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- ItemAcesso aberto (Open Access)Análise da expressão dos receptores envolvidos no controle vesical em pacientes com bexiga desfuncionalizada e do comportamento miccional após o transplante renal(Universidade Federal de São Paulo (UNIFESP), 2017-11-09) Neves Neto, João Ferreira [UNIFESP]; Mesquita, Roberto Andre Soler [UNIFESP]; http://lattes.cnpq.br/9038872306641159; http://lattes.cnpq.br/0556885434249812; Universidade Federal de São Paulo (UNIFESP)Objective: End-stage renal disease (ESRD) patients undergoing dialysis may develop anuria. Long periods of anuria lead to interruption of the physiological storage and voiding cycle, a condition known as defunctionalized bladder (DB). The objective of this study is to evaluate the expression of bladder receptors in patients with DB and to assess voiding behavior after refunctionalization. Methods: A total of 68 patients with ESRD undergoing dialysis who were candidates to kidney transplant were divided in two groups: DB (diuresis < 300 mL/24 h; n=33) and NDB (non-DB; diuresis 300 mL/24 h; n=35). During kidney transplant a sample of the already dissected mucosa and detrusor at the site of the future ureteral implantation were collected. The expression of the following receptors was evaluated by real-time polymerase chain reaction (RT-PCR) in the mucosa and detrusor: M2, M3, 1D, 3, P2X1, P2X2, P2X3, TRPV1, TRPV4, TRPA1 and TRPM8. At 3, 6 and 12 months after kidney transplant patients answered IPSS and ICIQ-OAB questionnaires. They also filled a 3-day 24 h frequency/volume chart at 6 and 12 months. Results: There was no difference in sex and age between DB and NDB groups. Lower diuresis volume in 24 h and longer pretransplant dialysis duration was observed in DB patients. The expression of all receptors in the mucosa and in the detrusor was similar in both groups, except from 1D, which was overexpressed in the detrusor of DB relatively to NDB group. TRPM8 expression was not demonstrated in any bladder layer of any group. ICIQ-OAB symptom score was similar between the groups at 3, 6 and 12 months. There was a reduction of this score in both groups throughout the follow-up. The same pattern was found for IPSS score. Bother scores were similar between groups. No difference was observed for all parameters extracted from the frequency-volume charts between DB and NDB patients. Conclusion: Gene expression of bladder receptors involved in micturition control was similar in patients with or without DB. Bladder behavior had a similar pattern independently of pretransplant residual diuresis. These findings question the relevance of the term DB in pretransplant patients.
- ItemSomente MetadadadosAtorvastatin reduced soluble receptors of tnf-alpha in systemic lupus erythematosus(Clinical & exper rheumatology, 2016) Ferreira, G. A.; Teixeira, A. L.; Calderaro, D. C.; Sato, E. I. [UNIFESP]Objective The aim of this study was to evaluate the efficacy of atorvastatin to reduce the plasma levels of TNF system molecules (TNF-alpha, sTNFR1 and sTNFR2) and to assess their association with risk factors for accelerate atherosclerosis and clinical disease activity scores in SLE patients. Methods In a previous study, 64 female SLE patients received 20 mg/day of atorvastatin and 24 SLE patients (non-treated group) were followed for 8 weeks. Plasma levels of TNF-alpha, sTNFR 1 and sTNFR 2 were measured by ELISA, at baseline and at the end of the study. Results The plasma levels of sTNFR1 and sTNFR 2 showed a positive correlation with SLEDAI score. We also found a positive correlation between TNF-alpha and sTNFR 1 levels and SLICC score. Patients with current nephritis and patients with anti-dsDNA antibodies presented higher sTNFR1 and sTNFR2 levels. Patients with abdominal obesity and arterial hypertension also had higher plasma levels of soluble receptors. At the end of 8 weeks, we observed a significant decrease in sTNFR1 plasma levels in patients receiving atorvastatin [median (percentile), 876.5 (717-1284 pg/ml) vs. 748 (629.6-917.3 pg/ml), p=0.03], without difference regarding TNF-alpha and sTNFR2 plasma levels. The SLEDAI and SLICC scores were independent determinants of the plasma levels of sRTNF1. Conclusion Atorvastatin reduced soluble receptors of TNF-alpha. The plasma levels of TNF-alpha, sTNFR1 and sTNFR2 may play a role in SLE activity and atherosclerosis, and might be evaluated as targets for new therapies.
