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Estudo da sinalização de mastócitos mediada por IgE: desenvolvimento de inibidores e efeito de níveis reduzidos de fosfatidilinositol 4,5-bifosfato; Study of IgE-mediated mast cell signaling: development of inhibitors and effect of reduced levels of phosphatidylinositol 4,5-biphosphate

Santos, Marcela de Souza
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 03/07/2012 PT
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556.4302%
As doenças alérgicas alcançaram proporções mundialmente epidêmicas. A ativação de receptores para IgE, Fc RI, em mastócitos, é o mecanismo chave para a iniciação e propagação das respostas patofisiológicas dos processos alérgicos. Após a interação destas células com um alérgeno, há a ativação de uma cascata de eventos de sinalização, a qual resulta na secreção de mediadores alérgicos pré-formados, através de um processo regulado de exocitose, além da síntese e secreção de mediadores lipídicos e citocinas. Desta forma, a inibição da responsividade dos mastócitos, quando ativados por um alérgeno, representa uma via importante para o desenvolvimento de novos candidatos a fármacos com indicação antialérgica. Neste sentido, este trabalho buscou, num primeiro momento, contribuir com a compreensão dos papéis desempenhados por um glicerofosfolipídeo de membrana, fosfatidilinositol 4,5-bifosfato (PtdIns(4,5)P2), em eventos de sinalização em mastócitos, mediados por IgE. Este trabalho permitiu destacar a importância de PtdIns(4,5)P2 como um regulador chave das respostas de Ca2+ e das alterações de morfologia de mastócitos estimulados por um alérgeno. Foi observado ainda que níveis reduzidos de PtdIns(4...

Desenvolvimento de método de preparação de biomarcadores moleculares relacionados a N-acetilglicosaminas para estudos de sinalização celular; Development of preparation method of molecular biomarkers related N-acetylclucosamines for studies of cell signaling

Nunes, Paulo Sergio Gonçalves
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 28/03/2014 PT
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Os carboidratos apresentam-se envolvidos em diversos eventos celulares, tais como geração de energia, sustentação celular, reconhecimento celular, processos de sinalização, etc. A OGlcNAcilação, uma das alterações proteicas pós-traducionais relacionada à adição de Nacetilglicosamina a resíduos de serina ou treonina em proteínas citoplasmáticas ou nucleares, vem demonstrando ser uma das alterações recíproca a O-fosforilação de proteínas e pode estar envolvida no desencadeamento de patologias como câncer, diabetes tipo II, e doenças neurodegenerativas. Tendo em vista à relevância da O-GlcNAcilação e a necessidade de ferramentas para seu estudo, temos como objetivo, desenvolver uma rota sintética para a obtenção de moléculas modificadas derivadas de N-acetilglicosamina, contendo o átomo de flúor ligado ao grupo N-acetil. As moléculas correspondem aos derivados glicopiranosídeo de metila 1 e glicoaminoácidos de serina 2 e treonina 3. Uma vez padronizada, os intermediários finais da rota serão utilizados para futura marcação com o 18F, o qual poderá ser empregado em estudos do processo de sinalização celular por O-GlcNAcilação, e no diagnóstico de câncer por PET. Assim, foram propostas, inicialmente...

