Roberta Saldanha-Gama
Rio de Janeiro State University
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Publication
Featured researches published by Roberta Saldanha-Gama.
Apoptosis | 2005
I. Tanjoni; R. Weinlich; M. S. Della-Casa; P. B. Clissa; Roberta Saldanha-Gama; M.S. de Freitas; Christina Barja-Fidalgo; Gustavo P. Amarante-Mendes; A. M. Moura-da-Silva
Jararhagin is a snake venom metalloproteinase (SVMP) from Bothrops jararaca involved in several hemostatic and inflammatory disorders that occur in human envenomings. In this study, we evaluated the effect of jararhagin on endothelial cells (tEnd). The exposure of tEnd to jararhagin (20 and 40μg/ml) resulted in apoptosis with activation of pro-caspase-3 and alterations in the ratio between Bax/Bcl-xL. We observed that apoptosis was followed by decrease of cell viability and the loss of cell adhesion. Jararhagin induced changes in cell shape with a decrease in cell spreading, rounding up and detachment. This was accompanied by a rearrangement of actin network and a decrease in FAK association to actin and in tyrosine phosphorylated proteins. Morphological alterations and apoptosis were abolished when jararhagin catalytic activity was inhibited, indicating the importance of catalysis. Treatment of murine peritoneal adherent cells or fibroblasts with jararhagin did not result in apoptosis. The data indicate that the pro-apoptotic effect of jararhagin is selective to endothelial cells, interfering with the adhesion mechanisms and inducing anoikis. The present model might be useful for the study of the relationships between the architectural changes in the cytoskeleton and the complex phenomenon named anoikis.
Brazilian Journal of Medical and Biological Research | 2005
Christina Barja-Fidalgo; Ana Lúcia J. Coelho; Roberta Saldanha-Gama; E. Helal-Neto; Andrea Mariano-Oliveira; M.S. de Freitas
Extracellular matrix proteins and cell adhesion receptors (integrins) play essential roles in the regulation of cell adhesion and migration. Interactions of integrins with the extracellular matrix proteins lead to phosphorylation of several intracellular proteins such as focal adhesion kinase, activating different signaling pathways responsible for the regulation of a variety of cell functions, including cytoskeleton mobilization. Once leukocytes are guided to sites of infection, inflammation, or antigen presentation, integrins can participate in the initiation, maintenance, or termination of the immune and inflammatory responses. The modulation of neutrophil activation through integrin-mediated pathways is important in the homeostatic control of the resolution of inflammatory states. In addition, during recirculation, T lymphocyte movement through distinct microenvironments is mediated by integrins, which are critical for cell cycle, differentiation and gene expression. Disintegrins are a family of low-molecular weight, cysteine-rich peptides first identified in snake venom, usually containing an RGD (Arg-Gly-Asp) motif, which confers the ability to selectively bind to integrins, inhibiting integrin-related functions in different cell systems. In this review we show that, depending on the cell type and the microenvironment, disintegrins are able to antagonize the effects of integrins or to act agonistically by activating integrin-mediated signaling. Disintegrins have proven useful as tools to improve the understanding of the molecular events regulated by integrin signaling in leukocytes and prototypes in order to design therapies able to interfere with integrin-mediated effects.
