Navegando por Palavras-chave "TGF beta"
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- ItemAcesso aberto (Open Access)Adipose tissue fibrosis in human cancer cachexia: the role of TGF beta pathway(Biomed Central Ltd, 2017) Alves, Michele Joana; Figueredo, Raquel Galvao; Azevedo, Flavia Figueiredo; Cavallaro, Diego Alexandre [UNIFESP]; Pinto Neto, Nelson Inacio [UNIFESP]; Carola Lima, Joanna Darck; Matos-Neto, Emidio; Radloff, Katrin; Riccardi, Daniela Mendes; Camargo, Rodolfo Gonzalez; Martins De Alcantara, Paulo Sergio; Otoch, Jose Pinhata; Batista Junior, Miguel Luiz; Seelaender, MariliaBackground: Cancer cachexia is a multifactorial syndrome that dramatically decreases survival. Loss of white adipose tissue (WAT) is one of the key characteristics of cachexia. WAT wasting is paralleled by microarchitectural remodeling in cachectic cancer patients. Fibrosis results from uncontrolled ECM synthesis, a process in which, transforming growth factor-beta (TGF beta) plays a pivotal role. So far, the mechanisms involved in adipose tissue (AT) re-arrangement, and the role of TGF beta in inducing AT remodeling in weight-losing cancer patients are poorly understood. This study examined the modulation of ECM components mediated by TGF beta pathway in fibrotic AT obtained from cachectic gastrointestinal cancer patients. Methods: After signing the informed consent form, patients were enrolled into the following groups: cancer cachexia (CC, n = 21), weight-stable cancer (WSC, n = 17), and control (n = 21). The total amount of collagen and elastic fibers in the subcutaneous AT was assessed by histological analysis and by immunohistochemistry. TGF beta isoforms expression was analyzed by Multiplex assay and by immunohistochemistry. Alpha-smooth muscle actin (aSMA), fibroblast-specific protein (FSP1), Smad3 and 4 were quantified by qPCR and/or by immunohistochemistry. Interleukin (IL) 2, IL5, IL8, IL13 and IL17 content, cytokines known to be associated with fibrosis, was measured by Multiplex assay. Results: There was an accumulation of collagen and elastic fibers in the AT of CC, as compared with WSC and controls. Collagens type I, III, VI, and fibronectin expression was enhanced in the tissue of CC, compared with both WSC and control. The pronounced expression of aSMA in the surrounding of adipocytes, and the increased mRNA content for FSP1 (20-fold) indicate the presence of activated myofibroblasts
- ItemSomente MetadadadosAmifostine does not prevent activation of TGF beta 1 but induces smad 7 activation in megakaryocytes irradiated in vivo(Wiley-Blackwell, 2002-11-01) Segreto, Helena Regina Comodo [UNIFESP]; Ferreira, Alice Teixeira [UNIFESP]; Kimura, Edna Teruko [UNIFESP]; Franco, Marcello [UNIFESP]; Egami, Mizue Imoto [UNIFESP]; Silva, Maria Regina Regis da [UNIFESP]; Segreto, Roberto Araujo [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP)Experiments were undertaken to assess the role of amifostine in the activation of latent TGFbeta1 and in the smad proteins cascade (smad 2/3, smad4, smad7), focusing on megakaryocytes, in the bone marrow irradiated in vivo. Non-irradiated megakaryocytes were negative for active TGFbeta1. Immunopositivity to active TGFbeta1 was detected in megakaryocytes 10 days after irradiation in amifostine- treated and untreated marrows. Smad 2/3 and smad 4 were strongly positive in the nucleus of megakaryocytes 10 days after irradiation. At the same time, a predominant hypocellular bone marrow with foci of hematopoiesis was observed with few megakaryocytes. An increase in the number of reticulin fibers was also seen. in amifostine-treated marrows, smad 2/3 and smad4 were not detected in the nucleus but were positive in the cytoplasm of megakaryocytes 10 days after irradiation. Coincidentally, bone marrows were cellular with megakaryocytes. Smad7 immunoexpression was detected in the cytoplasm of megakaryocytes in the non-irradiated, amifostine-treated and in the irradiated, amifostine-treated marrows. Data indicate that amifostine does not prevent latent TGFbeta1 activation in irradiated megakaryocytes. While TGFbeta1 signal transduction occurs in megakaryocytes in untreated bone marrows, it is inhibited in megakaryocytes in amifostine-treated marrows due to the induction of smad 7 activation. This is the first report showing smad 7 activation by amifostine. Our results also suggest a role for TGFbeta1 as an inhibitor of megakaryocytes in vivo. (C) 2002 Wiley-Liss, Inc.
