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[PMID]:28544621
[Au] Autor:Lee P; Yeo GC; Weiss AS
[Ad] Endereço:School of Life and Environmental Sciences, University of Sydney, Australia.
[Ti] Título:A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors.
[So] Source:FEBS J;284(14):2216-2230, 2017 Jul.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Tropoelastin is the dominant monomer that assembles to form elastin, which confers elasticity to vertebrate elastic tissues including skin, arteries, and lungs. Tropoelastin interacts with cells through cell surface receptors including integrins and glycosaminoglycans (GAGs). As the region 17-18 is recognized as a key region in cell attachment and spreading, we utilized C-terminal truncated tropoelastin constructs containing dissected sections of domain 18. We mapped a cell-interactive sequence of tropoelastin to domain 17 and the first six amino acids (aa) of domain 18. Further delineation identified a 21-residue sequence (Peptide 302-322) which promoted cell attachment and spreading indistinguishable from that to N18, a construct encompassing the full domains 17-18. Alanine substitution of the lysines at positions 11 and 14 in Peptide 302-322 effectively abolished cell binding. This reliance on lysines pointed to a role for GAGs, which was assessed by heparan sulfate inhibition, leading to 85.9 ± 4.2% decreased cell binding, while inhibition of integrins using ethylenediaminetetraacetic acid did not affect attachment. In contrast, selective antibody blocking of the integrin α family prevented cell spreading by 92.5 ± 8.9%. We propose a two-step mechanism by which cell interactions occur at this central region of tropoelastin: initially, cell adhesion is mediated by GAGs, which contact the lysine residues within the target sequence, and subsequently facilitate cell spreading modulated by integrins, specifically α ß and α ß . We conclude that this region comprises a tropoelastin-derived, cell-interactive sequence that independently mediates potent cell binding and spreading via sequential recognition of GAG and integrin cell surface receptors.
[Mh] Termos MeSH primário: Comunicação Celular
Derme/citologia
Derme/metabolismo
Tropoelastina/química
Tropoelastina/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Adesão Celular
Células Cultivadas
Derme/efeitos dos fármacos
Fibroblastos/citologia
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Glicosaminoglicanos/metabolismo
Seres Humanos
Integrina alfaVbeta3/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Receptores de Vitronectina/metabolismo
Tropoelastina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glycosaminoglycans); 0 (Integrin alphaVbeta3); 0 (Peptide Fragments); 0 (Receptors, Vitronectin); 0 (Tropoelastin); 0 (integrin alphaVbeta5)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14114


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[PMID]:28522565
[Au] Autor:Zhang D; Li C; Song Y; Zhou J; Li Y; Li J; Bai C
[Ad] Endereço:Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou City, Zhejiang Province, China.
[Ti] Título:Integrin αvß5 inhibition protects against ischemia-reperfusion-induced lung injury in an autophagy-dependent manner.
[So] Source:Am J Physiol Lung Cell Mol Physiol;313(2):L384-L394, 2017 Aug 01.
[Is] ISSN:1522-1504
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Integrin αvß5 mediates pulmonary endothelial barrier function and acute lung injury (LI), but its roles in cell apoptosis and autophagy are unclear. Thus, the aims of this study were to investigate the significance of αvß5 in ischemia-reperfusion (I/R)-induced apoptosis and LI and to explore the relationship between αvß5 and autophagy. Human pulmonary microvascular endothelial cells (HPMVECs) were pretreated with an αvß5-blocking antibody (ALULA) and challenged with oxygen-glucose deprivation/oxygen-glucose restoration, which mimics I/R; then, cellular autophagy and apoptosis were detected, and cell permeability was assessed. In vivo, mice were pretreated with the autophagy inhibitor chloroquine (CLQ), followed by treatment with ALULA. The mice then underwent operative lung I/R. LI was assessed by performing a pathological examination, calculating the wet/dry lung weight ratio and detecting the bronchial alveolar lavage fluid (BALF) protein concentration. αvß5 inhibition promoted HPMVEC autophagy under I/R in vitro, alleviated cell permeability, decreased the apoptosis ratio, and activated caspase-3 expression. These outcomes were significantly diminished when autophagy was inhibited with a small-interfering RNA construct targeting autophagy-related gene 7 (si 7). Moreover, ALULA pretreatment alleviated I/R-induced LI (I/R-LI), which manifested as a decreased wet/dry lung weight ratio, an altered BALF protein concentration, and lung edema. Preinhibiting autophagy with CLQ, however, eliminated the protective effects of ALULA on I/R-LI. Therefore, inhibiting αvß5 effectively ameliorated I/R-induced endothelial cell apoptosis and I/R-LI. This process was dependent on improved autophagy and its inhibitory effects on activated caspase-3.
