164 results on '"Freire-de-Lima, Leonardo"'
Search Results
2. Cellular stress and senescence induction during 'Trypanosoma cruzi' infection
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Guimaraes-Pinto, Kamila, Ferreira, Jesuino RM, da Costa, Andre LA, Morrot, Alexandre, Freire-de-Lima, Leonardo, Decote-Ricardo, Debora, Freire-de-Lima, Celio Geraldo, and Filardy, Alessandra A
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- 2022
3. Immune responses in leishmaniasis: An overview
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Costa-da-Silva, Ana Caroline, de Oliveira Nascimento, Danielle, Ferreira, Jesuino RM, Guimaraes-Pinto, Kamila, Freire-de-Lima, Leonardo, Morrot, Alexandre, Decote-Ricardo, Debora, Filardy, Alessandra Almeida, and Freire-de-Lima, Celio Geraldo
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- 2022
4. Non-self glycan structures as possible modulators of cancer progression: would polysaccharides from Cryptococcus spp. impact this phenomenon?
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Diniz-Lima, Israel, da Fonseca, Leonardo Marques, Dos Reis, Jhenifer Santos, Decote-Ricardo, Debora, Morrot, Alexandre, Previato, Jose Osvaldo, Previato, Lucia Mendonça, Freire-de-Lima, Celio Geraldo, and Freire-de-Lima, Leonardo
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- 2023
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5. Expression of O-glycosylated oncofetal fibronectin in alternatively activated human macrophages
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da Costa Santos, Marcos Andre Rodrigues, dos Reis, Jhenifer Santos, do Nascimento Santos, Carlos Antonio, da Costa, Kelli Monteiro, Barcelos, Pedro Marçal, de Oliveira Francisco, Karen Queiroz, Barbosa, Pedro Antônio Guimarães Notaroberto, da Silva, Emanuelle Damasceno Souza, Freire-de-Lima, Celio Geraldo, Morrot, Alexandre, Decote-Ricardo, Debora, Diniz-Lima, Israel, Previato, Jose Osvaldo, Mendonca-Previato, Lucia, da Fonseca, Leonardo Marques, and Freire-de-Lima, Leonardo
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- 2023
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6. Resistance to cisplatin in human lung adenocarcinoma cells: effects on the glycophenotype and epithelial to mesenchymal transition markers
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da Fonseca, Leonardo Marques, da Silva, Vanessa Amil, da Costa, Kelli Monteiro, dos Reis, Jhenifer Santos, Previato, José Osvaldo, Previato, Lucia Mendonça, and Freire-de-Lima, Leonardo
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- 2022
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7. Correction to: Expression of O-glycosylated oncofetal fibronectin in alternatively activated human macrophages
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da Costa Santos, Marcos Andre Rodrigues, dos Reis, Jhenifer Santos, do Nascimento Santos, Carlos Antonio, da Costa, Kelli Monteiro, Barcelos, Pedro Marçal, de Oliveira Francisco, Karen Queiroz, Barbosa, Pedro Antônio Guimarães Notaroberto, da Silva, Emanuelle Damasceno Souza, Freire-de-Lima, Celio Geraldo, Morrot, Alexandre, Decote-Ricardo, Debora, Diniz-Lima, Israel, Previato, Jose Osvaldo, Mendonca-Previato, Lucia, da Fonseca, Leonardo Marques, and Freire-de-Lima, Leonardo
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- 2023
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8. Inhibition of Microbicidal Activity of Canine Macrophages DH82 Cell Line by Capsular Polysaccharides from Cryptococcus neoformans.
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LaRocque-de-Freitas, Isabel F., da Silva-Junior, Elias Barbosa, Gemieski, Leticia Paixão, da Silva Dias Lima, Beatriz, Diniz-Lima, Israel, de Carvalho Vivarini, Aislan, Lopes, Ulisses G., Freire-de-Lima, Leonardo, Morrot, Alexandre, Previato, José Osvaldo, Mendonça-Previato, Lucia, Pinto-da-Silva, Lucia Helena, Freire-de-Lima, Celio G., and Decote-Ricardo, Debora
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CRYPTOCOCCUS neoformans ,POLYSACCHARIDES ,CELL lines ,MACROPHAGES ,CELL populations ,CENTRAL nervous system ,T cells - Abstract
Cryptococcus neoformans is a lethal fungus that primarily affects the respiratory system and the central nervous system. One of the main virulence factors is the capsule, constituted by the polysaccharides glucuronoxylomannan (GXM) and glucuronoxylomanogalactan (GXMGal). Polysaccharides are immunomodulators. One of the target cell populations for modulation are macrophages, which are part of the first line of defense and important for innate and adaptive immunity. It has been reported that macrophages can be modulated to act as a "Trojan horse," taking phagocytosed yeasts to strategic sites or having their machinery activation compromised. The scarcity of information on canine cryptococcosis led us to assess whether the purified capsular polysaccharides from C. neoformans would be able to modulate the microbicidal action of macrophages. In the present study, we observed that the capsular polysaccharides, GXM, GXMGal, or capsule total did not induce apoptosis in the DH82 macrophage cell line. However, it was possible to demonstrate that the phagocytic activity was decreased after treatment with polysaccharides. In addition, recovered yeasts from macrophages treated with polysaccharides after phagocytosis could be cultured, showing that their viability was not altered. The polysaccharides led to a reduction in ROS production and the mRNA expression of IL-12 and IL-6. We observed that GXMGal inhibits MHC class II expression and GXM reduces ERK phosphorylation. In contrast, GXMGal and GXM were able to increase the PPAR-γ expression. Furthermore, our data suggest that capsular polysaccharides can reduce the microbicidal activity of canine macrophages DH82. [ABSTRACT FROM AUTHOR]
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- 2024
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9. A Comparative Analysis of Innate Immune Responses and the Structural Characterization of Spike from SARS-CoV-2 Gamma Variants and Subvariants.
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Scovino, Aline Miranda, Dahab, Elizabeth Chen, Diniz-Lima, Israel, de Senna Silveira, Etiele, Barroso, Shana Priscila Coutinho, Cardoso, Karina Martins, Nico, Dirlei, Makhoul, Gustavo José, da Silva-Junior, Elias Barbosa, Freire-de-Lima, Celio Geraldo, Freire-de-Lima, Leonardo, Fonseca, Leonardo Marques da, Valente, Natalia, Nacife, Valeria, Machado, Ana, Araújo, Mia, Vieira, Gustavo Fioravanti, Pauvolid-Corrêa, Alex, Siqueira, Marilda, and Morrot, Alexandre
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SARS-CoV-2 ,IMMUNE response ,COVID-19 ,COMPARATIVE studies ,VIRAL replication ,NEUTROPHILS - Abstract
The SARS-CoV-2 P.1 variant, responsible for an outbreak in Manaus, Brazil, is distinguished by 12 amino acid differences in the S protein, potentially increasing its ACE-2 affinity and immune evasion capability. We investigated the innate immune response of this variant compared to the original B.1 strain, particularly concerning cytokine production. Blood samples from three severe COVID-19 patients were analyzed post-infection with both strains. Results showed no significant difference in cytokine production of mononuclear cells and neutrophils for either variant. While B.1 had higher cytopathogenicity, neither showed viral replication in mononuclear cells. Structural analyses of the S protein highlighted physicochemical variations, which might be linked to the differences in infectivity between the strains. Our studies point to the increased infectivity of P.1 could stem from altered immunogenicity and receptor-binding affinity. [ABSTRACT FROM AUTHOR]
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- 2024
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10. X-linked immunodeficient (XID) mice exhibit high susceptibility to Cryptococcus gattii infection
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Diniz-Lima, Israel, da Rosa, Pablo Rodrigo, da Silva-Junior, Elias Barbosa, Guimarães-de-Oliveira, Joyce Cristina, de Freitas, Elisangela Oliveira, de Oliveira Nascimento, Danielle, Morrot, Alexandre, Nimrichter, Leonardo, Previato, Jose Osvaldo, Mendonça-Previato, Lucia, Freire-de-Lima, Leonardo, Decote-Ricardo, Debora, and Freire-de-Lima, Celio Geraldo
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- 2021
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11. The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19)
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Arcanjo, Angélica, Logullo, Jorgete, Menezes, Camilla Cristie Barreto, de Souza Carvalho Giangiarulo, Thais Chrispim, dos Reis, Mirella Carneiro, de Castro, Gabriellen Menezes Migliani, da Silva Fontes, Yasmin, Todeschini, Adriane Regina, Freire-de-Lima, Leonardo, Decoté-Ricardo, Debora, Ferreira-Pereira, Antônio, Freire-de-Lima, Celio Geraldo, Barroso, Shana Priscila Coutinho, Takiya, Christina, Conceição-Silva, Fátima, Savino, Wilson, and Morrot, Alexandre
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- 2020
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12. Bittersweet Sugars: How Unusual Glycan Structures May Connect Epithelial-to-Mesenchymal Transition and Multidrug Resistance in Cancer.
