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[PMID]: 28449309 [Au] Autor: Zanella S; Angerani S; Pina A; López Rivas P; Giannini C; Panzeri S; Arosio D; Caruso M; Gasparri F; Fraietta I; Albanese C; Marsiglio A; Pignataro L; Belvisi L; Piarulli U; Gennari C [Ad] Endereço: Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi 19, 20133, Milano, Italy. [Ti] Título: Tumor Targeting with an isoDGR-Drug Conjugate. [So] Source: Chemistry;23(33):7910-7914, 2017 Jun 12. [Is] ISSN: 1521-3765 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Herein we report the first example of an isoDGR-drug conjugate (2), designed to release paclitaxel selectively within cancer cells expressing integrin α ß . Conjugate 2 was synthesized by connecting the isoDGR peptidomimetic 5 with paclitaxel via the lysosomally cleavable Val-Ala dipeptide linker. Conjugate 2 displayed a low nanomolar affinity for the purified integrin α ß receptor (IC =11.0 nm). The tumor targeting ability of conjugate 2 was assessed in vitro in anti-proliferative assays on two isogenic cancer cell lines characterized by different integrin α ß expression: human glioblastoma U87 (α ß +) and U87 ß -KO (α ß -). The isoDGR-PTX conjugate 2 displayed a remarkable targeting index (TI=9.9), especially when compared to the strictly related RGD-PTX conjugate 4 (TI=2.4). [Mh] Termos MeSH primário: Oligopeptídeos/química Paclitaxel/química [Mh] Termos MeSH secundário: Sequência de Aminoácidos Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Seres Humanos Concentração Inibidora 50 Integrina alfaVbeta3/antagonistas & inibidores Integrina alfaVbeta3/genética Integrina alfaVbeta3/metabolismo Peptidomiméticos/química Peptidomiméticos/toxicidade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Integrin alphaVbeta3); 0 (Oligopeptides); 0 (Peptidomimetics); 78VO7F77PN (arginyl-glycyl-aspartic acid); P88XT4IS4D (Paclitaxel) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE [do] DOI: 10.1002/chem.201701844

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[PMID]: 29275565 [Au] Autor: Li P; Li WL; Qi JX [Ad] Endereço: Department of Head Neck and Thyroid, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, China. [Ti] Título: [Expression of integrin αvß3, CXC chemokine receptor 4 and CXC chemokine receptor 7 and their relationship with lymph node metastasis in squamous cell carcinoma of head and neck]. [So] Source: Zhonghua Kou Qiang Yi Xue Za Zhi;52(12):723-729, 2017 Dec 09. [Is] ISSN: 1002-0098 [Cp] País de publicação: China [La] Idioma: chi [Ab] Resumo: To investigate the expression of integrin αvß3, CXC chemokine receptor (CXCR)4 and CXCR7 and their relationship with lymph node metastasis in squamous cell carcinoma of head and neck (SCCHN). The expression of integrin αvß3, CXCR4 and CXCR7 was detected by immunohistochemistry SABC in 92 cases of primary SCCHN, metastatic lymph node, normal oral mucosa tissues and normal lymph nodes. The positive rate of the expression of integrin αvß3, CXCR4 and CXCR7 was 75% (69/92), 81%(75/92) and 76%(70/92), respectively in primary SCCHN, and was 82%(75/92), 76%(70/92) and 65%(60/92), respectively in metastatic lymph node. The expression of integrin αvß3 and CXCR4 in primary SCCHN ( 0.813, 0.05) and lymph node metastasis ( 0.541, 0.05) was positively correlated. Integrin αvß3 and CXCR7 expression in primary SCCHN ( 0.683, 0.05) and lymph node metastasis ( 0.708, 0.05) was positively correlated. CXCR4 and CXCR7 expression in primary SCCHN ( 0.644, 0.05) and lymph node metastasis ( 0.707, 0.05) had a positive correlation. The expression level was associated with tumor size ( 0.040, 0.001, 0.009), lymph node metastasis ( 0.001, 0.000, 0.000) and surrounding tissue invasion ( 0.046, 0.002, 0.001), but not related to age ( 0.097, 0.274, 0.162), gender ( 0.103, 0.309, 0.187). The overexpression of integrin αvß3, CXCR4 and CXCR7 in primary head and neck squamous carcinoma and metastatic lymph nodes was related to lymph node metastasis. The co-expression of integrin αvß3, CXCR4 and CXCR7 may play a synergistic role in lymphatic metastasis