DosReis, Alexandre Morrot
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077568
Abstract: Background The Trypanosoma cruzi infection is associated with severe T cell unresponsiveness to antigens and mitogens characterized by decreased IL-2 synthesis. Trypanosoma cruzi mucin (Tc Muc) has been implicated in this phenomenom. These molecules contain a unique type of glycosylation consisting of several sialylated O-glycans linked to the protein backbone via N-acetylglucosamine residues. Methodology/Principal Findings In this study, we evaluated the ability of Tc Muc to modulate the activation of CD4+ T cells. Our data show that cross-linking of CD3 on na?ve CD4+ T cells in the presence of Tc Muc resulted in the inhibition of both cytokine secretion and proliferation. We further show that the sialylated O-Linked Glycan residues from tc mucin potentiate the suppression of T cell response by inducing G1-phase cell cycle arrest associated with upregulation of mitogen inhibitor p27kip1. These inhibitory effects cannot be reversed by the addition of exogenous IL-2, rendering CD4+ T cells anergic when activated by TCR triggering. Additionally, in vivo administration of Tc Muc during T. cruzi infection enhanced parasitemia and aggravated heart damage. Analysis of recall responses during infection showed lower frequencies of IFN-γ producing CD4+ T cells in the spleen of Tc Muc treated mice, compared to untreated controls. Conclusions/Significance Our results indicate that Tc Muc mediates inhibitory efects on CD4+ T expansion and cytokine production, by blocking cell cycle progression in the G1 phase. We propose that the sialyl motif of Tc Muc is able to interact with sialic acid-binding Ig-like lectins (Siglecs) on CD4+ T cells, which may allow the parasite to modulate the immune system.
Early Double-Negative Thymocyte Export in Trypanosoma cruzi Infection Is Restricted by Sphingosine Receptors and Associated with Human Chagas Disease
Ailin Lepletier,Liliane de Almeida,Leonardo Santos,Luzia da Silva Sampaio,Bruno Paredes,Florencia Belén González,Célio Geraldo Freire-de-Lima,Juan Beloscar,Oscar Bottasso,Marcelo Einicker-Lamas,Ana Rosa Pérez,Wilson Savino,Alexandre Morrot
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0003203
Abstract: The protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironmental and lymphoid compartments. Acute infection results in severe atrophy of the organ and early release of immature thymocytes into the periphery. To date, the pathophysiological effects of thymic changes promoted by parasite-inducing premature release of thymocytes to the periphery has remained elusive. Herein, we show that sphingosine-1-phosphate (S1P), a potent mediator of T cell chemotaxis, plays a role in the exit of immature double-negative thymocytes in experimental Chagas disease. In thymuses from T. cruzi-infected mice we detected reduced transcription of the S1P kinase 1 and 2 genes related to S1P biosynthesis, together with increased transcription of the SGPL1 sphingosine-1-lyase gene, whose product inactivates S1P. These changes were associated with reduced intrathymic levels of S1P kinase activity. Interestingly, double-negative thymocytes from infected animals expressed high levels of the S1P receptor during infection, and migrated to lower levels of S1P. Moreover, during T. cruzi infection, this thymocyte subset expresses high levels of IL-17 and TNF-α cytokines upon polyclonal stimulation. In vivo treatment with the S1P receptor antagonist FTY720 resulted in recovery the numbers of double-negative thymocytes in infected thymuses to physiological levels. Finally, we showed increased numbers of double-negative T cells in the peripheral blood in severe cardiac forms of human Chagas disease.