[Mh] Termos MeSH primário: Lesão Pulmonar Aguda/tratamento farmacológico
Autofagia/efeitos dos fármacos
Pulmão/efeitos dos fármacos
Substâncias Protetoras/farmacologia
Receptores de Vitronectina/antagonistas & inibidores
Receptores de Vitronectina/metabolismo
Traumatismo por Reperfusão/tratamento farmacológico
[Mh] Termos MeSH secundário: Lesão Pulmonar Aguda/metabolismo
Animais
Apoptose/efeitos dos fármacos
Líquido da Lavagem Broncoalveolar/química
Caspase 3/metabolismo
Células Cultivadas
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/metabolismo
Glucose/metabolismo
Seres Humanos
Pulmão/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Oxigênio/metabolismo
Traumatismo por Reperfusão/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protective Agents); 0 (Receptors, Vitronectin); 0 (integrin alphaVbeta5); EC 3.4.22.- (Caspase 3); IY9XDZ35W2 (Glucose); S88TT14065 (Oxygen)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1152/ajplung.00391.2016


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[PMID]:28477227
[Au] Autor:Haddad T; Qin R; Lupu R; Satele D; Eadens M; Goetz MP; Erlichman C; Molina J
[Ad] Endereço:Division of Medical Oncology, Mayo Clinic, 200 First Street S.W., Rochester, MN, 55905, USA.
[Ti] Título:A phase I study of cilengitide and paclitaxel in patients with advanced solid tumors.
[So] Source:Cancer Chemother Pharmacol;79(6):1221-1227, 2017 Jun.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Cilengitide is a potent and selective inhibitor of the integrins αvß3 and αvß5. The primary objective of this phase I clinical trial was to establish the maximum tolerated dose and determine safety/tolerability of cilengitide in combination with paclitaxel in patients with advanced solid tumors. Secondary objectives included the evaluation of the preliminary clinical outcomes. PATIENTS AND METHODS: Patients with advanced solid tumors experiencing disease progression on standard treatment were assigned to two different dose levels of cilengitide (2000 mg intravenously once or twice weekly) in combination with fixed-dose, weekly paclitaxel (90 mg/m intravenously). RESULTS: Twelve evaluable patients were treated per protocol. A single dose limiting toxicity (DLT) of grade 4 neutropenia was observed at the starting dose level of once weekly cilengitide. There were no grade ≥3 adverse events that occurred with >10% frequency. One patient achieved a partial response to therapy. Five patients experienced stable disease as best response, 3 of which discontinued study participation due to progressive, peripheral neuropathy. CONCLUSIONS: Cilengitide in combination with paclitaxel was well tolerated. Antitumor activity was observed. The recommended phase II dose is twice weekly cilengitide (2000 mg) with weekly paclitaxel (90 mg/m ). Further studies evaluating drugs that target this pathway are warranted.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Neoplasias/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Inibidores da Angiogênese/administração & dosagem
Antineoplásicos Fitogênicos/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Relação Dose-Resposta a Droga
Feminino
Seres Humanos
Integrina alfaVbeta3/antagonistas & inibidores
Masculino
Dose Máxima Tolerável
Meia-Idade
Neutropenia/induzido quimicamente
Paclitaxel/administração & dosagem
Doenças do Sistema Nervoso Periférico/induzido quimicamente
Receptores de Vitronectina/antagonistas & inibidores
Venenos de Serpentes/administração & dosagem
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Antineoplastic Agents, Phytogenic); 0 (Integrin alphaVbeta3); 0 (Receptors, Vitronectin); 0 (Snake Venoms); 0 (integrin alphaVbeta5); 4EDF46E4GI (Cilengitide); P88XT4IS4D (Paclitaxel)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170507
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-017-3322-9


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[PMID]:28220032
[Au] Autor:Chang Y; Lau WL; Jo H; Tsujino K; Gewin L; Reed NI; Atakilit A; Nunes ACF; DeGrado WF; Sheppard D
[Ad] Endereço:Division of Nephrology, Department of Medicine, University of California Irvine, Irvine, California; cyongen@uci.edu.