Signaling path of the action of AVP on distal K+ secretion

Amorim, JBO; Musa-Aziz, R.; Mello-Aires, M.; Malnic, G.
Fonte: Blackwell Publishing Publicador: Blackwell Publishing
Tipo: Artigo de Revista Científica Formato: 696-704
ENG
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Background. Previous studies from our laboratory have shown that luminal perfusion with arginine vasopressin (AVP) stimulates distal tubule secretory potassium flux (J(K)) via V1 receptors (Am J Physiol 278: F809- F816, 2000). In the present work, we investigate the cell signaling mechanism of this process.Methods. In vivo stationary microperfusion was performed in rat cortical distal tubules and luminal K was measured using double K+ resin/reference microelectrodes.Results. In control conditions, J(K) was 0.71 +/- 0.05 nmol. cm(-2).second(-1); this process was inhibited (14%) by 10(-5) mol/L 8-bromo-cyclic adenosine monophosphate (cAMP), and increased by 35% with 10(-8) mol/L phorbol ester [phorbol 12-myristate 13-acetate (PMA), which activates protein kinase C (PKC)]. During luminal perfusion with 10(-11) mol/L AVP, J(K) increased to 0.88 +/- 0.08 nmol. cm(-2).seconds(-1). In the presence of 10(-11) mol/L AVP, J(K) was not affected by 10(-4) mol/L H89, a blocker of protein kinase A (PKA), but was inhibited (45%) by 10(-5) mol/L staurosporine, an inhibitor of PKC, and by 41% during perfusion with 5 x 10(-5) mol/L of the cell Ca2+ chelator bis (2-aminophenoxy) ethane-tetraacetic acid (BAPTA). In order to study the role of Ca2+-dependent K channels in the luminal hormonal action...

HPV16-associated tumors control myeloid cell homeostasis in lymphoid organs, generating a suppressor environment for T cells

Stone, Simone Cardozo; Marques Rossetti, Renata Ariza; Bolpetti, Aline; Boccardo, Enrique; Araujo Souza, Patricia Savio de; Lepique, Ana Paula
Fonte: Federation Amer Soc Exp Biol Publicador: Federation Amer Soc Exp Biol
Tipo: Artigo de Revista Científica Formato: 619-631
ENG
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553.05535%
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Processo FAPESP: 10/20010-2; Processo FAPESP: 08/03232-1; Tumors are complex structures containing different types of cells and molecules. The importance of the tumor microenvironment in tumor progression, growth, and maintenance is well-established. However, tumor effects are not restricted to the tumor microenvironment. Molecules secreted by, as well as cells that migrate from tumors, may circulate and reach other tissues. This may cause a series of systemic effects, including modulation of immune responses, and in some cases, leukocytosis and metastasis promotion. Leukocytosis has been described as a poor prognostic factor in patients with cervical cancer. The main etiological factor for cervical cancer development is persistent infection with high oncogenic risk HPV. Our laboratory has been exploring the effects of high oncogenic risk, HPV-associated tumors on lymphoid organs of the host. In the present study, we observed an increase in myeloid cell proliferation and alteration in cell signaling in APCs in the spleen of tumor-bearing mice. In parallel, we characterized the cytokines secreted in the inflammatory and tumor cell compartments in the tumor microenvironment and in the spleen of tumor-bearing mice. We show evidence of constitutive activation of the IL-6/STAT3 signaling pathway in the tumor...

The role of TCTEX1D4/PPP1 complex in cell proliferation and migration; O papel do complexo TCTEX1D4/PPP1 na proliferação e migração celular

Felgueiras, Juliana Carina Cardoso
Fonte: Universidade de Aveiro Publicador: Universidade de Aveiro
Tipo: Dissertação de Mestrado
ENG
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Prostate cancer is one of the most prevalent and incident cancer in men, being a disquieting cause of men’s death worldwide. The widespread implementation of prostate-specific antigen (PSA) screening and the improvements on prostate cancer therapy have been leading to a markedly decrease in mortality. However, PSA use is controversial since it has been leading to the diagnosis and treatment of several prostate cancer cases that would not otherwise cause symptoms or threaten man’s life. Hence, the establishment of a panel of biomarkers and the discovery of new therapeutical targets for prostate cancer is a pressing need. Changes in several cell signaling pathways have been associated with de onset, development, and progression of prostate cancer. TGFβ signaling counterbalanced the mitogenic effects of androgens, thus being one of the most prominent pathways involved in controlling prostate growth. Mediators of TGFβ signaling pathway are strictly regulated by several mechanisms, among which reversible phosphorylation. This process involves a fine equilibrium between the action of protein kinases and phosphatases. PPP1 is a major serine/threonine phosphatase that regulates numerous cellular events, including TGFβ signaling. The majority of its functions are accomplished by association with regulatory subunits...