of SCCHN. [Mh] Termos MeSH primário: Carcinoma de Células Escamosas/metabolismo Carcinoma de Células Escamosas/secundário Neoplasias de Cabeça e Pescoço/metabolismo Neoplasias de Cabeça e Pescoço/patologia Integrina alfaVbeta3/metabolismo Receptores CXCR4/metabolismo Receptores CXCR/metabolismo [Mh] Termos MeSH secundário: Seres Humanos Imuno-Histoquímica Metástase Linfática RNA Mensageiro/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (CXCR4 protein, human); 0 (CXCR7 protein, human); 0 (Integrin alphaVbeta3); 0 (RNA, Messenger); 0 (Receptors, CXCR); 0 (Receptors, CXCR4) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180209 [Lr] Data última revisão: 180209 [Sb] Subgrupo de revista: D; IM [Da] Data de entrada para processamento: 171226 [St] Status: MEDLINE [do] DOI: 10.3760/cma.j.issn.1002-0098.2017.12.003

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[PMID]: 29198914 [Au] Autor: Cosset É; Ilmjärv S; Dutoit V; Elliott K; von Schalscha T; Camargo MF; Reiss A; Moroishi T; Seguin L; Gomez G; Moo JS; Preynat-Seauve O; Krause KH; Chneiweiss H; Sarkaria JN; Guan KL; Dietrich PY; Weis SM; Mischel PS; Cheresh DA [Ad] Endereço: Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA. Electronic address: erika.cosset@unige.ch. [Ti] Título: Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma. [So] Source: Cancer Cell;32(6):856-868.e5, 2017 Dec 11. [Is] ISSN: 1878-3686 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvß3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors. [Mh] Termos MeSH primário: Neoplasias Encefálicas/metabolismo Glioblastoma/metabolismo Transportador de Glucose Tipo 3/metabolismo Integrina alfaVbeta3/metabolismo Transcriptoma [Mh] Termos MeSH secundário: Animais Antineoplásicos/farmacologia Neoplasias Encefálicas/mortalidade Linhagem Celular Tumoral Perfilação da Expressão Gênica Glioblastoma/mortalidade Seres Humanos Estimativa de Kaplan-Meier Camundongos Camundongos Nus Transdução de Sinais Venenos de Serpentes/farmacologia Ensaios Antitumorais Modelo de Xenoenxerto [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Glucose Transporter Type 3); 0 (Integrin alphaVbeta3); 0 (SLC2A3 protein, human); 0 (Snake Venoms); 4EDF46E4GI (Cilengitide) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171220 [Lr] Data última revisão: 171220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171205 [St] Status: MEDLINE

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[PMID]: 28462989 [Au] Autor: Summer D; Grossrubatscher L; Petrik M; Michalcikova T; Novy Z; Rangger C; Klingler M; Haas H; Kaeopookum P; von Guggenberg E; Haubner R; Decristoforo C [Ad] Endereço: Department of Nuclear Medicine, Medical University Innsbruck , Anichstrasse 35, A-6020 Innsbruck, Austria. [Ti] Título: Developing Targeted Hybrid Imaging Probes by Chelator Scaffolding. [So] Source: Bioconjug Chem;28(6):1722-1733, 2017 06 21. [Is] ISSN: 1520-4812 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Positron emission tomography (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncological applications but also show restrictions depending on the clinical field of interest. Therefore, the combination of both methods, particularly in a single molecule, could improve versatility in clinical routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analogue (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin α ß targeting cyclic pentapeptides (RGD)) and a near-infrared fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro experiments including determination of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG α ß - and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved especially at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clinical setting. [Mh] Termos MeSH primário: Quelantes/química Sondas Moleculares/farmacocinética Imagem Multimodal/métodos Neoplasias/diagnóstico por imagem [Mh] Termos MeSH secundário: Animais Quelantes/farmacocinética Compostos Férricos/farmacocinética Radioisótopos de Gálio/farmacocinética Xenoenxertos Seres Humanos Ácidos Hidroxâmicos/farmacocinética Integrina