- ItemAcesso aberto (Open Access)Avaliação do perfil de agregado plaquetário circulante e da expressão de OX40, CD40L e 4-1BB em pacientes idosos com câncer colorretal(Universidade Federal de São Paulo (UNIFESP), 2017-12-20) Lima, Petrus Moura de Andrade [UNIFESP]; Forones, Nora Manoukian [UNIFESP]; Torres, Leuridan Cavalcante [UNIFESP]; http://lattes.cnpq.br/4973562538598237; http://lattes.cnpq.br/7314943504526739; http://lattes.cnpq.br/5026314977391614; Universidade Federal de São Paulo (UNIFESP)A cada ano, mais de 1,2 milhões de pessoas são diagnosticadas com câncer colorretal (CCR) e cerca de 600.000 pessoas morrem por causa dessa doença. A incidência do câncer de cólon aumenta com a idade. O prognóstico dos pacientes com CCR tem melhorado nas últimas décadas, contudo, persiste uma sobrevida global menor nos idosos. O ambiente tumoral é composto por células do sistema imune, que refletem a tentativa desse sistema em promover uma resposta antitumoral. Complexas interações entre células e mediadores imunes no microambiente tecidual regulam o crescimento de tumores, progressão, metástase e angiogênese. O entendimento das alterações da imunidade na população idosa com CCR permitirá o surgimento de novos tratamentos com maiores taxas de resposta. O presente estudo teve por objetivo avaliar o perfil de agregado plaquetário circulante e da expressão de OX40, CD40L e 4-1BB em idosos com câncer colorretal. Foi realizado um estudo de corte transversal e translacional com grupo de comparação interna, envolvendo 41 idosos portadores de CCR e 75 idosos saudáveis. Foi realizada a análise dos valores percentuais de leucócitos, de agregado de plaquetas ativadas aos linfócitos, monócitos e neutrófilos no sangue periférico, e também a análise dos percentuais de expressão de OX40, p-selectina (CD62P) e CD40L em células T, B, neutrófilo e plaquetas por citometria de fluxo. Dosagem no plasma de s4-1BB e sCD40L por enzyme linked immunosorbentassay (ELISA). Testes de Mann-Whitney e Kruskal-Wallis foram usados para análise de medianas entre dois e três grupos, respectivamente. As variáveis de distribuição normal foram apresentadas em média e desvio padrão. Foi utilizado o teste t e ANOVA para a comparação das médias entre dois e três grupos, respectivamente. Foram considerados significantes valores de p<0.05. Toda a análise estatística foi realizada através do GraphPadPrism v6.0 Verificou-se níveis percentuais diminuídos de plaquetas/OX40+ nos pacientes com CCR (p<0,0001). Os níveis percentuais de linfócitos B/OX40+ estiveram aumentados nos pacientes metastáticos (p=0,01). Na análise do agregado de plaquetas em leucócitos no sangue periférico, verificou-se que os pacientes apresentaram níveis percentuais reduzidos de AGP-neutrófilos (p=0,004). Os pacientes apresentaram um elevado percentual de plaquetas expressando CD62P quando comparado aos controles (p=0,003). Observou-se nos pacientes valores percentuais reduzidos de expressão de CD40L em plaquetas (p<0,0001) e agregado de plaquetas a leucócitos. Os pacientes apresentaram níveis séricos reduzidos de sCD40L quando comparado aos controles (p=0,002). Os idosos com CCR possuem uma imunossupressão que favorece a progressão da doença. Esse conhecimento reveste-se de importância pela possibilidade do surgimento de novas terapias que possam ativar os mecanismos da resposta imune frente aos antígenos tumorais no CCR.