Biochimica et Biophysica Acta | 2010
Roberta Saldanha-Gama; João Alfredo de Moraes; Andrea Mariano-Oliveira; Ana Lúcia J. Coelho; Erin M. Walsh; Cezary Marcinkiewicz; Christina Barja-Fidalgo
Integrin signaling is comprised of well-characterized pathways generally involved in cell survival. alpha(9)beta(1) integrin has recently become a target of study and has been shown to present pro-survival effects on neutrophils. However, there are no detailed studies on how alpha(9)beta(1) integrin-coupled signaling pathways interact and how they converge to finally modulate spontaneous apoptosis in neutrophils. In this regard we sought to investigate the main signaling events triggered by alpha(9)beta(1) integrin engagement and how these signaling pathways modulate the apoptotic program of human neutrophils. Using VLO5, a snake venom disintegrin shown to bind to alpha(9)beta(1) integrin in neutrophils, we demonstrate that alpha(9)beta(1) integrin engagement leads to the activation of integrin signaling pathways and potently reduces neutrophil spontaneous apoptosis. These effects are dependent on the activation of PI3K and MAPK pathways, since both LY294002 (PI3K inhibitor) or PD95059 (MEK inhibitor) reverted the effects of VLO5/alpha(9)beta(1) interaction. Moreover we show that VLO5/alpha(9)beta(1) engagement induces NF-kappaB nuclear translocation and increases the ratio between anti- and pro-apoptotic proteins by inducing the degradation of pro-apoptotic protein Bad and increasing the expression of anti-apoptotic protein Bcl-x(L). VLO5 also inhibited the early steps of neutrophil spontaneous apoptosis by preventing Bax translocation to the outer mitochondrial membrane and consequent cytochrome c release. In conclusion, as the mechanistic details of alpha(9)beta(1) integrin signaling pathways in human neutrophils becomes clearer, it should become possible to develop new therapeutic agents for human diseases where neutrophils play a prominent role.
Journal of Leukocyte Biology | 2015
Rafael Silveira Amendola; Ana Carolina Baptista Moreno Martin; Heloisa S. Selistre-de-Araujo; Heitor A. Paula-Neto; Roberta Saldanha-Gama; Christina Barja-Fidalgo
ADAM9 is a member of the ADAM family whose expression positively correlates with tumor progression. Besides the metalloprotease activity, ADAM9D interacts with different integrins, modulating cell‐adhesion events. Previous studies pointed to an important role for neutrophils in tumor development, as the inhibition of neutrophil migration or depletion of this immune cell impairs tumor growth. However, our understanding of the molecular mechanisms involved in this process, as well as the main key players acting on neutrophils, is very limited. Here, we investigated the possible modulatory effects of ADAM9D on human neutrophil functions. Our results show that ADAM9D promotes neutrophil activation and chemotaxis in a process that depends on the engagement of αvβ3 and α9β1 integrins and on the activation of PI3K/Akt and MAPK signaling pathway. ADAM9D impairs migration of neutrophils toward fMLP, LTB4, and IL‐8 as classic chemoattractants. This effect is blocked by PTX, a G(i)PCR inhibitor. Furthermore, CXCR2 antagonists RPTX and SB225002 also impaired neutrophil chemotaxis in response to ADAM9D, suggesting a hierarchical cross‐talk of integrins with CXCR2. Our results indicate that ADAM9D activates neutrophil functions and may be implicated in the inflammatory events associated with cancer and other disorders.
Journal of Cellular Physiology | 2016
Edward Helal-Neto; Renata M. Brandão-Costa; Roberta Saldanha-Gama; Cristiane Ribeiro-Pereira; Victor Midlej; Marlene Benchimol; Verônica Morandi; Christina Barja-Fidalgo
The unique composition of tumor‐produced extracellular matrix (ECM) can be a determining factor in changing the profile of endothelial cells in the tumor microenvironment. As the main receptor for ECM proteins, integrins can activate a series of signaling pathways related to cell adhesion, migration, and differentiation of endothelial cells that interact with ECM proteins. We studied the direct impact of the decellularized ECM produced by a highly metastatic human melanoma cell line (MV3) on the activation of endothelial cells and identified the intracellular signaling pathways associated with cell differentiation. Our data show that compared to the ECM derived from a human melanocyte cell line (NGM‐ECM), ECM produced by a melanoma cell line (MV3‐ECM) is considerably different in ultrastructural organization and composition and possesses a higher content of tenascin‐C and laminin and a lower expression of fibronectin. When cultured directly on MV3‐ECM, endothelial cells change morphology and show increased adhesion, migration, proliferation, and tubulogenesis. Interaction of endothelial cells with MV3‐ECM induces the activation of integrin signaling, increasing FAK phosphorylation and its association with Src, which activates VEGFR2, potentiating the receptor response to VEGF. The blockage of αvβ3 integrin inhibited the FAK‐Src association and VEGFR activation, thus reducing tubulogenesis. Together, our data suggest that the interaction of endothelial cells with the melanoma‐ECM triggers integrin‐dependent signaling, leading to Src pathway activation that may potentiate VEGFR2 activation and up‐regulate angiogenesis. J. Cell. Physiol. 231: 2464–2473, 2016.