alfaVbeta3/metabolismo Camundongos Sondas Moleculares/química Neoplasias/metabolismo Tomografia Computadorizada com Tomografia por Emissão de Pósitrons Receptor de Colecistocinina B/metabolismo Células Tumorais Cultivadas [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Chelating Agents); 0 (Ferric Compounds); 0 (Gallium Radioisotopes); 0 (Hydroxamic Acids); 0 (Integrin alphaVbeta3); 0 (Molecular Probes); 0 (Receptor, Cholecystokinin B); 19624-79-4 (fusigen) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171219 [Lr] Data última revisão: 171219 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE [do] DOI: 10.1021/acs.bioconjchem.7b00182

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[PMID]: 28943429 [Au] Autor: Cui X; Zhang X; Bu H; Liu N; Li H; Guan X; Yan H; Wang Y; Zhang H; Ding Y; Cheng M [Ad] Endereço: Clinical Medical School, Weifang Medical University, Weifang, Shandong, 261053, PR China. [Ti] Título: Shear stress-mediated changes in the expression of complement regulatory protein CD59 on human endothelial progenitor cells by ECM-integrinα ß -F-actin pathway in vitro. [So] Source: Biochem Biophys Res Commun;494(1-2):416-421, 2017 Dec 09. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Membrane regulatory proteins, such as CD46, CD55, and CD59, prevent excess complement activation and to protect cells from damage. Previous investigations confirmed that shear stress in the physiological range was more favorable for endothelial progenitor cells (EPCs) to repair injured vascular endothelial cells and operates mainly in atheroprotective actions. However, detailed events that contribute to shear stress-induced protection in EPCs, particularly the mechanisms of signal transduction, remain poorly understood. In this study, we observed shear stress-mediated changes in the expression of complement regulatory proteins CD46, CD55, and CD59 on human EPCs and focused on the mechanical transmission mechanism in transformed cells in response to the ECM-F-actin pathway in vitro. Shear stress was observed to promote the expression of complement regulatory protein CD59, but not CD46 or CD55, on EPCs. In addition, the shear stress-induced CD59 expression was confirmed to be associated with the ECM components and was alleviated in EPCs pretreated with GRGDSP, which inhibits ECM components-integrin interaction. Furthermore, shear stress also promotes the rearrangement and polymerization of F-actin. However, shear stress-induced CD59 expression was reduced when the F-actin stress fiber formation process was delayed by Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) or destroyed by cytochalasin D (Cyto D), while Jasplakinolide (JAS) reversed the expression of CD59 through promotion of F-actin polymerization and its stabilizing capacities. Our results indicates that shear stress is an important mediator in EPC expression of CD59 regulated by the ECM-F-actin pathway, which is a key factor in preventing membrane attack complex (MAC) -mediated cell autolysis. [Mh] Termos MeSH primário: Citoesqueleto de Actina/metabolismo Actinas/genética Antígenos CD59/genética Células Progenitoras Endoteliais/metabolismo Integrina alfaVbeta3/genética Mecanotransdução Celular [Mh] Termos MeSH secundário: Citoesqueleto de Actina/efeitos dos fármacos Citoesqueleto de Actina/ultraestrutura Actinas/metabolismo Antígenos CD55/genética Antígenos CD55/metabolismo Antígenos CD59/metabolismo Complexo de Ataque à Membrana do Sistema Complemento/efeitos dos fármacos Citocalasina D/farmacologia Depsipeptídeos/farmacologia Células Progenitoras Endoteliais/citologia Células Progenitoras Endoteliais/efeitos dos fármacos Matriz Extracelular/química Matriz Extracelular/efeitos dos fármacos Matriz Extracelular/metabolismo Sangue Fetal/citologia Sangue Fetal/efeitos dos fármacos Sangue Fetal/metabolismo Regulação da Expressão Gênica Seres Humanos Integrina alfaVbeta3/metabolismo Proteína Cofatora de Membrana/genética Proteína Cofatora de Membrana/metabolismo Oligopeptídeos/farmacologia Cultura Primária de Células Estresse Mecânico [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Actins); 0 (CD46 protein, human); 0 (CD55 Antigens); 0 (CD59 Antigens); 0 (Complement Membrane Attack Complex); 0 (Depsipeptides); 0 (Integrin alphaVbeta3); 0 (Membrane Cofactor Protein); 0 (Oligopeptides); 101754-01-2 (CD59 protein, human); 102396-24-7 (jasplakinolide); 22144-77-0 (Cytochalasin D); 91037-75-1 (glycyl-arginyl-glycyl-aspartyl-seryl-proline) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170926 [St] Status: MEDLINE