[Ti] Título:Pharmacologic Blockade of v 1 Integrin Ameliorates Renal Failure and Fibrosis .
[So] Source:J Am Soc Nephrol;28(7):1998-2005, 2017 Jul.
[Is] ISSN:1533-3450
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells is poorly understood. PDGF receptor (PDGFR ) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR promoter-driven Cre system to delete v integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFR -Cre line to isolate and study renal fibroblasts We found that renal fibroblasts express three v integrins, namely v 1, v 3, and v 5. Blockade of v 1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF- 1 and prevented activation of the latent TGF- complex. Continuous administration of a recently described potent small molecule inhibitor of v 1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of v 1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.
[Mh] Termos MeSH primário: Guanidinas/farmacologia
Guanidinas/uso terapêutico
Rim/patologia
Receptores de Vitronectina/antagonistas & inibidores
Insuficiência Renal/prevenção & controle
Sulfonamidas/farmacologia
Sulfonamidas/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Fibrose/etiologia
Fibrose/prevenção & controle
Masculino
Camundongos
Receptores de Vitronectina/fisiologia
Insuficiência Renal/etiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Guanidines); 0 (Receptors, Vitronectin); 0 (Sulfonamides); 0 (integrin alphavbeta1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170222
[St] Status:MEDLINE
[do] DOI:10.1681/ASN.2015050585


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[PMID]:28081359
[Au] Autor:Choi HJ; Chung TW; Park MJ; Kim HS; You S; Lee MS; Joo BS; Lee KS; Kim KJ; Wee G; Kim CY; Kim CH; Ha KT
[Ad] Endereço:School of Korean Medicine and Healthy Aging Korean Medicine Research Center, Pusan National University, Yangsan 50612, Republic of Korea.
[Ti] Título:Benzoic Acid Enhances Embryo Implantation through LIF-Dependent Expression of Integrin αVß3 and αVß5.
[So] Source:J Microbiol Biotechnol;27(4):668-677, 2017 Apr 28.
[Is] ISSN:1738-8872
[Cp] País de publicação:Korea (South)
[La] Idioma:eng
[Ab] Resumo:Embryo implantation is the crucial step for a successful pregnancy. Diverse factors, including adhesion molecules, growth factors, and cytokines are important for embryo implantation through improving endometrial receptivity. Benzoic acid (BA), a component of various plants, has been shown to have antifungal and antioxidant effects. However, the effect of BA on embryo implantation remains unknown. Here, we showed the contribution of BA for the enhancement of endometrial receptivity through the leukemia inhibitory factor (LIF)-dependent increase of integrin αV, ß3, and ß5 expression. Furthermore, in vivo study using a mifepristone-induced implantation failure model showed that BA definitely improves the numbers of implantation embryos. Taken together, we suggest that BA has a novel function for embryo implantation through the up-regulation of LIF-mediated integrins, and may be a candidate for therapeutic medicine to increase the pregnancy rate.
[Mh] Termos MeSH primário: Ácido Benzoico/farmacologia
Implantação do Embrião/efeitos dos fármacos
Integrina alfaVbeta3/metabolismo
Fator Inibidor de Leucemia/metabolismo
Receptores de Vitronectina/metabolismo
[Mh] Termos MeSH secundário: Animais
Adesão Celular/efeitos dos fármacos
Moléculas de Adesão Celular/efeitos dos fármacos
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Citocinas/metabolismo
Endométrio/efeitos dos fármacos
Receptor alfa de Estrogênio
Feminino
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Gravidez
Taxa de Gravidez
RNA Interferente Pequeno
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Adhesion Molecules); 0 (Cytokines); 0 (Estrogen Receptor alpha); 0 (Integrin alphaVbeta3); 0 (Leukemia Inhibitory Factor); 0 (RNA, Small Interfering); 0 (Receptors, Vitronectin); 0 (integrin alphaVbeta5); 8SKN0B0MIM (Benzoic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170113
[St] Status:MEDLINE
[do] DOI:10.4014/jmb.1609.09028


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[PMID]:28062569
[Au] Autor:McCurley A; Alimperti S; Campos-Bilderback SB; Sandoval RM; Calvino JE; Reynolds TL; Quigley C; Mugford JW; Polacheck WJ; Gomez IG; Dovey J; Marsh G; Huang A; Qian F; Weinreb PH; Dolinski BM; Moore S; Duffield JS; Chen CS; Molitoris BA; Violette SM; Crackower MA
[Ad] Endereço:Biogen Inc., Cambridge, Massachusetts; amy.mccurley@biogen.com.