Neutrophils Increase or Reduce Parasite Burden in Trypanosoma cruzi-Infected Macrophages, Depending on Host Strain: Role of Neutrophil Elastase
Tatiana Luna-Gomes, Alessandra A. Filardy, Juliana Dutra B. Rocha, Debora Decote-Ricardo, Isabel Ferreira LaRocque-de-Freitas, Alexandre Morrot, Patrícia T. Bozza, Hugo C. Castro-Faria-Neto, George A. DosReis, Marise P. Nunes, Célio G. Freire-de-Lima
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090582
Abstract: Neutrophils are involved in the initial steps of most responses to pathogens and are essential components of the innate immune response. Due to the ability to produce and release various soluble mediators, neutrophils may participate in the regulation of the inflammatory response. Little is known about the role of neutrophils during protozoan infections including infection by Trypanosoma cruzi. In the present study we investigated the importance of inflammatory neutrophils on macrophage activation and T. cruzi replication in vitro, in cells obtained from BALB/c mice and C57Bl/6 mice. Co-cultures of BALB/c apoptotic or live neutrophils with infected peritoneal macrophages resulted in increased replication of the parasites and in the production of TGF-β and PGE2. The treatment with anti-TGF-β neutralizing antibody and COX inhibitor blocked the parasite replication in vitro. On the other hand, co-cultures of T. cruzi infected macrophages with live neutrophils isolated from C57BL/6 mice resulted in decreased number of trypomastigotes in culture and increased production of TNF-α and NO. The addition of anti-TNF-α neutralizing antibody or elastase inhibitor resulted in the abolishment of macrophage microbicidal effect and increased parasite replication. Addition of elastase to infected macrophages reduced the replication of the parasites, and on the other hand, addition of a selective inhibitor of iNOS increased parasite growth, suggesting the role of NO in this system. Our findings reveal that neutrophils may regulate T. cruzi experimental infection and determine susceptibility and resistance to infection.
Infection with Leishmania major Induces a Cellular Stress Response in Macrophages
Alessandra A. Filardy, Ana Caroline Costa-da-Silva, Carolina M. Koeller, Kamila Guimar?es-Pinto, Flávia L. Ribeiro-Gomes, Marcela F. Lopes, Norton Heise, Célio G. Freire-de-Lima, Marise P. Nunes, George A. DosReis
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085715
Abstract: We investigated early cellular responses induced by infection with Leishmania major in macrophages from resistant C57/BL6 mice. Infection increased production of reactive oxygen species by resident, but not inflammatory peritoneal macrophages. In addition, infection increased activation of stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK) in resident, but not in inflammatory peritoneal macrophages. Infection also increased expression of membrane and soluble FasL, but infected macrophages remained viable after 48 h. Infection increased secretion of cytokines/chemokines TNF-α, IL-6, TIMP-1, IL-1RA, G-CSF, TREM, KC, MIP-1α, MIP-1β, MCP-1, and MIP-2 in resident macrophages. Addition of antioxidants deferoxamine and N-acetylcysteine reduced ROS generation and JNK activation. Addition of antioxidants or JNK inhibitor SP600125 reduced secretion of KC. Furthermore, treatment with antioxidants or JNK inhibitor also reduced intracellular parasite replication. These results indicated that infection triggers a rapid cellular stress response in resident macrophages which induces proinflammatory signals, but is also involved in parasite survival and replication in host macrophages.
Cissampelos sympodialis Eichl (Menispermaceae) leaf extract induces interleukin-10-dependent inhibition of Trypanosoma cruzi killing by macrophages
Alexandre-Moreira M.S.,Freire-de-Lima C.G.,Trindade M.N.,Castro-Faria-Neto H.C.
Brazilian Journal of Medical and Biological Research , 2003,
Abstract: The aqueous fraction of the ethanolic extract (AFL) of Cissampelos sympodialis Eichl (Menispermaceae), popularly known as milona, has been shown to have both immunosuppressive and anti-inflammatory effects. In the present study we investigated the modulation of macrophage antimicrobicidal activity by in vitro treatment with the extract from C. sympodialis. Normal and thioglycolate-elicited mouse peritoneal macrophages were infected in vitro with the protozoan Trypanosoma cruzi DM28c clone. We observed that the AFL (used at doses ranging from 13 to 100 μg/ml) increased T. cruzi growth and induced a 75% reduction in nitric oxide production. This inhibition could be mediated by the stimulation of macrophage interleukin-10 (IL-10) secretion since the in vitro treatment with the AFL stimulated IL-10 production by T. cruzi-infected macrophages. These results suggest that the anti-inflammatory effect of the AFL from C. sympodialis could be, at least in part, mediated by the inhibition of macrophage functions and that the inhibition of macrophage microbicidal activity induced by the C. sympodialis extract may be mediated by the decrease in macrophage function mediated by interleukin-10 production.