- ItemEmbargoFarmacologia da musculatura lisa de filhotes de ratas de mães tratadas com álcool etílico na gravidez e aleitamento.(Universidade Federal de São Paulo (UNIFESP), 2008-11-26) Verde, Luciana Ferreira [UNIFESP]; Jurkiewicz, Aron [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Em mães etilistas, a ingestão de álcool durante o período da prenhez e aleitamento produziu: 1. Menor ingestão de calorias provenientes da ração em relação ao consumo das mães controles. 2. Menor ingestão de calorias, mesmo consumindo duas fontes de energias diferentes (ração e álcool). 3. O consumo alimentar das mães etilistas foi afetado pelo consumo de etanol, demonstrando que a ingestão de etanol afetou o estado nutricional das mães, sugerindo que a absorção de nutrientes e a metabolização estejam alterados. 4. Baixo ganho de peso durante a prenhez e diminuição de peso corporal durante o aleitamento. 5. Grande variação na concentração sanguínea de álcool nas mães etilistas , que pode ser explicada pelo baixo consumo alimentar, tempo de exposição ao álcool, dose consumida. 6. Maior número de abortos, morte das parturientes, filhotes natimortos e diminuição no tamanho da ninhada. 7. Ausência de atraso no parto de todos grupos estudados. Em filhotes machos e fêmeas de mães etilistas, a ingestão de álcool durante o período da prenhez e aleitamento produziu: 8. Diminuição na Taxa de desmame (T.D.) e Aumento da Taxa de mortalidade (T.M.) Associado ao alto índice de mortalidade nos filhotes: canibalismo das mães (logo após o nascimento ou durante o desmame), altos níveis de álcool no sangue, baixo peso corporal até o 45º dia de vida de filhotes machos e fêmeas. 9. Diminuição no peso de órgãos (ovário, fundus e coração, ddr e testículos), de filhotes machos e fêmeas 10. Altos níveis de álcool no sangue dos filhotes machos e fêmeas, que também está associado ao alto índice de mortes dos filhotes e também explica o porque muitos deles não sobrevivem até o desmame, ou morrem logo após o parto. 11. Embora o baixo peso nos filhotes tenha persistido durante toda a evolução corporal dos filhotes, há uma tendência a recuperação, conforme foi vista pelo aumento de peso quando o etanol foi suspenso com o desmame. Contudo, o tempo de interrupção (28-45° dia de vida dos filhotes) não foi suficiente para a recuperação do peso dos filhotes. 12. Diminuição da reatividade do DDR quando induzida por drogas (CaCl2, KCl, noradrenalina) ou por estímulo elétrico transmurral, mostrando que o componente fásico parece estar afetado. 13. Alteração de eventos pré e pós-sinápticos dos ductos deferentes de filhotes, sendo que os eventos pós-sinápticos parecem ser mais afetados, já que a concentração intracelular do íon cálcio pode estar relacionada com alterações da mobilização celular do cálcio. 14. Diminuição da reatividade do DDR, corroborando que os sistemas receptores deste órgão, pelo menos o adrenérgico, foram susceptíveis às perturbações. causadas pelo tratamento com álcool.
- ItemSomente MetadadadosGene expression profile of cytokines and receptors of inflammation from cultured keratinocytes of burned patients(Elsevier B.V., 2014-08-01) Gragnani, Alfredo [UNIFESP]; Cezillo, Marcus V. B. [UNIFESP]; Silva, Ismael D. C. G. da [UNIFESP]; Ribeiro de Noronha, Samuel M. [UNIFESP]; Corrêa, Silvana Aparecida Alves [UNIFESP]; Ferreira, Lydia M. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Introduction: At all stages of wound healing, growth factors and cytokines play a particularly important role in the interaction with keratinocytes cellular receptors. Keratinocytes have received little attention about their potential to act as a source and target of cytokines. Changes in the cytokine levels after the burning occur prior to the metabolic abnormalities. Thus, it may be possible to develop therapeutic interventions that can mitigate the acute inflammatory response and modulating expression of these cytokines. the objective was to evaluate the expression of 84 genes mediators of the inflammatory response by using PCR array in a primary human epidermal cultured keratinocytes from patients with burns.Methods: Keratinocytes cultured from normal skin around injury from small and large burn patient were treated for DNA synthesis. the samples were analyzed by the PCR Superarray (R) assay and curve analyses were performed for 84 relevant human genes and their involvement in the inflammatory cytokines pathway and receptors. These genes were checked for the up or down regulation. and it was used MetaCore (TM) for the analysis of networks and Gene Ontology (GO) processes.Results: Chemokines of the CXC family were more expressed in the large burn group, except CXCL12. the C, CC and CX3C chemokine family were downregulated, especially in the small burn group. the interleukins IL8 and IL1B were more expressed in large burn than in small burn; except IL13RA1, IL13 and IL5RA that were downregulated, mainly in the small burn group.Conclusions: the cytokine profile showed some important differences between the large and small burn patients, and from this original database, we can create new interventional trials in acute inflammation in burns. (C) 2013 Elsevier Ltd and ISBI. All rights reserved.