Heparan sulfate proteoglycans: structure, protein interactions and cell signaling

Dreyfuss,Juliana L.; Regatieri,Caio V.; Jarrouge,Thais R.; Cavalheiro,Renan P.; Sampaio,Lucia O.; Nader,Helena B.
Fonte: Academia Brasileira de Ciências Publicador: Academia Brasileira de Ciências
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/2009 EN
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Heparan sulfate proteoglycans are ubiquitously found at the cell surface and extracellular matrix in all the animal species. This review will focus on the structural characteristics of the heparan sulfate proteoglycans related to protein interactions leading to cell signaling. The heparan sulfate chains due to their vast structural diversity are able to bind and interact with a wide variety of proteins, such as growth factors, chemokines, morphogens, extracellular matrix components, enzymes, among others. There is a specificity directing the interactions of heparan sulfates and target proteins, regarding both the fine structure of the polysaccharide chain as well precise protein motifs. Heparan sulfates play a role in cellular signaling either as receptor or co-receptor for different ligands, and the activation of downstream pathways is related to phosphorylation of different cytosolic proteins either directly or involving cytoskeleton interactions leading to gene regulation. The role of the heparan sulfate proteoglycans in cellular signaling and endocytic uptake pathways is also discussed.

Specific structural features of syndecans and heparan sulfate chains are needed for cell signaling

Lopes,C.C.; Dietrich,C.P.; Nader,H.B.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/2006 EN
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The syndecans, heparan sulfate proteoglycans, are abundant molecules associated with the cell surface and extracellular matrix and consist of a protein core to which heparan sulfate chains are covalently attached. Each of the syndecan core proteins has a short cytoplasmic domain that binds cytosolic regulatory factors. The syndecans also contain highly conserved transmembrane domains and extracellular domains for which important activities are becoming known. These protein domains locate the syndecan on cell surface sites during development and tumor formation where they interact with other receptors to regulate signaling and cytoskeletal organization. The functions of cell surface heparan sulfate proteoglycan have been centered on the role of heparan sulfate chains, located on the outer side of the cell surface, in the binding of a wide array of ligands, including extracellular matrix proteins and soluble growth factors. More recently, the core proteins of the syndecan family transmembrane proteoglycans have also been shown to be involved in cell signaling through interaction with integrins and tyrosine kinase receptors.

Itchy, a Nedd4 Ubiquitin Ligase, Downregulates Latent Membrane Protein 2A Activity in B-Cell Signaling

Ikeda, Akiko; Caldwell, Robert G.; Longnecker, Richard; Ikeda, Masato
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2003 EN
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Nedd4 family ubiquitin protein ligases (E3s) specifically associate with latent membrane protein 2A (LMP2A) of Epstein-Barr virus. Our previous studies analyzing LMP2A function in vitro have suggested that Nedd4 family E3s regulate LMP2A function. To determine the role of Nedd4 family E3s in LMP2A B-cell signaling, LMP2A transgenic (LMP2A+) mice were crossed with mice with the Itch-deficient (Itch−/−) background. Itchy, a mouse homologue of human AIP4, is a Nedd4 family E3 and is also the most abundant Nedd4 family E3 found in LMP2A affinity precipitates from B cells. There were significantly fewer B-cell receptor-positive B cells in spleen and bone marrow B cells in LMP2A+ Itch−/− mice than in LMP2A+ mice. In addition, LMP2A+ Itch−/− bone marrow B cells formed larger colonies in cultures treated with interleukin-7 (IL-7) than control bone marrow B cells did. Finally, there was a dramatic increase in tyrosine phosphorylation of LMP2A and Syk in IL-7-cultured LMP2A+ Itch−/− B cells. These results indicate that Nedd4 family E3s, in particular Itchy, downmodulate LMP2A activity in B-cell signaling.