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Fonseca, Leonardo Marques da, Diniz-Lima, Israel, da Costa Santos, Marcos André Rodrigues, Franklim, Tatiany Nunes, da Costa, Kelli Monteiro, Santos, Ariely Costa dos, Morrot, Alexandre, Decote-Ricardo, Debora, Valente, Raphael do Carmo, Freire-de-Lima, Celio Geraldo, dos Reis, Jhenifer Santos, and Freire-de-Lima, Leonardo
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GLYCAN structure ,MULTIDRUG resistance ,EPITHELIAL-mesenchymal transition ,CARBOHYDRATE metabolism ,SUGARS - Abstract
Cancer cells are characterized by metabolic reprogramming, which enables their survival in of-ten inhospitable conditions. A very well-documented example that has gained attraction in re-cent years and is already considered a hallmark of transformed cells is the reprogramming of carbohydrate metabolism. Such a feature, in association with the differential expression of en-zymes involved in the biosynthesis of glycoconjugates, generically known as glycosyltransfer-ases, contributes to the expression of structurally atypical glycans when compared to those ex-pressed in healthy tissues. The latest studies have demonstrated that glycophenotypic alterations are capable of modulating multifactorial events essential for the development and/or progres-sion of the disease. Herein, we will address the importance of glycobiology in modern medi-cine, focusing on the ability of unusual/truncated O-linked glycans to modulate two complex and essential phenomena for cancer progression: the acquisition of the multidrug resistance (MDR) phenotype and the activation of molecular pathways associated with the epithelial–mesenchymal transition (EMT) process, an event deeply linked with cancer metastasis. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Involvement of the capsular GalXM-induced IL-17 cytokine in the control of Cryptococcus neoformans infection
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LaRocque-de-Freitas, Isabel Ferreira, Rocha, Juliana Dutra B., Nunes, Marise Pinheiro, Oliveira, Priscila Angelica V., Nascimento, Danielle de Oliveira, Freire-de-Lima, Leonardo, Takiya, Christina Maeda, Morrot, Alexandre, Decote-Ricardo, Debora, Previato, Jose Osvaldo, DosReis, George A., Mendonça-Previato, Lucia, and Freire-de-Lima, Celio Geraldo
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- 2018
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14. ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression.
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da Costa, Kelli Monteiro, Freire-de-Lima, Leonardo, da Fonseca, Leonardo Marques, Previato, José Osvaldo, Mendonça-Previato, Lucia, and Valente, Raphael do Carmo
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P-glycoprotein , *EPITHELIAL-mesenchymal transition , *MULTIDRUG resistance , *CANCER invasiveness , *ATP-binding cassette transporters , *FIBRONECTINS - Abstract
Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which cells acquire a migratory phenotype, invading new tissues. ABC transporters' role during EMT is still elusive, though cells undergoing EMT exhibit enhanced ABCB1 expression. We demonstrated increased ABCB1 expression but no change in activity after TGF-β-induced EMT in A549 cells. Moreover, ABCB1 inhibition by verapamil increased snail and fibronectin expression, an event associated with upregulation of ABCB1, evidencing coincident cell signaling pathways leading to ABCB1 and EMT-related markers transcription, rather than a direct effect of transport. Additionally, for the first time, increased ABCC1 expression and activity was observed after EMT, and use of ABCC1 inhibitors partially inhibited EMT-marker snail, although increased ABCC1 function translated into collateral sensibility to daunorubicin. More investigations must be done to evaluate the real benefits that the gain of ABC transporters might have on the process of metastasis. Considering ABCC1 is involved in the stress response, affecting intracellular GSH content and drug detoxification, this transporter could be used as a therapeutic target in cancer cells undergoing EMT. [ABSTRACT FROM AUTHOR]
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- 2023
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15. Increased Trypanosoma cruzi Growth during Infection of Macrophages Cultured on Collagen I Matrix.
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Logullo, Jorgete, Diniz-Lima, Israel, Rocha, Juliana Dutra B., Cortê-Real, Suzana, Silva-Júnior, Elias Barbosa da, Guimarães-de-Oliveira, Joyce Cristina, Morrot, Alexandre, Fonseca, Leonardo Marques da, Freire-de-Lima, Leonardo, Decote-Ricardo, Debora, and Freire-de-Lima, Celio Geraldo
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TRYPANOSOMA cruzi ,MACROPHAGES ,CELL morphology ,ELECTRON microscope techniques ,EXTRACELLULAR matrix ,CELL culture - Abstract
The interactions between cell and cellular matrix confers plasticity to each body tissue, influencing the cellular migratory capacity. Macrophages rely on motility to promote their physiological function. These phagocytes are determinant for the control of invasive infections, and their immunological role largely depends on their ability to migrate and adhere to tissue. Therefore, they interact with the components of the extracellular matrix through their adhesion receptors, conferring morphological modifications that change their shape during migration. Nevertheless, the need to use in vitro cell growth models with the conditioning of three-dimensional synthetic matrices to mimic the dynamics of cell-matrix interaction has been increasingly studied. This becomes more important to effectively understand the changes occurring in phagocyte morphology in the context of infection progression, such as in Chagas disease. This disease is caused by the intracellular pathogen Trypanosoma cruzi, capable of infecting macrophages, determinant cells in the anti-trypanosomatid immunity. In the present study, we sought to understand how an in vitro extracellular matrix model interferes with T. cruzi infection in macrophages. Using different time intervals and parasite ratios, we evaluated the cell morphology and parasite replication rate in the presence of 3D collagen I matrix. Nevertheless, microscopy techniques such as scanning electron microscopy were crucial to trace macrophage-matrix interactions. In the present work, we demonstrated for the first time that the macrophage-matrix interaction favors T. cruzi in vitro replication and the release of anti-inflammatory cytokines during macrophage infection, in addition to drastically altering the morphology of the macrophages and promoting the formation of migratory macrophages. [ABSTRACT FROM AUTHOR]
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- 2023
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16. The Blessed Union of Glycobiology and Immunology: A Marriage That Worked.
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dos Reis, Jhenifer Santos, Diniz-Lima, Israel, Santos, Marcos André Rodrigues da Costa, Barcelos, Pedro Marçal, da Costa, Kelli Monteiro, Valente, Raphael do Carmo, Chaves, Lorrane de Souza, de Campos, Luma Petel, dos Santos, Ariely Costa, Correia de Lima, Rafaela Gomes, Decote-Ricardo, Debora, Morrot, Alexandre, Previato, Jose Osvaldo, Mendonça-Previato, Lucia, Freire-de-Lima, Celio Geraldo, Fonseca, Leonardo Marques da, and Freire-de-Lima, Leonardo
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CARCINOEMBRYONIC antigen ,TRANSMISSIBLE tumors ,GLYCOMICS ,GALECTINS ,GLYCOCONJUGATES - Abstract
In this article, we discuss the main aspects regarding the recognition of cell surface glycoconjugates and the immunomodulation of responses against the progression of certain pathologies, such as cancer and infectious diseases. In the first part, we talk about different aspects of glycoconjugates and delve deeper into the importance of N-glycans in cancer immunotherapy. Then, we describe two important lectin families that have been very well studied in the last 20 years. Examples include the sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), and galectins. Finally, we discuss a topic that needs to be better addressed in the field of glycoimmunology: the impact of oncofetal antigens on the cells of the immune system. New findings in this area are of great importance for advancement, especially in the field of oncology, since it is already known that cellular interactions mediated by carbohydrate–carbohydrate and/or carbohydrate proteins are able to modulate the progression of different types of cancer in events that compromise the functionality of the immune responses. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Humoral response in Leishmaniasis.