Increase of O-Glycosylated Oncofetal Fibronectin in High Glucose-Induced Epithelial-Mesenchymal Transition of Cultured Human Epithelial Cells
Frederico Alisson-Silva, Leonardo Freire-de-Lima, Joana L. Donadio, Miguel C. Lucena, Luciana Penha, Julliana N. Sá-Diniz, Wagner B. Dias, Adriane R. Todeschini
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060471
Abstract: Growing evidences indicate that aberrant glycosylation can modulate tumor cell invasion and metastasis. The process termed "epithelial-mesenchymal transition" (EMT) provides a basic experimental model to shed light on this complex process. The EMT involves a striking decline in epithelial markers, accompanied by enhanced expression of mesenchymal markers, culminating in cell morphology change and increased cell motility. Few recent studies have established the participation glycosylation during EMT. Studies now come into knowledge brought to light the involvement of a site-specific O-glycosylation in the IIICS domain of human oncofetal fibronectin (onfFN) during the EMT process. Herein we show that high glucose induces EMT in A549 cells as demonstrated by TGF-β secretion, cell morphology changes, increased cellular motility and the emergence of mesenchymal markers. The hyperglycemic conditions increased onfFN protein levels, promoted an up regulation of mRNA levels for ppGalNAc-T6 and FN IIICS domain, which contain the hexapeptide (VTHPGY) required for onfFN biosynthesis. Glucose effect involves hexosamine (HBP) biosynthetic pathway as overexpression of glutamine: fructose-6-phosphate amidotransferase increases mesenchymal markers, onfFN levels and mRNA levels for FN IIICS domain. In summary, our results demonstrate, for the first time that the metabolism of glucose through HBP promotes O-glycosylation of the oncofetal form of FN during EMT modulating tumorogenesis.
Sweet and Sour: The Impact of Differential Glycosylation in Cancer Cells Undergoing Epithelial–Mesenchymal Transition
Leonardo Freire-de-Lima
Frontiers in Oncology , 2014, DOI: 10.3389/fonc.2014.00059
Abstract: Glycosylation changes are a feature of disease states. One clear example is cancer cells, which commonly express glycans at atypical levels or with different structural attributes than those found in normal cells. Epithelial–mesenchymal transition (EMT) was initially recognized as an important step for morphogenesis during embryonic development, and is now shown to be one of the key steps promoting tumor metastasis. Cancer cells undergoing EMT are characterized by significant changes in glycosylation of the extracellular matrix (ECM) components and cell-surface glycoconjugates. Current scientific methodology enables all hallmarks of EMT to be monitored in vitro and this experimental model has been extensively used in oncology research during the last 10 years. Several studies have shown that cell-surface carbohydrates attached to proteins through the amino acids, serine, or threonine (O-glycans), are involved in tumor progression and metastasis, however, the impact of O-glycans on EMT is poorly understood. Recent studies have demonstrated that transforming growth factor-beta (TGF-β), a known EMT inducer, has the ability to promote the up-regulation of a site-specific O-glycosylation in the IIICS domain of human oncofetal fibronectin, a major ECM component expressed by cancer cells and embryonic tissues. Armed with the knowledge that cell-surface glycoconjugates play a major role in the maintenance of cell homeostasis and that EMT is closely associated with glycosylation changes, we may benefit from understanding how unusual glycans can govern the molecular pathways associated with cancer progression. This review initially focuses on some well-known changes found in O-glycans expressed by cancer cells, and then discusses how these alterations may modulate the EMT process.