An Ehrlichia chaffeensis Tandem Repeat Protein Interacts with Multiple Host Targets Involved in Cell Signaling, Transcriptional Regulation, and Vesicle Trafficking▿

Wakeel, Abdul; Kuriakose, Jeeba A.; McBride, Jere W.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
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548.7287%
Ehrlichia chaffeensis is an obligately intracellular bacterium that exhibits tropism for mononuclear phagocytes forming cytoplasmic membrane-bound microcolonies called morulae. To survive and replicate within phagocytes, E. chaffeensis exploits the host cell by modulating a number of host cell processes, but the ehrlichial effector proteins involved are unknown. In this study, we determined that p47, a secreted, differentially expressed, tandem repeat (TR) protein, interacts with multiple host proteins associated with cell signaling, transcriptional regulation, and vesicle trafficking. Yeast two-hybrid analysis revealed that p47 interacts with polycomb group ring finger 5 (PCGF5) protein, Src protein tyrosine kinase FYN (FYN), protein tyrosine phosphatase non-receptor type 2 (PTPN2), and adenylate cyclase-associated protein 1 (CAP1). p47 interaction with these proteins was further confirmed by coimmunoprecipitation assays and colocalization in HeLa cells transfected with p47-green fluorescent fusion protein (AcGFP1-p47). Moreover, confocal microscopy demonstrated p47-expressing dense-cored (DC) ehrlichiae colocalized with PCGF5, FYN, PTPN2, and CAP1. An amino-terminally truncated form of p47 containing TRs interacted only with PCGF5 and not with FYN...

Cell Signaling, Internalization, and Nuclear Localization of the Angiotensin Converting Enzyme in Smooth Muscle and Endothelial Cells*

Lucero, Héctor A.; Kintsurashvili, Ekaterina; Marketou, Maria E.; Gavras, Haralambos
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
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554.84168%
The angiotensin converting enzyme (ACE) catalyzes the extracellular formation of angiotensin II, and degradation of bradykinin, thus regulating blood pressure and renal handling of electrolytes. We have previously shown that exogenously added ACE elicited transcriptional regulation independent of its enzymatic activity. Because transcriptional regulation generates from protein-DNA interactions within the cell nucleus we have investigated the initial cellular response to exogenous ACE and the putative internalization of the enzyme in smooth muscle cells (SMC) and endothelial cells (EC). The following phenomena were observed when ACE was added to cells in culture: 1) it bound to SMC and EC with high affinity (Kd = 361.5 ± 60.5 pm) and with a low binding occupancy (Bmax = 335.0 ± 14.0 molecules/cell); 2) it triggered cellular signaling resulting in late activation of focal adhesion kinase and SHP2; 3) it modulated platelet-derived growth factor receptor-β signaling; 4) it was endocytosed by SMC and EC; and 5) it transited through the early endosome, partially occupied the late endosome and the lysosome, and was localized to the nuclei. The incorporation of ACE or a fragment of it into the nuclei reached saturation at 120 min, and was preceded by a lag time of 40 min. Internalized ACE was partially cleaved into small fragments. These results revealed that extracellular ACE modulated cell signaling properties...

Cell–cell signaling drives the evolution of complex traits: introduction—lung evo-devo

Torday, John S.; Rehan, V. K.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
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Physiology integrates biology with the environment through cell–cell interactions at multiple levels. The evolution of the respiratory system has been “deconvoluted” (Torday and Rehan in Am J Respir Cell Mol Biol 31:8–12, 2004) through Gene Regulatory Networks (GRNs) applied to cell–cell communication for all aspects of lung biology development, homeostasis, regeneration, and aging. Using this approach, we have predicted the phenotypic consequences of failed signaling for lung development, homeostasis, and regeneration based on evolutionary principles. This cell–cell communication model predicts other aspects of vertebrate physiology as adaptational responses. For example, the oxygen-induced differentiation of alveolar myocytes into alveolar adipocytes was critical for the evolution of the lung in land dwelling animals adapting to fluctuating Phanarezoic oxygen levels over the past 500 million years. Adipocytes prevent lung injury due to oxygen radicals and facilitate the rise of endothermy. In addition, they produce the class I cytokine leptin, which augments pulmonary surfactant activity and alveolar surface area, increasing selection pressure for both respiratory oxygenation and metabolic demand initially constrained by high-systemic vascular pressure...