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Conde, Luciana, Maciel, Gabriela, Meira de Assis, Gustavo, Freire-de-Lima, Leonardo, Nico, Dirlei, Vale, André, Geraldo Freire-de-Lima, Célio, and Morrot, Alexandre
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HUMORAL immunity ,LEISHMANIASIS ,VISCERAL leishmaniasis ,B cells ,CUTANEOUS leishmaniasis - Abstract
Leishmaniasis presents different types of clinical manifestations that can be divided into cutaneous leishmaniasis and visceral leishmaniasis. The host's immune system, associated with genetic and nutritional factors, is strongly involved in the evolution of the disease or parasite escape. Humoral immunity is characterized by the production of antibodies capable of promoting neutralization, opsonization, and activation of the complement system. In this scenario, B lymphocytes produce antibodies that play an important role in Leishmania infection although neglected for a long time. Thus, relevant aspects in the establishment of Leishmania infection will be addressed, highlighting the importance of humoral immunity during the entire process of Leishmania infection. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process
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Freire-de-Lima, Leonardo, Gelfenbeyn, Kirill, Ding, Yao, Mandel, Ulla, Clausen, Henrik, Handa, Kazuko, and Hakomori, Sen-itiroh
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- 2011
19. Critically ill COVID-19 patients exhibit hyperactive cytokine responses associated with effector exhausted senescent T cells in acute infection
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Arcanjo, Angélica, Pinto, Kamila Guimarães, Logullo, Jorgete, Leite, Paulo Emílio Corrêa, Menezes, Camilla Cristie Barreto, Freire-de-Lima, Leonardo, Diniz-Lima, Israel, Decoté-Ricardo, Debora, Rodrigues-da-Silva, Rodrigo Nunes, Freire-de-Lima, Celio Geraldo, Filardy, Alessandra Almeida, Lima-Junior, Josué da Costa, Bertho, Alvaro Luiz, De Luca, Paula Mello, Granjeiro, José Mauro, Barroso, Shana Priscila Coutinho, Conceição-Silva, Fátima, Savino, Wilson, and Morrot, Alexandre
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Exhausted/senescent T cells ,AcademicSubjects/MED00290 ,CD28 Antigens ,SARS-CoV-2 ,Critical Illness ,Major Article ,SARS-CoV-2 coronavirus ,COVID-19 ,Cytokines ,Humans ,Immunopathology - Abstract
Coronavirus disease 2019 (COVID-19) can progress to severe pneumonia with respiratory failure and is aggravated by the deregulation of the immune system causing an excessive inflammation including the cytokine storm.In this study, we report that severe acutely infected patients have high levels of both type-1 and type-2 cytokines.Our results show abnormal cytokine levels upon T-cell stimulation, in a nonpolarized profile. Furthermore, our findings indicate that this hyperactive cytokine response is associated with a significantly increased frequency of late-differentiated T cells with particular phenotype of effector exhausted/senescent CD28-CD57+ cells. Of note, we demonstrated for the first time an increased frequency of CD3+CD4+CD28-CD57+ T cells with expression of programmed death 1, one of the hallmarks of T-cell exhaustion.These findings reveal that COVID-19 is associated with acute immunodeficiency, especially within the CD4+ T-cell compartment, and points to possible mechanisms of loss of clonal repertoire and susceptibility to viral relapse and reinfection events.
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- 2021
20. Pulmonary Fibrosis and Hypereosinophilia in TLR9 -/- Mice Infected by Cryptococcus gattii.
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da Silva-Junior, Elias Barbosa, Diniz-Lima, Israel, Silva, Amanda Couto, Guimarães-de-Oliveira, Joyce Cristina, Morrot, Alexandre, Freire-de-Lima, Leonardo, da Fonseca, Leonardo Marques, de Brito-Gitirana, Lycia, Decote-Ricardo, Debora, de Matos Guedes, Herbert Leonel, and Freire-de-Lima, Celio Geraldo
- Abstract
Cryptococcus gattii is a worldwide-distributed basidiomycetous yeast that can infect immunocompetent hosts. However, little is known about the mechanisms involved in the disease. The innate immune response is essential to the control of infections by microorganisms. Toll-like receptor 9 (TLR9) is an innate immune receptor, classically described as a non-methylated DNA recognizer and associated with bacteria, protozoa and opportunistic mycosis infection models. Previously, our group showed that TLR9
-/- mice were more susceptible to C. gattii after 21 days of infection. However, some questions about the innate immunity involving TLR9 response against C. gattii remain unknown. In order to investigate the systemic cryptococcal infection, we evaluated C57BL/6 mice and C57BL/6 TLR9-/- after intratracheal infection with 104 C. gattii yeasts for 21 days. Our data evidenced that TLR9-/- was more susceptible to C. gattii. TLR9-/- mice had hypereosinophilia in pulmonary mixed cellular infiltrate, severe bronchiolitis and vasculitis and type 2 alveolar cell hyperplasia. In addition, TLR9-/- mice developed severe pulmonary fibrosis and areas with strongly birefringent fibers. Together, our results corroborate the hypothesis that TLR9 is important to support the Th1/Th17 response against C. gattii infection in the murine experimental model. [ABSTRACT FROM AUTHOR]- Published
- 2022
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21. The History of the ABC Proteins in Human Trypanosomiasis Pathogens.
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da Costa, Kelli Monteiro, Valente, Raphael do Carmo, Fonseca, Leonardo Marques da, Freire-de-Lima, Leonardo, Previato, Jose Osvaldo, and Mendonça-Previato, Lucia
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Human trypanosomiasis affects nearly eight million people worldwide, causing great economic and social impact, mainly in endemic areas. T. cruzi and T. brucei are protozoan parasites that present efficient mechanisms of immune system evasion, leading to disease chronification. Currently, there is no vaccine, and chemotherapy is effective only in the absence of severe clinical manifestations. Nevertheless, resistant phenotypes to chemotherapy have been described in protozoan parasites, associated with cross-resistance to other chemically unrelated drugs. Multidrug resistance is multifactorial, involving: (i) drug entry, (ii) activation, (iii) metabolism and (iv) efflux pathways. In this context, ABC transporters, initially discovered in resistant tumor cells, have drawn attention in protozoan parasites, owing to their ability to decrease drug accumulation, thus mitigating their toxic effects. The discovery of these transporters in the Trypanosomatidae family started in the 1990s; however, few members were described and functionally characterized. This review contains a brief history of the main ABC transporters involved in resistance that propelled their investigation in Trypanosoma species, the main efflux modulators, as well as ABC genes described in T. cruzi and T. brucei according to the nomenclature HUGO. We hope to convey the importance that ABC transporters play in parasite physiology and chemotherapy resistance. [ABSTRACT FROM AUTHOR]
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- 2022
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22. Control of cell motility by interaction of gangliosides, tetraspanins, and epidermal growth factor receptor in A431 versus KB epidermoid tumor cells
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Park, Seung-Yeol, Yoon, Seon-Joo, Freire-de-Lima, Leonardo, Kim, Jung-Hoe, and Hakomori, Sen-itiroh
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- 2009
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23. Special Issue: "Parasitic Infection and Host Immunity": Editorial.
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Decote-Ricardo, Debora, de Oliveira Nascimento, Danielle, Freire-de-Lima, Leonardo, Morrot, Alexandre, and Freire-de-Lima, Celio Geraldo
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PARASITIC diseases ,MULTIDRUG resistance-associated proteins ,IMMUNITY ,MONONUCLEAR leukocytes - Abstract
The number of studies on naturally acquired immune-response-induced VIR proteins in field populations from vivax malaria-endemic areas has been limited. The similar I vir i multigene from I P. vivax i has been studied as an important superfamily gene that takes part in the pathogenesis of vivax malaria besides triggering the host immune activation [[13]]. Parasite-host interactions depend on a complex interplay between the metabolism of the parasite, their antigens, and the host immune response system [[1]]. One of the key characteristics of I Schistossoma mansoni i infection is the eosinophilia accompanied by the granuloma formation, resulting from the migration of inflammatory cells to the site of infection during the control of infection [[18]]. [Extracted from the article]
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- 2023
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24. SARS-CoV-2's Variants of Concern: A Brief Characterization.