- ItemEmbargoIdentificação de diferentes modos de ligação do domínio N-terminal da angiotensina II com receptores AT, selvagem e mutantes(Universidade Federal de São Paulo (UNIFESP), 2009-08-26) Martin, Renan Paulo [UNIFESP]; Shimuta, Suma Imura [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Purpose: Our aim was to assess: a) the relative expression of endogenous and exogenous AT1 receptor in a rabbit smooth muscle cell line either expressing only the endogenous AT1 receptor or in addition the exogenous rat AT1 receptor; b) the binding affinity of the wild AT1 receptor and of the receptor bearing the Cys18Ser mutation (C18S); c) the intracellular predominance of the mutated receptor by using specific antagonists to revert the constitutive internalization and d) a possible defect in the maturation of the receptor by mutation. Methods: The real time PCR was carried out to determine the expression level of both, endogenous and exogenous AT1 receptor. The competitive binding test was used to evaluate the binding affinity of the mutant and of the wild AT1 receptor using AngII, [Lys2]-AngII or [Sar1]-AngII as ligands and 3H-AngII and 125I-AngII as radioactive tracers to find out the reason of the predominant intracellular localization of the mutant receptor. The hypothesis for constitutive internalization was tested, pre-treating the cells with the specific AT1 receptor antagonists, DuP753 or [Sar1Leu8]-AngII and the IP3 production and the intracellular calcium concentration [Ca2+]i were determined. The hypothesis that a defective maturation was also tested, using calnexin, a endoplasmic reticulum marker. Cells expressing the wild or mutant AT1 receptor conjugated with green fluorescent protein (GFP) were targeted to the anti-calnexin primary antibody and the Texas Red labeled anti-rabbit secondary antibody and then merged images were analysed under confocal microscopy. Results and conclusions: It was found that the expression of the exogenous rat AT1 receptor without the 3’,5’-UTR was much higher (about 200.000 fold) than that of the endogenous receptor expression in the rabbit arterial smooth muscle cell line, which could be responsible for the tachyphylatic effect to [Lys2]-AngII. The high expression of the recombinant receptor was probably due to the ubiquitin used as expression vector of the exogenous receptor, which is known to be a strong vector. In another approach, it was verified from the competitive binding profiles using 3H-AngII, that the affinity of C18S AT1 receptor mutant was higher to [Sar1]-AngII than to AngII whereas the binding to [Lys2]-AngII was prevented. On the other hand, when the 125IAngII was used as radiolabel, the binding to the mutant but not to the wild receptor was completed blocked. These results from binding assays showed that the lack of the second S-S bridge induced the receptor to a more unfavorable condition to bind AngII rather than [Sar1]-AngII whereas the mutation completely blocked the receptor to bind [Lys2]-AngII. Furthermore the mutation led the AT1 receptor to acquire a conformation causing a different binding mode that drastically affected the binding of 125I-AngII, probably due to the monoiodinated Tyr4 side chain in its molecule. Concerning the low expression of the C18S mutant on the plasma membrane, it can be concluded that it was due to its internalization rather than to an impaired transport of the mutant from the endoplasmic reticulum to the cell membrane surface, since the pre-treatment with AT1 receptor antagonist was capable to revert the basal activity of the receptor. Indeed, the low basal levels of IP3 and [Ca2+]i were recovered and the responses to AngII were increased to the level of that found in the WT receptor. The hypothesis for a lack of maturation of the mutant receptor was ruled out since calnexin, the endoplasmic reticulum marker was poorly co-localized with C18S receptor. Therefore, our results suggest that the mutant receptor assumed a conformational structure similar to that of active mode of the AT1 receptor, favouring its internalization even in the absence of the agonist.
- ItemSomente MetadadadosRelationship between central behavioral effects and peripheral sympathetic neurotransmission functionality during acute cocaine withdrawal syndrome in adult rats(Cuba Editora, 2016) Souza Bomfim, Guilherme Henrique [UNIFESP]; Garcia Garcia, Antonio; Jurkiewicz, Aron [UNIFESP]; Jurkiewicz, Neide Hyppolito [UNIFESP]Background: Acute cocaine withdrawal syndrome (ACWS) is characterized as a set of organic alterations triggered by abrupt discontinuation of chronic cocaine consumption, usually occurring at 24-40 hours after withdrawal. However, little is known about the relationship between central and peripheral sympathetic neurotransmission during ACWS. Objective and Methods: We investigated the mechanisms involved in central and peripheral sympathetic neurotransmission and how ACWS affects the sympathetic functionality. Cocaine was administered twice daily for 5 days in Wistar rats (at least 5 in each group): on the first and second day, 15 mg/kg/i.p.