Different roles of the cardiac Na+/Ca2+-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy

Bai, Yan; Morgan, Eric E.; Giovannucci, David R.; Pierre, Sandrine V.; Philipson, Kenneth D.; Askari, Amir; Liu, Lijun
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
EN
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546.95316%
Previous studies have shown that digitalis drugs, acting as specific inhibitors of cardiac Na+/K+-ATPase, not only cause positive inotropic effects, but also activate cell signaling pathways that lead to cardiac myocyte hypertrophy. A major aim of this work was to assess the role of Na+/Ca2+-exchanger, NCX1, in the above two seemingly related drug effects. Using a mouse with ventricular-specific knockout (KO) of NCX1, ouabain-induced positive inotropy that was evident in isolated wild-type (Wt) hearts was clearly reduced in KO hearts. Ouabain also increased Ca2+ transient amplitudes in Wt myocytes, but not in KO myocytes. Ouabain-induced activations of ERK 1/2 were noted in Wt myocytes, but not in KO myocytes; however, ouabain activated PI3K1A and Akt in both Wt and KO myocytes. Protein synthesis rate, as a measure of hypertrophy, was increased by ouabain in Wt and KO myocytes; these drug effects were prevented by a PI3K inhibitor but not by a MEK/ERK inhibitor. Hypertrophy caused by ET-1, but not that induced by ouabain, was accompanied by upregulation of BNP gene in Wt and KO myocytes. The findings indicate 1) the necessity of NCX1 for positive inotropic action of ouabain; 2) the irrelevance of NCX1 and ERK 1/2 activation to ouabain-induced hypertrophy; and 3) that hypertrophy caused by ouabain through the activation of PI3K1A/Akt pathway is likely to be beneficial to the heart.

Fuzzy Logic Analysis of Kinase Pathway Crosstalk in TNF/EGF/Insulin-Induced Signaling

Saez-Rodriguez, Julio; Lauffenburger, Douglas A.; Aldridge, Bree Beardsley; Muhlich, Jeremy; Sorger, Peter Karl
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
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555.8479%
When modeling cell signaling networks, a balance must be struck between mechanistic detail and ease of interpretation. In this paper we apply a fuzzy logic framework to the analysis of a large, systematic dataset describing the dynamics of cell signaling downstream of TNF, EGF, and insulin receptors in human colon carcinoma cells. Simulations based on fuzzy logic recapitulate most features of the data and generate several predictions involving pathway crosstalk and regulation. We uncover a relationship between MK2 and ERK pathways that might account for the previously identified pro-survival influence of MK2. We also find unexpected inhibition of IKK following EGF treatment, possibly due to down-regulation of autocrine signaling. More generally, fuzzy logic models are flexible, able to incorporate qualitative and noisy data, and powerful enough to produce quantitative predictions and new biological insights about the operation of signaling networks.

TCR Mechanobiology: Torques and Tunable Structures Linked to Early T Cell Signaling

Shin, Yongdae; Lang, Matthew J.; Kim, Sun Taek; Brazin, Kristine N.; Mallis, Robert J.; Sun, Zhen-Yu Jim; Wagner, Gerhard; Reinherz, Ellis Leonard
Fonte: Frontiers Research Foundation Publicador: Frontiers Research Foundation
Tipo: Artigo de Revista Científica
EN_US
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Mechanotransduction is a basis for receptor signaling in many biological systems. Recent data based upon optical tweezer experiments suggest that the TCR is an anisotropic mechanosensor, converting mechanical energy into biochemical signals upon specific peptide-MHC complex (pMHC) ligation. Tangential force applied along the pseudo-twofold symmetry axis of the TCR complex post-ligation results in the (alphaeta) heterodimer exerting torque on the CD3 heterodimers as a consequence of molecular movement at the T cell–APC interface. Accompanying TCR quaternary change likely fosters signaling via the lipid bilayer predicated on the magnitude and direction of the TCR–pMHC force. TCR glycans may modulate quaternary change, thereby altering signaling outcome as might the redox state of the CxxC motifs located proximal to the TM segments in the heterodimeric CD3 subunits. Predicted alterations in TCR TM segments and surrounding lipid will convert ectodomain ligation into the earliest intracellular signaling events.