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Scovino, Aline Miranda, Chen Dahab, Elizabeth, Vieira, Gustavo Fioravanti, Freire-de-Lima, Leonardo, Freire-de-Lima, Celio Geraldo, and Morrot, Alexandre
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SARS-CoV-2 ,ANGIOTENSIN I ,SARS-CoV-2 Delta variant ,SARS-CoV-2 Omicron variant ,CELL receptors - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disclose the variants of concern (VOC) including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P1), Delta (B.1.617.2), and Omicron (B.1.1.529). Its spike protein (S) present on the surface of the virus is recognized by the host cell receptor, the angiotensin-2 converting enzyme (ACE2) which promotes their entry into the cell. The mutations presented by VOCs are found in RBD and the N-terminal region of S protein. Therefore, mutations occurring in RBD can modify the biological and immunogenic characteristics of the virus, such as modifying the spike affinity for ACE2, increasing the virus transmissibility, or conferring the ability to escape the immune responses. The raise of a potential new SARS-CoV-2 variant capable of evading the host defenses at the same time maintaining its fitness justifies the importance of continued genetic monitoring of the pandemic coronavirus. [ABSTRACT FROM AUTHOR]
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- 2022
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25. Cryptococcus : History, Epidemiology and Immune Evasion.
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Diniz-Lima, Israel, Fonseca, Leonardo Marques da, Silva-Junior, Elias Barbosa da, Guimarães-de-Oliveira, Joyce Cristina, Freire-de-Lima, Leonardo, Nascimento, Danielle Oliveira, Morrot, Alexandre, Previato, Jose Osvaldo, Mendonça-Previato, Lucia, Decote-Ricardo, Debora, and Freire-de-Lima, Celio Geraldo
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CRYPTOCOCCUS ,CRYPTOCOCCUS neoformans ,PATHOGENIC fungi ,INFECTION ,EPIDEMIOLOGY ,FRAGILE X syndrome ,OPPORTUNISTIC infections - Abstract
Cryptococcosis is a disease caused by the pathogenic fungi Cryptococcus neoformans and Cryptococcus gattii, both environmental fungi that cause severe pneumonia and may even lead to cryptococcal meningoencephalitis. Although C. neoformans affects more fragile individuals, such as immunocompromised hosts through opportunistic infections, C. gattii causes a serious indiscriminate primary infection in immunocompetent individuals. Typically seen in tropical and subtropical environments, C. gattii has increased its endemic area over recent years, largely due to climatic factors that favor contagion in warmer climates. It is important to point out that not only C. gattii, but the Cryptococcus species complex produces a polysaccharidic capsule with immunomodulatory properties, enabling the pathogenic species of Cryptococccus to subvert the host immune response during the establishment of cryptococcosis, facilitating its dissemination in the infected organism. C. gattii causes a more severe and difficult-to-treat infection, with few antifungals eliciting an effective response during chronic treatment. Much of the immunopathology of this cryptococcosis is still poorly understood, with most studies focusing on cryptococcosis caused by the species C. neoformans. C. gattii became more important in the epidemiological scenario with the outbreaks in the Pacific Northwest of the United States, which resulted in phylogenetic studies of the virulent variant responsible for the severe infection in the region. Since then, the study of cryptococcosis caused by C. gattii has helped researchers understand the immunopathological aspects of different variants of this pathogen. [ABSTRACT FROM AUTHOR]
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- 2022
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26. The Sweet Side of Fungal Infections: Structural Glycan Diversity and Its Importance for Pathogenic Adaptation.
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Diniz-Lima, Israel, Marques da Fonseca, Leonardo, Santos dos Reis, Jhenifer, Rodrigues da Costa Santos, Marcos André, Monteiro da Costa, Kelli, do Nascimento Santos, Carlos Antonio, Marçal Barcelos, Pedro, Guimarães-Pinto, Kamila, Almeida Filardy, Alessandra, Edilson Freire-de-Lima, Marco, Decote-Ricardo, Debora, Morrot, Alexandre, Geraldo Freire-de-Lima, Celio, and Freire-de-Lima, Leonardo
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MYCOSES ,IMMUNE system ,CRYPTOCOCCUS ,PATHOGENIC fungi ,EPIDEMIOLOGY - Abstract
Fungal infections are the most common secondary infections in debilitated individuals in a state of chronic disease or immunosuppression. Despite this, most fungal infections are neglected, mainly due to the lower frequency of their more severe clinical forms in immunocompetent individuals with a healthy background. However, over the past few years, several cases of severe fungal infections in healthy individuals have provoked a change in the epidemiological dynamics of fungal infections around the world, both due to recurrent outbreaks in previously infrequent regions and the greater emergence of more pathogenic fungal variants affecting healthy individuals, such as in the Cryptococcus genus. Therefore, before the arrival of a scenario of prevalent severe fungal infections, it is necessary to assess more carefully what are the real reasons for the increased incidence of fungal infection globally. What are the factors that are currently contributing to this new possible epidemiological dynamic? Could these be of a structural nature? Herein, we propose a discussion based on the importance of the virulence factors of glycoconjugate composition in the adaptation of pathogenic fungal species into the current scenario of increasing severity of these infections. [ABSTRACT FROM AUTHOR]
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- 2022
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27. Glycobiology of Cancer: Sugar Drives the Show.
- Author
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Santos dos Reis, Jhenifer, Rodrigues da Costa Santos, Marcos André, Pereira Mendonça, Daniella, Martins do Nascimento, Stefani Ingrid, Marçal Barcelos, Pedro, Correia de Lima, Rafaela Gomes, Monteiro da Costa, Kelli, Geraldo Freire-de-Lima, Celio, Morrot, Alexandre, Osvaldo Previato, Jose, Mendonça Previato, Lucia, Marques da Fonseca, Leonardo, and Freire-de-Lima, Leonardo
- Subjects
GLYCOMICS ,CANCER treatment ,GLYCOSYLATION ,GLYCOSYLTRANSFERASES ,IMMUNE response - Abstract
Cancer development and progression is associated with aberrant changes in cellular glycosylation. Cells expressing altered glycan-structures are recognized by cells of the immune system, favoring the induction of inhibitory immune processes which subsequently promote tumor growth and spreading. Here, we discuss about the importance of glycobiology in modern medicine, taking into account the impact of altered glycan structures expressed in cancer cells as potential glycobiomarkers of disease, as well as on cancer development and progression. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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28. The toxic effects of piperine against Trypanosoma cruzi: ultrastructural alterations and reversible blockage of cytokinesis in epimastigote forms
- Author
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Freire-de-Lima, Leonardo, Ribeiro, Tatiana Santana, Rocha, Gustavo Miranda, Brandão, Bruno Alves, Romeiro, Alexandre, Mendonça-Previato, Lucia, Previato, José Osvaldo, de Lima, Marco Edilson Freire, de Carvalho, Técia Maria Ulisses, and Heise, Norton
- Published
- 2008
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29. Critically Ill Coronavirus Disease 2019 Patients Exhibit Hyperactive Cytokine Responses Associated With Effector Exhausted Senescent T Cells in Acute Infection.