- ItemAcesso aberto (Open Access)Avaliação do procesamento proteolítico da citocina TGF beta em secretomas de melanoma(Universidade Federal de São Paulo, 2022-07-28) Barcick, Uilla [UNIFESP]; Zelanis, André [UNIFESP]; http://lattes.cnpq.br/8149569348608834; http://lattes.cnpq.br/2713524149879217O câncer é o termo utilizado que abrange um conjunto de mais de 100 doenças que possuem em comum o crescimento desordenado e descontrolado de células anormais. Dentre esse tipo de doença encontra-se o melanoma, que é um tipo de câncer de pele que acomete os melanócitos, e é tido como o mais grave dentre os câncer de pele por sua alta capacidade de progredir para metástase. Num estudo recente realizado pelo nosso grupo acerca do processamento proteolítico no secretoma de um modelo pareado de melanoma murino, composto pelas linhagens Melan- a (melanócito normal) e Tm1 (o fenótipo tumoral correspondente) foi possível identificar, exclusivamente no fenótipo tumoral, eventos de processamento proteolítico em proteínas de importante papel no desenvolvimento tumoral. Dentre os sítios de clivagem observados, identificamos um peptídeo correspondente ao processamento da proteína precursora do TGFβ-3 em uma porção imediatamente anterior ao sítio de clivagem canônico para esta citocina. Do ponto de vista funcional, este achado sugere uma ativação não-canônica e autócrina de TGFβ-3 por melanócitos transformados. Para identificar formas processadas da citocina TGFβ em secretomas de melanócitos tumorais, foi realizado um ensaio de Western Blotting em que foi possível perceber a presença dessa citocina em uma banda com massa adicional exclusivamente nos secretomas das linhagens tumorais. Com o intuito de associar esse achado com vias biológicas foram realizados ensaios de migração celular. Esse ensaio resultou numa diferença nos tempos de migração de uma linhagem endotelial ao sofrer estímulos dos secretomas de melanócitos e de melanoma. Por fim, foi feito uma lista de proteases que poderiam ser as responsáveis pela clivagem do TGF-3 no sítio não canônico. Porém, para confirmarmos o processamento não canônico e identificarmos o mecanismo envolvido nesse evento mais ensaios devem ser realizados.
- ItemRestritoCommunity-based network analyses reveal emerging connectivity patterns of protein-protein interactions in murine melanoma secretome(Juan J Calvete, 2021-02-10) Zelanis, André [UNIFESP]; Francisquini, Rodrigo [UNIFESP]; Berton, Rafael [UNIFESP]; Soares, Sandro - University of Cambridge; Pessotti, Dayelle [UNIFESP]; Camacho, Maurício [UNIFESP]; Andrade-Silva, Débora - Instituto Butantan; Barcick, Uilla [UNIFESP]; Serrano, Solange - Instituto Butantan; Chammas, Roger - Universidade de São Paulo; Nascimento, Mariá [UNIFESP]; http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4778207Z4Protein-protein interaction networks (PPINs) are static representations of protein connections in which topological features such as subgraphs (communities) may contain proteins functionally related, revealing an additional layer of interactome complexity. We created two PPINs from the secretomes of a paired set of murine melanocytes (a normal melanocyte and its transformed phenotype). Community structures, identified by a graph clustering algorithm, resulted in the identification of subgraphs in both networks. Interestingly, the underlying structure of such communities revealed shared and exclusive proteins (core and exclusive nodes, respectively), in addition to proteins that changed their location within each community (rewired nodes). Functional enrichment analysis of core nodes revealed conserved biological functions in both networks whereas exclusive and rewired nodes in the tumoral phenotype network were enriched in cancer-related processes, including TGFβ signaling. We found a remarkable shift in the tumoral interactome, resulting in an emerging pattern which was driven by the presence of exclusive nodes and may represent functional network motifs. Our findings suggest that the rearrangement in the tumoral interactome may be correlated with the malignant transformation of melanocytes associated with substrate adhesion impediment. The interactions found in core and new/rewired nodes might potentially be targeted for therapeutic intervention in melanoma treatment.