[Ti] Título:Inhibition of v 5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury.
[So] Source:J Am Soc Nephrol;28(6):1741-1752, 2017 Jun.
[Is] ISSN:1533-3450
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The v 5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibit v 5 in a rat model of renal IRI. Pretreatment with this anti- v 5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the v 5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that v 5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with v 5 antibody treatment. Immunostaining for v 5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role for v 5 in modulating vascular leak. Additional studies showed v 5 functions in the adhesion and migration of kidney pericytes Initial studies monitoring renal blood flow after IRI did not find significant effects with v 5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for v 5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal v 5 inhibition as a promising therapeutic strategy for AKI.
[Mh] Termos MeSH primário: Permeabilidade Capilar/efeitos dos fármacos
Rim/irrigação sanguínea
Receptores de Vitronectina/antagonistas & inibidores
Traumatismo por Reperfusão/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Masculino
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Vitronectin); 0 (integrin alphaVbeta5)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170108
[St] Status:MEDLINE
[do] DOI:10.1681/ASN.2016020200


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[PMID]:27974569
[Au] Autor:Storm RJ; Persson BD; Skalman LN; Frängsmyr L; Lindström M; Rankin G; Lundmark R; Domellöf FP; Arnberg N
[Ad] Endereço:Division of Virology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
[Ti] Título:Human Adenovirus Type 37 Uses α ß and α ß Integrins for Infection of Human Corneal Cells.
[So] Source:J Virol;91(5), 2017 Mar 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epidemic keratoconjunctivitis (EKC) is a severe, contagious ocular disease that affects 20 to 40 million individuals worldwide every year. EKC is mainly caused by six types of human adenovirus (HAdV): HAdV-8, -19, -37, -53, -54, and -56. Of these, HAdV-8, -19, and -37 use sialic acid-containing glycans as cellular receptors. αVß3, αVß5, and a few additional integrins facilitate entry and endosomal release of other HAdVs. With the exception of a few biochemical analyses indicating that HAdV-37 can interact physically with αVß5, little is known about the integrins used by EKC-causing HAdVs. Here, we investigated the overall integrin expression on human corneal cells and found expression of α2, α3, α6, αV, ß1, and ß4 subunits in human corneal epithelium and/or in a human corneal epithelial (HCE) cell line but no or less accessible expression of α4, α5, ß3, or ß5. We also identified the integrins used by HAdV-37 through a series of binding and infection competition experiments and different biochemical approaches. Together, our data suggest that HAdV-37 uses αVß1 and α3ß1 integrins for infection of human corneal epithelial cells. Furthermore, to confirm the relevance of these integrins in the HAdV-37 life cycle, we developed a corneal multilayer tissue system and found that HAdV-37 infection correlated well with the patterns of αV, α3, and ß1 integrin expression. These results provide further insight into the tropism and pathogenesis of EKC-causing HAdVs and may be of importance for future development of new antiviral drugs. Keratitis is a hallmark of EKC, which is caused by six HAdV types (HAdV-8, -19, -37, -53, -54, and -56). HAdV-37 and some other HAdV types interact with integrin αVß5 in order to enter nonocular human cells. In this study, we found that αVß5 is not expressed on human corneal epithelial cells, thus proposing other host factors mediate corneal infection. Here, we first characterized integrin expression patterns on corneal tissue and corneal cells. Among the integrins identified, competition binding and infection experiments and biochemical assays pointed out αVß1 and α3ß1 to be of importance for HAdV-37 infection of corneal tissue. In the absence of a good animal model for EKC-causing HAdVs, we also developed an system with multilayer HCE cells and confirmed the relevance of the suggested integrins during HAdV-37 infection.
[Mh] Termos MeSH primário: Infecções por Adenovirus Humanos/virologia
Adenovírus Humanos/fisiologia
Integrina alfa3beta1/fisiologia
Receptores de Vitronectina/fisiologia
[Mh] Termos MeSH secundário: Células A549
Córnea/patologia
Córnea/virologia
Seres Humanos
Receptores Virais
Ligação Viral
Internalização do Vírus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin alpha3beta1); 0 (Receptors, Virus); 0 (Receptors, Vitronectin); 0 (integrin alphavbeta1)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170529
[Lr] Data última revisão:
170529
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161216
[St] Status:MEDLINE


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[PMID]:27484721
[Au] Autor:Cho C; Horzempa C; Jones D; McKeown-Longo PJ
[Ad] Endereço:Center for Cell Biology & Cancer Research (MC-165), Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA.