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Arcanjo, Angélica, Pinto, Kamila Guimarães, Logullo, Jorgete, Leite, Paulo Emílio Corrêa, Menezes, Camilla Cristie Barreto, Freire-de-Lima, Leonardo, Diniz-Lima, Israel, Decoté-Ricardo, Debora, Rodrigues-da-Silva, Rodrigo Nunes, Freire-de-Lima, Celio Geraldo, Filardy, Alessandra Almeida, Lima-Junior, Josué da Costa, Bertho, Alvaro Luiz, Luca, Paula Mello De, Granjeiro, José Mauro, Barroso, Shana Priscila Coutinho, Conceição-Silva, Fátima, Savino, Wilson, Morrot, Alexandre, and De Luca, Paula Mello
- Subjects
COVID-19 ,T cells ,CYTOKINES ,CRITICALLY ill ,CYTOKINE release syndrome - Abstract
Background: Coronavirus disease 2019 (COVID-19) can progress to severe pneumonia with respiratory failure and is aggravated by the deregulation of the immune system causing an excessive inflammation including the cytokine storm.Methods: In this study, we report that severe acutely infected patients have high levels of both type-1 and type-2 cytokines.Results: Our results show abnormal cytokine levels upon T-cell stimulation, in a nonpolarized profile. Furthermore, our findings indicate that this hyperactive cytokine response is associated with a significantly increased frequency of late-differentiated T cells with particular phenotype of effector exhausted/senescent CD28-CD57+ cells. Of note, we demonstrated for the first time an increased frequency of CD3+CD4+CD28-CD57+ T cells with expression of programmed death 1, one of the hallmarks of T-cell exhaustion.Conclusions: These findings reveal that COVID-19 is associated with acute immunodeficiency, especially within the CD4+ T-cell compartment, and points to possible mechanisms of loss of clonal repertoire and susceptibility to viral relapse and reinfection events. [ABSTRACT FROM AUTHOR]- Published
- 2021
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30. A new class of mechanism-based inhibitors for Trypanosoma cruzi trans-sialidase and their influence on parasite virulence
- Author
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Carvalho, Sebastião T, Sola-Penna, Mauro, Oliveira, Isadora A, Pita, Samuel, Gonçalves, Arlan S, Neves, Bianca C, Sousa, Francisco R, Freire-de-Lima, Leonardo, Kurogochi, Masaki, Hinou, Hiroshi, Nishimura, Shin-Ichiro, Mendonça-Previato, Lucia, Previato, Jose O, and Todeschini, Adriane R
- Published
- 2010
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31. Trypanosoma cruzi trans -Sialidase as a Potential Vaccine Target Against Chagas Disease.
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da Costa, Kelli Monteiro, Marques da Fonseca, Leonardo, dos Reis, Jhenifer Santos, Santos, Marcos André Rodrigues da Costa, Previato, José Osvaldo, Mendonça-Previato, Lucia, and Freire-de-Lima, Leonardo
- Subjects
TRYPANOSOMA cruzi ,NEURAMINIDASE ,CHAGAS' disease ,PHYSICIANS ,DIAGNOSIS ,VACCINES ,THERAPEUTICS - Abstract
Chagas' disease is caused by the protozoan Trypanosoma cruzi , described in the early 20
th century by the Brazilian physician Dr. Carlos Chagas. There was a great amount of research devoted to diagnosis, treatment and prevention of the disease. One of the most important discoveries made since then, impacting the understanding of how the parasite interacts with the host's immune system, was the description of trans -sialidase. It is an unique enzyme, capable of masking the parasite's presence from the host, while at the same time dampening the activation of CD8+ T cells, the most important components of the immune response. Since the description of Chagas' disease in 1909, extensive research has identified important events in the disease in order to understand the biochemical mechanism that modulates T. cruzi -host cell interactions and the ability of the parasite to ensure its survival. The importance of the trans -sialidase enzyme brought life to many studies for the design of diagnostic tests, drugs and vaccines. While many groups have been prolific, such efforts have encountered problems, among them: the fact that while T. cruzi have many genes that are unique to the parasite, it relies on multiple copies of them and the difficulty in providing epitopes that result in effective and robust immune responses. In this review, we aim to convey the importance of trans -sialidase as well as to provide a history, including the initial failures and the most promising successes in the chasing of a working vaccine for a disease that is endemic in many tropical countries, including Brazil. [ABSTRACT FROM AUTHOR]- Published
- 2021
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32. Resistance to paclitaxel induces glycophenotype changes and mesenchymal-to-epithelial transition activation in the human prostate cancer cell line PC-3.
- Author
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da Fonseca, Leonardo Marques, Calvalhan, Danilo Macedo, Previato, Jose Osvaldo, Mendonça Previato, Lucia, and Freire-de-Lima, Leonardo
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PACLITAXEL ,EPITHELIAL-mesenchymal transition ,CANCER cells ,CELL lines ,MULTIDRUG resistance ,HUMAN phenotype ,PROSTATE cancer - Abstract
The development of the multidrug resistance phenotype is one of the major challenges faced in the treatment of cancer. The multidrug resistance phenotype is characterized by cross-resistance to drugs with different chemical structures and mechanisms of action. In this work, we hypothesized that the acquisition of resistance in cancer is accompanied by activation of the epithelial-to-mesenchymal transition process, where the tumor cell acquires a more mobile and invasive phenotype; a fundamental step in tumor progression and in promoting the invasion of other organs and tissues. In addition, it is known that atypical glycosylations are characteristic of tumor cells, being used as biomarkers. We believe that the acquisition of the multidrug resistance phenotype and the activation of epithelial-to-mesenchymal transition provoke alterations in the cell glycophenotype, which can be used as glycomarkers for chemoresistance and epithelial-to-mesenchymal transition processes. Herein, we induced the multidrug resistance phenotype in the PC-3 human prostate adenocarcinoma line through the continuous treatment with the drug paclitaxel. Our results showed that the induced cell multidrug resistance phenotype (1) acquired a mixed profile between epithelial and mesenchymal phenotypes and (2) modified the glycophenotype, showing an increase in the level of sialylation and in the number of branched glycans. Both mechanisms are described as indicators of poor prognosis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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33. Editorial: Drug-resistance in cancer cells: A new wine in an old bottle.
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da Fonseca, Leonardo Marques, Takeo Tatsuta, Seung-Yeol Park, and Freire-de-Lima, Leonardo
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CANCER cells ,WINE bottles ,CELLULAR signal transduction ,DRUG resistance in cancer cells - Published
- 2023
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34. Targeting the Hexosamine Biosynthetic Pathway Prevents Plasmodium Developmental Cycle and Disease Pathology in Vertebrate Host.
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Gomes, Pollyanna Stephanie, Tanghe, Scott, Gallego-Delgado, Julio, Conde, Luciana, Freire-de-Lima, Leonardo, Lima, Ana Carolina, Freire-de-Lima, Célio Geraldo, Lima Junior, Josué da Costa, Moreira, Otacílio, Totino, Paulo, Rodriguez, Ana, Todeschini, Adriane Regina, and Morrot, Alexandre
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CEREBRAL malaria ,PATHOLOGY ,PLASMODIUM falciparum ,HEXOSAMINES ,VERTEBRATES ,GLYCOCONJUGATES - Abstract
Cerebral malaria (CM) is a clinical syndrome involving irreversible and lethal signs of brain injury associated to infection by parasites of the genus Plasmodium. The pathogenesis of CM derives from infection-induced proinflammatory cytokines associated with cytoadherence of parasitized red blood cells to brain microvasculature. Glycoconjugates are very abundant in the surface of Plasmodium spp., and are critical mediators of parasite virulence in host–pathogen interactions. Herein, we show that 6-Diazo-5-oxo-L-norleucine (DON) therapeutically used for blocking hexosamine biosynthetic pathway leads to recovery in experimental murine cerebral malaria. DON-induced protection was associated with decreased parasitism, which severely reduced Plasmodium transmission to mosquitoes. These findings point to a potential use of DON in combination therapies against malaria. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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35. Theft and Reception of Host Cell's Sialic Acid: Dynamics of Trypanosoma Cruzi Trans -sialidases and Mucin-Like Molecules on Chagas' Disease Immunomodulation.