Toxins | 2018
Victor David; Barbara Barbosa Succar; João Alfredo de Moraes; Roberta Saldanha-Gama; Christina Barja-Fidalgo; Russolina B. Zingali
Disintegrins are a family of small cysteine-rich peptides, found in a wide variety of snake venoms of different phylogenetic origin. These peptides selectively bind to integrins, which are heterodimeric adhesion receptors that play a fundamental role in the regulation of many physiological and pathological processes, such as hemostasis and tumor metastasis. Most disintegrins interact with integrins through the RGD (Arg-Gly-Asp) sequence loop, resulting in an active site that modulates the integrin activity. Some variations in the tripeptide sequence and the variability in its neighborhood result in a different specificity or affinity toward integrin receptors from platelets, tumor cells or neutrophils. Recombinant forms of these proteins are obtained mainly through Escherichia coli, which is the most common host used for heterologous expression. Advances in the study of the structure-activity relationship and importance of some regions of the molecule, especially the hairpin loop and the C-terminus, rely on approaches such as site-directed mutagenesis and the design and expression of chimeric peptides. This review provides highlights of the biological relevance and contribution of recombinant disintegrins to the understanding of their binding specificity, biological activities and therapeutic potential. The biological and pharmacological relevance on the newest discoveries about this family of integrin-binding proteins are discussed.
Anti-inflammatory & anti-allergy agents in medicinal chemistry | 2006
Christina Barja-Fidalgo; Maria A. C. Arruda; Roberta Saldanha-Gama; Marta Sampaio de Freitas
In response to a chemotactic gradient of inflammatory mediators and chemokines, neutrophils adhere to vascular endothelium and directly migrate, leaving blood vessels, toward inflamed tissue areas, to exert their primary defense function. These events are mediated by distinct classes of cell surface receptors in human neutrophils, that not only drive cell adhesion and motility, but also interfere with the cells activation status, modulating different functions and survival. In this review we summarize the current understanding of the series of events that begins at the level of G-protein coupled receptor activation by chemoattractants, and the signaling pathways triggered by cell adhesion molecule interactions that lead to neutrophil adhesion, migration and activation during inflammation. Integrins, as adhesion receptors able to act as anchoring molecules (allowing firm cellular attachment to the ECM) and signaling receptors (transducing signals in both directions, outside-in and inside-out) are targets that potentially provide both therapeutic and diagnostic opportunities. We also present data obtained with integrin-selective ligands, the disintegrins, which could be useful tools to understand cellular processes as adhesion, migration, proliferation, activation and cell survival and may be also suggested as prototypes for designing therapeutic agents for the prevention or activation of integrin-mediated effects.
Toxicon | 2007
Isabela Oliva; Raphael Molinaro Coelho; Gabriel Gjorup Barcellos; Roberta Saldanha-Gama; Luciana S. Wermelinger; Cezary Marcinkiewicz; Russolina B. Zingali; Christina Barja-Fidalgo
Toxicology and Applied Pharmacology | 2005
Aline C. Brando-Lima; Roberta Saldanha-Gama; Maria das Graças Henriques; Ana C.O. Monteiro-Moreira; Renato A. Moreira; Christina Barja-Fidalgo
International Immunopharmacology | 2006
Aline C. Brando-Lima; Roberta Saldanha-Gama; Cristiane Ribeiro Pereira; Christina Gaspar Villela; André Luiz Franco Sampaio; Ana C.O. Monteiro-Moreira; Maria das Graças Henriques; Renato A. Moreira; Christina Barja-Fidalgo