[Ti] Título:The fibronectin III-1 domain activates a PI3-Kinase/Akt signaling pathway leading to αvß5 integrin activation and TRAIL resistance in human lung cancer cells.
[So] Source:BMC Cancer;16:574, 2016 08 02.
[Is] ISSN:1471-2407
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Fibronectin is a mechanically sensitive protein which is organized in the extracellular matrix as a network of interacting fibrils. The lung tumor stroma is enriched for fibronectin which is thought to contribute to metastasis and drug resistance. Fibronectin is an elastic, multi-modular protein made up of individually folded domains, some of which can stretch in response to increased mechanical tension. Very little is known about the relationship of fibronectin's unfolded domains to lung cancer resistance to chemotherapy. In the present study, we evaluated the impact of unfolding the first Type III domain of fibronectin (FnIII-1c) on TNF-related apoptosis inducing ligand (TRAIL) resistance. METHODS: NCI-H460 non-small cell lung cancer cells were treated with FnIII-1c then assessed for TRAIL-induced apoptosis. Subsequent analysis of FnIII-1c-mediated signaling pathways was also completed. Human non-small cell lung cancer tissue sections were assessed for the expression of vitronectin by immunohistochemistry. RESULTS: FnIII-1c inhibited TRAIL-induced activation of caspase 8 and subsequent apoptosis in NCI-H460 lung cancer cells. FnIII-1c treatment was associated with the activation of the phosphatidylinositol-3-kinase/alpha serine/threonine kinase (PI3K/Akt) pathway and the αvß5 integrin receptor for vitronectin, both of which were required for TRAIL resistance. Immunohistochemical staining of sections from non-small cell lung cancers showed that vitronectin was localized around blood vessels and in the tumor-stroma interface. CONCLUSIONS: Unfolding of Type III domains within the fibronectin matrix may promote TRAIL resistance through the activation of a PI3K/Akt/αvß5 signaling axis and point to a novel mechanism by which changes in secondary structure of fibronectin contribute to cancer cell resistance to apoptosis.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/metabolismo
Resistência a Medicamentos Antineoplásicos
Fibronectinas/farmacologia
Neoplasias Pulmonares/metabolismo
Receptores de Vitronectina/metabolismo
Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
[Mh] Termos MeSH secundário: Caspase 8/metabolismo
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Domínio de Fibronectina Tipo III
Fibronectinas/química
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Fosfatidilinositol 3-Quinases/metabolismo
Dobramento de Proteína
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais
Vitronectina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Fibronectins); 0 (Receptors, Vitronectin); 0 (TNF-Related Apoptosis-Inducing Ligand); 0 (Vitronectin); 0 (integrin alphaVbeta5); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.22.- (CASP8 protein, human); EC 3.4.22.- (Caspase 8)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160804
[St] Status:MEDLINE
[do] DOI:10.1186/s12885-016-2621-6


  9 / 1645 MEDLINE  
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[PMID]:27391025
[Au] Autor:Bachsais M; Naddaf N; Yacoub D; Salti S; Alaaeddine N; Aoudjit F; Hassan GS; Mourad W
[Ad] Endereço:Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre Hospitalier de l'Université de Montréal, 900 rue Saint-Denis, Tour Viger, Room 10-482, Montréal, QC, Canada.
[Ti] Título:The Interaction of CD154 with the α5ß1 Integrin Inhibits Fas-Induced T Cell Death.