- Author
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Fonseca, Leonardo Marques da, da Costa, Kelli Monteiro, Chaves, Victoria de Sousa, Freire-de-Lima, Célio Geraldo, Morrot, Alexandre, Mendonça-Previato, Lucia, Previato, Jose Osvaldo, and Freire-de-Lima, Leonardo
- Subjects
SIALIC acids ,TRYPANOSOMA ,MUCIN analysis ,CHAGAS' disease ,IMMUNOREGULATION - Abstract
The last decades have produced a plethora of evidence on the role of glycans, from cell adhesion to signaling pathways. Much of that information pertains to their role on the immune system and their importance on the surface of many human pathogens. A clear example of this is the flagellated protozoan Trypanosoma cruzi , which displays on its surface a great variety of glycoconjugates, including O -glycosylated mucin-like glycoproteins, as well as multiple glycan-binding proteins belonging to the trans -sialidase (TS) family. Among the latter, different and concurrently expressed molecules may present or not TS activity, and are accordingly known as active (aTS) and inactive (iTS) members. Over the last thirty years, it has been well described that T. cruzi is unable to synthesize sialic acid (SIA) on its own, making use of aTS to steal the host's SIA. Although iTS did not show enzymatic activity, it retains a substrate specificity similar to aTS (α-2,3 SIA-containing glycotopes), displaying lectinic properties. It is accepted that aTS members act as virulence factors in mammals coursing the acute phase of the T. cruzi infection. However, recent findings have demonstrated that iTS may also play a pathogenic role during T. cruzi infection, since it modulates events related to adhesion and invasion of the parasite into the host cells. Since both aTS and iTS proteins share structural substrate specificity, it might be plausible to speculate that iTS proteins are able to assuage and/or attenuate biological phenomena depending on the catalytic activity displayed by aTS members. Since SIA-containing glycotopes modulate the host immune system, it should not come as any surprise that changes in the sialylation of parasite's mucin-like molecules, as well as host cell glycoconjugates might disrupt critical physiological events, such as the building of effective immune responses. This review aims to discuss the importance of mucin-like glycoproteins and both aTS and iTS for T. cruzi biology, as well as to present a snapshot of how disturbances in both parasite and host cell sialoglycophenotypes may facilitate the persistence of T. cruzi in the infected mammalian host. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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- View/download PDF
36. NH36 and F3 Antigen-Primed Dendritic Cells Show Preserved Migrating Capabilities and CCR7 Expression and F3 Is Effective in Immunotherapy of Visceral Leishmaniasis.
- Author
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Nico, Dirlei, Martins Almeida, Fernanda, Maria Motta, Juliana, Soares dos Santos Cardoso, Fellipe, Freire-de-Lima, Celio Geraldo, Freire-de-Lima, Leonardo, de Luca, Paula Melo, Maria Blanco Martinez, Ana, Morrot, Alexandre, and Palatnik-de-Sousa, Clarisa Beatriz
- Subjects
DENDRITIC cells ,IMMUNOTHERAPY ,VISCERAL leishmaniasis ,THERAPEUTICS - Abstract
Physical contact between dendritic cells (DCs) and T cell lymphocytes is necessary to trigger the immune cell response. CCL19 and CCL21 chemokines bind to the CCR7 receptor of mature DCs, and of T cells and regulate DCs migration to the white pulp (wp) of the spleen, where they encounter lymphocytes. In visceral leishmaniasis (VL), cellular immunosuppression is mediated by impaired DC migration due to the decreased chemokine secretion by endothelium and to the reduced DCs CCR7 expression. The Leishmania (L.) donovani nucleoside hydrolase NH36 and its C-terminal domain, the F3 peptide are prominent antigens in the generation of preventive immunity to VL. We assessed whether these vaccines could prevent the migrating defect of DCs by restoring the expression of CCR7 receptors. C57Bl6 mice were vaccinated with NH36 and F3 and challenged with L. (L.) infantum chagasi. The F3 vaccine induced a 100% of survival and a long-lasting immune protection with an earlier CD4
+ Th1 response, with secretion of higher IFN-γ and TNF-α/IL-10 ratios, and higher frequencies of CD4+ T cells secreting IL-2+ , TNF-α+ , or IFN-γ+ , or a combination of two or the three cytokines (IL-2+ TNF-α+ IFN-γ+ ). The CD8+ T cell response was promoted earlier by the NH36-vaccine, and later by the F3-vaccine. Maximal number of F3-primed DCs migrated in vitro in response to CCL19 and showed a high expression of CCR7 receptors (26.06%). Anti-CCR7 antibody treatment inhibited DCs migration in vitro (90%) and increased parasite load in vivo. When transferred into 28-day-infected mice, only 8% of DCs from infected, 59% of DCs from NH36-vaccinated, and 84% of DCs from F3-vaccinated mice migrated to the wp. Consequently, immunotherapy of infected mice with F3-primed DCs only, promoted increases in corporal weight and reductions of spleen and liver parasite loads and relative weights. Our findings indicate that vaccination with F3-vaccine preserves the maturation, migration properties and CCR7 expression of DCs, which are essential processes for the generation of cell-mediated immunity. The F3 vaccine is more potent in reversing the migration defect that occurs in VL and, therefore, more efficient in immunotherapy of VL. [ABSTRACT FROM AUTHOR]- Published
- 2018
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- View/download PDF
37. Antibody Repertoires Identify β-Tubulin as a Host Protective Parasite Antigen in Mice Infected With Trypanosoma cruzi.
- Author
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Montalvão, Fabricio, Nascimento, Danielle Oliveira, Nunes, Marise P., Koeller, Carolina M., Morrot, Alexandre, Lery, Leticia Miranda S., Bisch, Paulo M., Teixeira, Santuza M. R., Vasconcellos, Rita, Freire-de-Lima, Leonardo, Lopes, Marcela F., Heise, Norton, DosReis, George A., and Freire-de-Lima, Célio Geraldo
- Subjects
TUBULINS ,TRYPANOSOMA cruzi ,LYMPHOCYTE transformation - Abstract
Few studies investigate the major protein antigens targeted by the antibody diversity of infected mice with Trypanosoma cruzi. To detect global IgG antibody specificities, sera from infected mice were immunoblotted against whole T. cruzi extracts. By proteomic analysis, we were able to identify the most immunogenic T. cruzi proteins. We identified three major antigens as pyruvate phosphate dikinase, Hsp-85, and β-tubulin. The major protein band recognized by host IgG was T. cruzi β-tubulin. The T. cruzi β-tubulin gene was cloned, expressed in E. coli, and recombinant T. cruzi β-tubulin was obtained. Infection increased IgG reactivity against recombinant T. cruzi β-tubulin. A single immunization of mice with recombinant T. cruzi β-tubulin increased specific IgG reactivity and induced protection against T. cruzi infection. These results indicate that repertoire analysis is a valid approach to identify antigens for vaccines against Chagas disease. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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- View/download PDF
38. Metabolic Symbiosis and Immunomodulation: How Tumor Cell-Derived Lactate May Disturb Innate and Adaptive Immune Responses.
- Author
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Morrot, Alexandre, Fonseca, Leonardo Marques da, Salustiano, Eduardo J., Gentile, Luciana Boffoni, Conde, Luciana, Filardy, Alessandra Almeida, Franklim, Tatiany Nunes, da Costa, Kelli Monteiro, Freire-de-Lima, Celio Geraldo, and Freire-de-Lima, Leonardo
- Subjects
IMMUNOREGULATION ,CANCER cells ,TUMOR microenvironment - Abstract
The tumor microenvironment (TME) is composed by cellular and non-cellular components. Examples include the following: (i) bone marrow-derived inflammatory cells, (ii) fibroblasts, (iii) blood vessels, (iv) immune cells, and (v) extracellular matrix components. In most cases, this combination of components may result in an inhospitable environment, in which a significant retrenchment in nutrients and oxygen considerably disturbs cell metabolism. Cancer cells are characterized by an enhanced uptake and utilization of glucose, a phenomenon described by Otto Warburg over 90 years ago. One of the main products of this reprogrammed cell metabolism is lactate. "Lactagenic" or lactate-producing cancer cells are characterized by their immunomodulatory properties, since lactate, the end product of the aerobic glycolysis, besides acting as an inducer of cellular signaling phenomena to influence cellular fate, might also play a role as an immunosuppressive metabolite. Over the last 10 years, it has been well accepted that in the TME, the lactate secreted by transformed cells is able to compromise the function and/or assembly of an effective immune response against tumors. Herein, we will discuss recent advances regarding the deleterious effect of high concentrations of lactate on the tumor-infiltrating immune cells, which might characterize an innovative way of understanding the tumor-immune privilege. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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- View/download PDF