Cissampelos sympodialis Eichl (Menispermaceae) leaf extract induces interleukin-10-dependent inhibition of Trypanosoma cruzi killing by macrophages
Alexandre-Moreira, M.S.;Freire-de-Lima, C.G.;Trindade, M.N.;Castro-Faria-Neto, H.C.;Piuvezam, M.R.;Pe?anha, L.M.T.;
Brazilian Journal of Medical and Biological Research , 2003, DOI: 10.1590/S0100-879X2003000200006
Abstract: the aqueous fraction of the ethanolic extract (afl) of cissampelos sympodialis eichl (menispermaceae), popularly known as milona, has been shown to have both immunosuppressive and anti-inflammatory effects. in the present study we investigated the modulation of macrophage antimicrobicidal activity by in vitro treatment with the extract from c. sympodialis. normal and thioglycolate-elicited mouse peritoneal macrophages were infected in vitro with the protozoan trypanosoma cruzi dm28c clone. we observed that the afl (used at doses ranging from 13 to 100 μg/ml) increased t. cruzi growth and induced a 75% reduction in nitric oxide production. this inhibition could be mediated by the stimulation of macrophage interleukin-10 (il-10) secretion since the in vitro treatment with the afl stimulated il-10 production by t. cruzi-infected macrophages. these results suggest that the anti-inflammatory effect of the afl from c. sympodialis could be, at least in part, mediated by the inhibition of macrophage functions and that the inhibition of macrophage microbicidal activity induced by the c. sympodialis extract may be mediated by the decrease in macrophage function mediated by interleukin-10 production.
Sialic acid: a sweet swing between mammalian host and Trypanosoma cruzi
Leonardo Freire-de-Lima,Isadora A. Oliveira,Jorge L. Neves,Luciana L. Penha,Frederico Alisson-Silva,Wagner B. Dias,Adriane R. Todeschini
Frontiers in Immunology , 2012, DOI: 10.3389/fimmu.2012.00356
Abstract: Commonly found at the outermost ends of complex carbohydrates in extracellular medium or on outer cell membranes, sialic acids play important roles in a myriad of biological processes. Mammals synthesize sialic acid through a complex pathway, but Trypanosoma cruzi, the agent of Chagas’ disease, evolved to obtain sialic acid from its host through a trans-sialidase (TcTS) reaction. Studies of the parasite cell surface architecture and biochemistry indicate that a unique system comprising sialoglycoproteins and sialyl-binding proteins assists the parasite in several functions including parasite survival, infectivity, and host–cell recognition. Additionally, TcTS activity is capable of extensively remodeling host cell glycomolecules, playing a role as virulence factor. This review presents the state of the art of parasite sialobiology, highlighting how the interplay between host and parasite sialic acid helps the pathogen to evade host defense mechanisms and ensure lifetime host parasitism.
Design, Synthesis and Trypanocidal Evaluation of Novel 1,2,4-Triazoles-3-thiones Derived from Natural Piperine
Tatiany Nunes Franklim,Leonardo Freire-de-Lima,Julliana de Nazareth Sá Diniz,José Osvaldo Previato,Rosane Nora Castro,Lucia Mendon?a-Previato,Marco Edilson Freire de Lima
Molecules , 2013, DOI: 10.3390/molecules18066366
Abstract: The work reported herein describes the synthesis and the assessment of the trypanocidal activity of thirteen new 1,2,4-triazole-3-thiones obtained from natural piperine, the main constituent of the dry fruits of Piper nigrum. It is part of a research program aiming to use abundant and easily available natural products as starting materials for the design and synthesis of new molecules potentially useful as antiparasitic drugs. The variously substituted triazole derivatives were synthesized from the natural amide in four steps with the use of microwave irradiation on overall yields ranging from 32% to 51%. The cyclohexyl substituted derivative showed the best trypanocidal profile on proliferative forms of Trypanosoma cruzi (Y strain), with IC 50s = 18.3 and 8.87 mM against epimastigotes and amastigotes, respectively.
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