[So] Source:PLoS One;11(7):e0158987, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CD154, a critical regulator of the immune response, is usually associated with chronic inflammatory, autoimmune diseases as well as malignant disorders. In addition to its classical receptor CD40, CD154 is capable of binding other receptors, members of the integrin family, the αIIbß3, αMß2 and α5ß1. Given the role attributed to integrins and particularly the ß1 integrins in inhibiting apoptotic events in normal as well as malignant T cells, we were highly interested in investigating the role of the CD154/α5ß1 interaction in promoting survival of malignant T cells contributing as such to tumor development and/or propagation. To support our hypothesis, we first show that soluble CD154 binds to the T-cell acute lymphoblastic leukemia cell line, Jurkat E6.1 in a α5ß1-dependent manner. Binding of soluble CD154 to α5ß1 integrin of Jurkat cells leads to the activation of key survival proteins, including the p38 and ERK1/2 mitogen-activated protein kinases (MAPKs), phosphoinositide 3 kinase (PI-3K), and Akt. Interestingly, soluble CD154 significantly inhibits Fas-mediated apoptosis in T cell leukemia-lymphoma cell lines, Jurkat E6.1 and HUT78 cells, an important hallmark of T cell survival during malignancy progression. These anti-apoptotic effects were mainly mediated by the activation of the PI-3K/Akt pathway but also involved the p38 and the ERK1/2 MAPKs cascades. Our data also demonstrated that the CD154-triggered inhibition of the Fas-mediated cell death response was dependent on a suppression of caspase-8 cleavage, but independent of de novo protein synthesis or alterations in Fas expression on cell surface. Together, our results highlight the impact of the CD154/α5ß1 interaction in T cell function/survival and identify novel targets for the treatment of malignant disorders, particularly of T cell origin.
[Mh] Termos MeSH primário: Ligante de CD40/imunologia
Regulação da Expressão Gênica/imunologia
Sistema de Sinalização das MAP Quinases/imunologia
Receptores de Vitronectina/imunologia
Linfócitos T/imunologia
Receptor fas/imunologia
[Mh] Termos MeSH secundário: Caspase 8/imunologia
Morte Celular/imunologia
Sobrevivência Celular/imunologia
MAP Quinases Reguladas por Sinal Extracelular/imunologia
Seres Humanos
Células Jurkat
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FAS protein, human); 0 (Receptors, Vitronectin); 0 (fas Receptor); 0 (integrin alphavbeta1); 147205-72-9 (CD40 Ligand); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.4.22.- (CASP8 protein, human); EC 3.4.22.- (Caspase 8)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160709
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0158987


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[PMID]:27226547
[Au] Autor:Yun BL; Guan XL; Liu YZ; Zhang Y; Wang YQ; Qi XL; Cui HY; Liu CJ; Zhang YP; Gao HL; Gao L; Li K; Gao YL; Wang XM
[Ad] Endereço:From the Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No. 427 Maduan Street, Nan Gang District, Harbin 150001, Heilongjiang Province and.
[Ti] Título:Integrin αvß1 Modulation Affects Subtype B Avian Metapneumovirus Fusion Protein-mediated Cell-Cell Fusion and Virus Infection.
[So] Source:J Biol Chem;291(28):14815-25, 2016 Jul 08.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Avian metapneumovirus (aMPV) fusion (F) protein mediates virus-cell membrane fusion to initiate viral infection, which requires F protein binding to its receptor(s) on the host cell surface. However, the receptor(s) for aMPV F protein is still not identified. All known subtype B aMPV (aMPV/B) F proteins contain a conserved Arg-Asp-Asp (RDD) motif, suggesting that the aMPV/B F protein may mediate membrane fusion via the binding of RDD to integrin. When blocked with integrin-specific peptides, aMPV/B F protein fusogenicity and viral replication were significantly reduced. Specifically we identified integrin αv and/or ß1-mediated F protein fusogenicity and viral replication using antibody blocking, small interfering RNAs (siRNAs) knockdown, and overexpression. Additionally, overexpression of integrin αv and ß1 in aMPV/B non-permissive cells conferred aMPV/B F protein binding and aMPV/B infection. When RDD was altered to RAE (Arg-Ala-Glu), aMPV/B F protein binding and fusogenic activity were profoundly impaired. These results suggest that integrin αvß1 is a functional receptor for aMPV/B F protein-mediated membrane fusion and virus infection, which will provide new insights on the fusogenic mechanism and pathogenesis of aMPV.
[Mh] Termos MeSH primário: Fusão Celular
Metapneumovirus/fisiologia
Infecções por Paramyxoviridae/fisiopatologia
Receptores de Vitronectina/fisiologia
Proteínas Virais de Fusão/fisiologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Infecções por Paramyxoviridae/virologia
Replicação Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, Vitronectin); 0 (Viral Fusion Proteins); 0 (integrin alphavbeta1)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170708
[Lr] Data última revisão:
170708
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160527
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.711382



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