39. Circulating Plasma MicroRNA-208a as Potential Biomarker of Chronic Indeterminate Phase of Chagas Disease.
- Author
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Linhares-Lacerda, Leandra, Granato, Alessandra, Gomes-Neto, João Francisco, Conde, Luciana, Freire-de-Lima, Leonardo, de Freitas, Elisangela O., Freire-de-Lima, Celio G., Coutinho Barroso, Shana P., Jorge de Alcântara Guerra, Rodrigo, Pedrosa, Roberto C., Savino, Wilson, and Morrot, Alexandre
- Subjects
DIAGNOSIS of Chagas' disease ,MICRORNA ,BIOLOGICAL tags ,CARDIOMYOPATHIES ,ARRHYTHMIA ,BLOOD plasma - Abstract
Chagas cardiomyopathy is the most severe clinical manifestation of chronic Chagas disease. The disease affects most of the Latin American countries, being considered one of the leading causes of morbidity and death in the continent. The pathogenesis of Chagas cardiomyopathy is very complex, withmechanisms involving parasite-dependent cytopathy, immune-mediated myocardial damage and neurogenic disturbances. These pathological changes eventually result in cardiac myocyte hypertrophy, arrhythmias, congestive heart failure and stroke during chronic infection phase. Herein, we show that miR-208a, a microRNA that is a key factor in promoting cardiovascular dysfunction during cardiac hypertrophy processes of heart failure, has its circulating levels increased during chronic indeterminate phase when compared to cardiac (CARD) clinical forms in patients with Chagas disease. In contrast, we have not found altered serum levels of miR-34a, a microRNA known to promote pro-apoptotic role in myocardial infarction during degenerative process of cardiac injuries thus indicating intrinsic differences in the nature of the mechanisms underlying the heart failure triggered by Trypanosoma cruzi infection. Our findings support that the chronic indeterminate phase is a progressive phase involved in the genesis of chagasic cardiopathy and point out the use of plasma levels of miR-208a as candidate biomarker in risk-prediction score for the clinical prognosis of Chagas disease. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
40. Functional Characterization of ABCC Proteins from Trypanosoma cruzi and Their Involvement with Thiol Transport.
- Author
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da Costa, Kelli Monteiro, Valente, Raphael C., Salustiano, Eduardo J., Gentile, Luciana B., Freire-de-Lima, Leonardo, Mendonça-Previato, Lucia, and Previato, José O.
- Subjects
ATP-binding cassette transporters ,TRYPANOSOMA cruzi ,THIOLS - Abstract
Chagas disease is a neglected disease caused by the protozoan Trypanosoma cruzi and affects 8 million people worldwide. The main chemotherapy is based on benznidazole. The efficacy in the treatment depends on factors such as the parasite strain, which may present different sensitivity to treatment. In this context, the expression of ABC transporters has been related to chemotherapy failure. ABC transporters share a well-conserved ABC domain, responsible for ATP binding and hydrolysis, whose the energy released is coupled to transport of molecules through membranes. The most known ABC transporters are ABCB1 and ABCC1, involved in the multidrug resistance phenotype in cancer, given their participation in cellular detoxification. In T. cruzi, 27 ABC genes were identified in the genome. Nonetheless, only four ABC genes were characterized: ABCA3, involved in vesicular trafficking; ABCG1, overexpressed in strains naturally resistant to benznidazole, and P-glycoprotein 1 and 2, whose participation in drug resistance is controversial. Considering P-glycoprotein genes are related to ABCC subfamily in T. cruzi according to the demonstration using BLASTP alignment, we evaluated both ABCB1-like and ABCC-like activities in epimastigote and trypomastigote forms of the Y strain. The transport activities were evaluated by the efflux of the fluorescent dyes Rhodamine 123 and Carboxyfluorescein in a flow cytometer. Results indicated that there was no ABCB1-like activity in both T. cruzi forms. Conversely, results demonstrated ABCC-like activity in both epimastigote and trypomastigote forms of T. cruzi. This activity was inhibited by ABCC transport modulators (probenecid, indomethacin, and MK-571), by ATP-depleting agents (sodium azide and iodoacetic acid) and by the thiol-depleting agent N-ethylmaleimide. Additionally, the presence of ABCC-like activity was supported by direct inhibition of the thiol-conjugated compound efflux with indomethacin, characteristic of ABCC subfamilymembers. Taken together, the results provide the first description of native ABCC-like activity in T. cruzi epimastigote and trypomastigote forms, indicating that the study of the biological role for that thiol transporter is crucial to reveal new molecular mechanisms for therapeutic approaches in the Chagas disease. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
41. Induction of epithelial-mesenchymal transition with O-glycosylated oncofetal fibronectin
- Author
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Ding, Yao, Gelfenbeyn, Kirill, Freire-de-Lima, Leonardo, Handa, Kazuko, and Hakomori, Sen-itiroh
- Published
- 2012
- Full Text
- View/download PDF
42. Role of Inactive and Active Trypanosoma cruzi Trans-sialidases on T Cell Homing and Secretion of Inflammatory Cytokines.
- Author
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Freire-de-Lima, Leonardo, Gentile, Luciana B., da Fonseca, Leonardo M., da Costa, Kelli M., Lemos, Jessica Santos, Jacques, Lucas Rodrigues, Morrot, Alexandre, Freire-de-Lima, Célio G., Nunes, Marise P., Takiya, Christina M., Previato, Jose O., and Mendonça-Previato, Lucia
- Subjects
TRYPANOSOMA cruzi ,NEURAMINIDASE ,CYTOKINES - Abstract
Trans-sialidase from Trypanosoma cruzi (Tc-TS) belongs to a superfamily of proteins that may have enzymatic activity. While enzymatically active members (Tc-aTS) are able to transfer sialic acid from the host cell sialyl-glycoconjugates onto the parasite or to other molecules on the host cell surface, the inactive members (Tc-iTS) are characterized by their lectinic properties. Over the last 10 years, several papers demonstrated that, individually, Tc-aTS or Tc-iTS is able to modulate several biological events. Since the genes encoding Tc-iTS and Tc-aTS are present in the same copy number, and both proteins portray similar substrate-specificities as well, it would be plausible to speculate that such molecules may compete for the same sialyl-glycan structures and govern numerous immunobiological phenomena. However, their combined effect has never been evaluated in the course of an acute infection. In this study, we investigated the ability of both proteins to modulate the production of inflammatory signals, as well as the homing of T cells to the cardiac tissue of infected mice, events that usually occur during the acute phase of T. cruzi infection. The results showed that the intravenous administration of Tc-iTS, but not Tc-aTS protected the cardiac tissue from injury caused by reduced traffic of inflammatory cells. In addition, the ability of Tc-aTS to modulate the production of inflammatory cytokines was attenuated and/or compromised when Tc-iTS was co-injected in the same proportions. These results suggest that although both proteins present structural similarities and compete for the same sialyl-glycan epitopes, they might present distinct immunomodulatory properties on T cells following T. cruzi infection. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
43. Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/Kb Transgenic Mice.