Diverse Roles of Cell Signaling during Early and Late Phases of Limb Development

Hu, Jimmy Kuang-Hsien
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
EN_US
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The development of the vertebrate limb is a progressive process characterized by initial induction and patterning, concomitant growth and morphogenesis, and subsequent cell differentiation and tissue formation. Many of these processes are regulated by specific signaling centers and the environment they create. Through both classical approaches and recent molecular studies, we are beginning to understand the roles of these signaling events during limb development. However, several questions still remain and need to be further addressed. In this dissertation, I first examine how signaling molecules regulate the proximal-distal (PD) patterning of the limb. We demonstrate that early limb mesenchyme is initially maintained in a state capable of generating all limb segments by a combination of proximal and distal signals. As the limb grows, the proximal limb is established by exposure to flank-derived signal(s), whereas the distal segments are determined by distal signals when cells grow beyond the proximal influence. Thus, these results support the “two signal model” and contradict the classical view of PD patterning by a clock-based system that was postulated in the “progress zone model”. In the second part of this work, I focus on a later developmental event and study the cell- and non-cell-autonomous function of Sonic hedgehog (Shh) during limb muscle formation. Muscle progenitor cells migrate from the lateral somites into the developing limb...

Down-regulation of intra-hepatic T-cell signaling associated with GB virus C in a HCV/HIV co-infected group with reduced liver disease

Berzsenyi, M.; Woollard, D.; McLean, C.; Preiss, S.; Perreau, V.; Beard, M.; Bowden, D.; Cowie, B.; Li, S.; Mijch, A.; Roberts, S.
Fonte: Elsevier BV Publicador: Elsevier BV
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
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BACKGROUND & AIMS: Studies have shown that GB virus C (GBV-C) infection leads to reduced liver disease in hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection. Considering that the underlying mechanism(s) are unknown, we aim to identify differential gene and protein expression associated with GBV-C in HCV/HIV co-infection that may be responsible for reduced liver disease. METHODS: Liver, peripheral blood mononuclear cells (PBMCs), and plasma samples were collected from 43 HCV/HIV patients. Plasma was tested for GBV-C RNA by RT-PCR with NS5B gene primers. A microarray was performed on the liver and RT-qPCRs on the liver/PBMC samples. Hepatic protein expression was measured by immunohistochemistry. RESULTS: Sixteen out of 43 patients had GBV-C RNA. GBV-C was associated with reduced hepatic fibrosis (p=0.005) and inflammation (p=0.007). The microarray analysis of the liver samples (n=10) showed down-regulation of genes critical to intra-hepatic T-cell signaling associated with GBV-C. Quantitative RT-PCR of the liver samples (n=13) confirmed the down-regulation of lymphocyte-specific protein tyrosine kinase (LCK) (p=0.02) and docking protein 2 (DOK2) (p=0.04). No differences in the expression levels of these genes were observed in PBMCs (n=22) according to the GBV-C status. The hepatic expression of the LCK protein...

Knocked out by Rho Rac T-cell biology

Bustelo, X.R.
Fonte: Murcia : F. Hernández Publicador: Murcia : F. Hernández
Tipo: Artigo de Revista Científica Formato: application/pdf
ENG
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551.79555%
The Rho/Rac family is a group of Ras-related proteins with demonstrated roles in the regulation of proliferation and cytoskeletal structures in a number of cell lineages. Despite this, the actual role of these proteins in T-cells could not be addressed in vivo due to the lack of adequate animal models. Recently, the use of knockout and transgenic animals for Rac1, Rac2, and RhoA has provided a genetic proof of the importance of Rho/Rac protein in different aspects of T-cell signaling. These animals have also allowed us to get better views about the influence of these GTPases proteins on the maturation decisions of immature lymphocytes and on the signaling strategies these GTPases utilize to favor the generation of coherent and robust immune responses.