- Author
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Ying Ma, Linfeng Cheng, Bin Yuan, Yusi Zhang, Chunmei Zhang, Yun Zhang, Kang Tang, Ran Zhuang, Lihua Chen, Kun Yang, Fanglin Zhang, Boquan Jin, Freire-de-Lima, Leonardo, and Decote-Ricardo, Debora
- Subjects
HLA histocompatibility antigens ,HANTAVIRUS diseases ,CYTOTOXIC T cells - Abstract
Hantavirus infections cause severe emerging diseases in humans and are associated with high mortality rates; therefore, they have become a global public health concern. Our previous study showed that the CD8
+ T-cell epitope aa129-aa137 (FVVPILLKA, FA9) of the Hantaan virus (HTNV) nucleoprotein (NP), restricted by human leukocyte antigen (HLA)-A*02, induced specific CD8+ T-cell responses that controlled HTNV infection in humans. However, the in vivo immunogenicity of peptide FA9 and the effect of FA9-specific CD8+ T-cell immunity remain unclear. Here, based on a detailed structural analysis of the peptide FA9/HLA-A*0201 complex and functional investigations using HLA-A2.1/Kb transgenic (Tg) mice, we found that the overall structure of the peptide FA9/HLA-A*0201 complex displayed a typical MHC class I fold with Val2 and Ala9 as primary anchor residues and Val3 and Leu7 as secondary anchor residues that allow peptide FA9 to bind tightly with an HLA-A*0201 molecule. Residues in the middle portion of peptide FA9 extruding out of the binding groove may be the sites that allow for recognition by T-cell receptors. Immunization with peptide FA9 in HLA-A2.1/Kb Tg mice induced FA9-specific cytotoxic T-cell responses characterized by the induction of high expression levels of interferon-, tumor necrosis factor-a, granzyme B, and CD107a. In an HTNV challenge trial, significant reductions in the levels of both the antigens and the HTNV RNA loads were observed in the liver, spleen, and kidneys of Tg mice pre-vaccinated with peptide FA9. Thus, our findings highlight the ability of HTNV epitope-specific CD8+ T-cell immunity to control HTNV and support the possibility that the HTNV-NP FA9 peptide, naturally processed in vivo in an HLA-A*02-restriction manner, may be a good candidate for the development HTNV peptide vaccines. [ABSTRACT FROM AUTHOR]- Published
- 2016
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- View/download PDF
44. Glycosylation in Cancer: interplay between Multidrug Resistance and epithelial-to-Mesenchymal Transition?
- Author
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da Fonseca, Leonardo Marques, da Silva, Vanessa Amil, Freire-de-Lima, Leonardo, Previato, José Osvaldo, Mendonça-Previato, Lucia, Capella, Márcia Alves Marques, Tosato, Valentina, and Berger, Walter
- Subjects
GLYCOSYLATION ,MULTIDRUG resistance ,EPITHELIAL cell tumors - Abstract
The expression of unusual glycan structures is a hallmark of cancer progression, and their functional roles in cancer biology have been extensively investigated in epithelial-to-mesenchymal transition (EMT) models. EMT is a physiological process involved in embryonic development and wound healing. It is characterized by loss of epithelial cell polarity and cell adhesion, permitting cell migration, and thus formation of new epithelia. However, this process is unwanted when occurring outside their physiological limit, resulting in fibrosis of organs and progression of cancer and metastasis. Several studies observed that EMT is related to the acquisition of multidrug resistance (MDR) phenotype, a condition in which cancer cells acquire resistance to multiple different drugs, which has virtually nothing in common. However, although some studies suggested interplay between these two apparently distinct phenomena, almost nothing is known about this possible relationship. A common pathway to them is the need for glycosylation, a post-translational modification that can alter biological function. Thus, this review intends to compile the main facts obtained until now in these two areas, as an effort to unravel the relationship between EMT and MDR. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
45. Modulation of Cell Sialoglycophenotype: A Stylish Mechanism Adopted by Trypanosoma cruzi to Ensure Its Persistence in the Infected Host.
- Author
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Freire-de-Lima, Leonardo, da Fonseca, Leonardo M., da Silva, Vanessa A., da Costa, Kelli M., Morrot, Alexandre, Freire-de-Lima, Célio G., Previato, Jose O., Mendonça-Previato, Lucia, Tsuji, Moriya, Campetella, Oscar, and Chammas, Roger
- Subjects
TRYPANOSOMA cruzi ,IMMUNE response ,T cells - Abstract
Trypanosoma cruzi, the etiological agent of Chagas disease exhibits multiple mechanisms to guarantee its establishment and persistence in the infected host. It has been well demonstrated that T. cruzi is not able to synthesize sialic acids (Sia). To acquire the monosaccharide, the parasite makes use of a multifunctional enzyme called trans-sialidase (Tc-TS). Since this enzyme has no analogous in the vertebrate host, it has been used as a target in drug therapy development. Tc-TS preferentially catalyzes the transfer of Sia from the host glycoconjugates to the terminal β-galactopyranosyl residues of mucin-like molecules present on the parasite's cell surface. Alternatively, the enzyme can sialylate/re-sialylate glycoconjugates expressed on the surface of host cells. Since its discovery, several studies have shown that T. cruzi employs the Tc-TS activity to modulate the host cell sialoglycophenotype, thus favoring its perpetuation in the infected vertebrate. In this review, we summarize the dynamic of host/parasite sialoglycophenotype modulation, highlighting its role in the subversion of host immune response in order to promote the establishment of persistent chronic infection. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
46. Host resistance to visceral leishmaniasis: prevalence and prevention.
- Author
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Maran, Naiara, Gomes, Pollyanna Stephanie, Freire-de-Lima, Leonardo, Freitas, Elisangela Oliveira, Freire-de-Lima, Célio Geraldo, Morrot, Alexandre, and Freire-de-Lima, Célio Geraldo
- Abstract
Visceral leishmaniasis (VL) is a chronic parasitic disease caused by the vector-borne Leishmania donovani and Leishmania (L.) infantum chagasi parasites. The disease affects about 12 million humans in more than 90 countries worldwide. If not treated, the visceral form of Leishmania infection is potentially fatal, yielding about 50000 deaths per year. In the vertebrate host, the Leishmania species causing VL spread systematically to propagate in macrophage reservoirs distributed in the tissues of internal organs, primarily the liver, spleen, bone marrow and the lymph nodes. The infection is associated with evolved mechanisms from the parasite to subvert the host immune system in order to establish a persistent infection. Currently, efforts are being deployed to develop new anti-leishmanial therapies in VL combining immunomodulatory treatment regimens that burst the host immune responses together with leishmanicidal drugs that target the parasite growth. Discoveries in this field are discussed in this article. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
47. The Sweet Side of immune evasion: Role of Glycans in the Mechanisms of Cancer Progression.
- Author
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Nardy, Ana Flávia Fernandes Ribas, Morrot, Alexandre, Freire-de-Lima, Leonardo, and Freire-de-Lima, Célio Geraldo
- Subjects
GLYCOSYLATION ,CELL differentiation ,SIALIC acids - Abstract
The article discusses the role of glycans in cancer progression which helps in cell differentiation, host-pathogen interactions and metastasis development and states its linkage to glycosylation, role of endogenous lectins and sialic acid in avoiding immunity against tumor cells.
- Published
- 2016
- Full Text
- View/download PDF
48. Trypanosoma cruzi Trans-Sialidase: Structural Features and Biological Implications.
- Author
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Oliveira, Isadora A., Freire-de-Lima, Leonardo, Penha, Luciana L., Dias, Wagner B., and Todeschini, Adriane R.
- Published
- 2014
- Full Text
- View/download PDF
49. Sweet and sour: the impact of differential glycosylation in cancer cells undergoing epithelial-mesenchymal transition.
- Author
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Freire-de-Lima, Leonardo
- Subjects
CANCER cells ,GLYCOSYLATION ,CANCER invasiveness ,FIBRONECTINS ,GLYCOSYLTRANSFERASES - 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 under-going EMT are characterized by significant changes in glycosylation of the extracellular matrix (ECM) components and cell-surface glycoconjugates. Current scientific methodol-ogy 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, ser-ine, 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-b), a known EMT inducer, has the ability to pro-mote 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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
50. Inhibitory Effects of Trypanosoma cruzi Sialoglycoproteins on CD4+ T Cells Are Associated with Increased Susceptibility to Infection.
- Author
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Nunes, Marise Pinheiro, Fortes, Bárbara, Silva-Filho, João Luiz, Terra-Granado, Eugênia, Santos, Leonardo, Conde, Luciana, de Araújo Oliveira, Isadora, Freire-de-Lima, Leonardo, Martins, Marina Vieira, Pinheiro, Ana Acacia Sá, Takyia, Christina Maeda, Freire-de-Lima, Célio Geraldo, Todeschini, Adriane Regina, DosReis, George Alexandre, and Morrot, Alexandre
- Subjects
TRYPANOSOMA cruzi ,SIALOGLYCOPROTEINS ,CD4 antigen ,T cells ,DISEASE susceptibility ,INFECTIOUS disease transmission ,ANTIGENS - 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 naïve 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. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
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