Roles of Cell Signaling Pathways in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission

Nanbo, Asuka; Terada, Haruna; Kachi, Kunihiro; Takada, Kenzo; Matsuda, Tadashi
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /09/2012 EN
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Epstein-Barr virus (EBV), a human gamma herpesvirus, establishes a life-long latent infection in B lymphocytes and epithelial cells following primary infection. Several lines of evidence indicate that the efficiency of EBV infection in epithelial cells is accelerated up to 104-fold by coculturing with EBV-infected Burkitt's lymphoma (BL) cells compared to infection with cell-free virions, indicating that EBV infection into epithelial cells is mainly mediated via cell-to-cell contact. However, the molecular mechanisms involved in this pathway are poorly understood. Here, we establish a novel assay to assess cell-to-cell contact-mediated EBV transmission by coculturing an EBV-infected BL cell line with an EBV-negative epithelial cell line under stimulation for lytic cycle induction. By using this assay, we confirmed that EBV was transmitted from BL cells to epithelial cells via cell-to-cell contact but not via cell-to-cell fusion. The inhibitor treatments of extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-κB pathways blocked EBV transmission in addition to lytic induction. The blockage of the phosphoinositide 3-kinase (PI3K) pathway impaired EBV transmission coupled with the inhibition of lytic induction. Knockdown of the RelA/p65 subunit of NF-κB reduced viral transmission. Moreover...

Adenylyl Cyclase Cell Signaling as a Target and Underlying Mechanism for Persistent Effects of Early-Life Organophosphate Exposure

Adigun, Abayomi Alexander
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação Formato: 14866629 bytes; application/pdf
Publicado em //2010 EN_US
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Organophosphates (OPs) are developmental neurotoxicants but also produce lasting effects on metabolism. This dissertation examines the cellular mechanisms underlying metabolic dysfunction after early-life OP exposure. We administered diazinon (DZN) or parathion (PRT) to rats on postnatal days (PN) 1-4 at doses straddling the threshold for cholinesterase inhibition and assessed the longitudinal effects on hepatic and cardiac cell function mediated through the adenylyl cyclase (AC) signaling cascade, which controls neuronal and hormonal inputs that regulate hepatic glucose metabolism and cardiac contractility. Specifically, we investigated if outcomes of metabolic dysfunction are related to hepatic AC dysregulation. In the liver, DZN elicited parallel upregulation of AC activity itself and of the responses to AC stimulants acting at beta-adrenergic receptors (BARs), glucagon receptors, or G-proteins. The effects intensified from adolescence to adulthood. In contrast, PRT elicited upregulation in adolescence that waned by adulthood. Effects on the liver were more substantial than those in the heart and a brain region (cerebellum) that shares similar AC cascade responses. These findings indicate that OPs produce lasting hepatic AC gain-of-function and alter the trajectory of hepatic cell signaling in a manner consistent with the observed emergence of prediabetes-like metabolic dysfunction. Since the effects are unrelated to cholinesterase inhibition...

The NCI-Nature Pathway Interaction Database: A cell signaling resource.

Shiva Krupa; Kira Anthony; Jeffrey R. Buchoff; Matthew Day; Timo Hannay; Carl F. Schaefer
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Poster
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The Pathway Interaction Database (*PID*, http://pid.nci.nih.gov) is a freely available collection of curated and peer-reviewed signaling pathways composed of human biomolecular interactions and cellular processes. Created in a collaboration between the U.S. National Cancer Institute and Nature Publishing Group, the database is a research tool for cell biologists, biochemists, computational biologists and bioinformaticians. The PID offers a range of tools to facilitate pathway exploration. Users can browse the pre-defi ned set of pathways and also create interaction network maps centered on a single molecule of interest or an extensive list of molecules. In addition, users can download complete data sets in extensible markup language (XML) and Biological Pathway Exchange (BioPAX) Level 2 formats. The database is updated every month and supplemented by a concise editorial section that provides synopses of recent noteworthy papers in cell signaling and specially commissioned articles on the practical uses of other relevant online tools. Users can sign up for free email alerts or RSS feeds to receive database updates.