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[PMID]: 28873464 [Au] Autor: Cedano Prieto DM; Cheng Y; Chang CC; Yu J; Takada YK; Takada Y [Ad] Endereço: Department of Dermatology, Biochemistry and Molecular Medicine, UC Davis School of Medicine, Research III Suite, 4645 Second Avenue, Sacramento, CA, United States of America. [Ti] Título: Direct integrin binding to insulin-like growth factor-2 through the C-domain is required for insulin-like growth factor receptor type 1 (IGF1R) signaling. [So] Source: PLoS One;12(9):e0184285, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We have reported that integrins crosstalk with growth factors through direct binding to growth factors (e.g., fibroblast growth factor-1, insulin-like growth factor 1 (IGF1), neuregulin-1, fractalkine) and subsequent ternary complex formation with cognate receptor [e.g., integrin/IGF1/IGF1 receptor (IGF1R)]. IGF1 and IGF2 are overexpressed in cancer and major therapeutic targets. We previously reported that IGF1 binds to integrins ανß3 and α6ß4, and the R36E/R37E mutant in the C-domain of IGF1 is defective integrin binding and signaling functions of IGF1, and acts as an antagonist of IGF1R. We studied if integrins play a role in the signaling functions of IGF2, another member of the IGF family. Here we describe that IGF2 specifically binds to integrins ανß3 and α6ß4, and induced proliferation of CHO cells (IGF1R+) that express ανß3 or α6ß4 (ß3- or α6ß4-CHO cells). Arg residues to Glu at positions 24, 34, 37 and/or 38 in or close to the C-domain of IGF2 play a critical role in binding to integrins and signaling functions. The R24E/R37E/R38E, R34E/R37E/R38E, and R24E/R34E/R37E/R38E mutants were defective in integrin binding and IGF2 signaling. These mutants suppressed proliferation induced by WT IGF2, suggesting that they are dominant-negative antagonists of IGF1R. These results suggest that IGF2 also requires integrin binding for signaling functions, and the IGF2 mutants that cannot bind to integrins act as antagonists of IGF1R. The present study defines the role of the C-domain in integrin binding and signaling. [Mh] Termos MeSH primário: Fator de Crescimento Insulin-Like II/química Fator de Crescimento Insulin-Like II/metabolismo Integrina alfa6beta4/metabolismo Integrina alfaVbeta3/metabolismo Receptor IGF Tipo 1/metabolismo Transdução de Sinais [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Células CHO Linhagem Celular Tumoral Proliferação Celular Cricetinae Cricetulus Seres Humanos Proteínas Mutantes Ligação Proteica Domínios Proteicos Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Integrin alpha6beta4); 0 (Integrin alphaVbeta3); 0 (Mutant Proteins); 67763-97-7 (Insulin-Like Growth Factor II); EC 2.7.10.1 (Receptor, IGF Type 1) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171016 [Lr] Data última revisão: 171016 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170906 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0184285

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[PMID]: 28767233 [Au] Autor: Duret D; Grassin A; Henry M; Jacquet T; Thoreau F; Denis-Quanquin S; Coll JL; Boturyn D; Favier A; Charreyre MT [Ad] Endereço: Univ Lyon, Université Lyon 1 , INSA de Lyon, CNRS, Laboratoire Ingénierie des Matériaux Polymères, UMR5223, F-69621 Villeurbanne, France. [Ti] Título: "Polymultivalent" Polymer-Peptide Cluster Conjugates for an Enhanced Targeting of Cells Expressing α ß Integrins. [So] Source: Bioconjug Chem;28(9):2241-2245, 2017 Sep 20. [Is] ISSN: 1520-4812 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: A new class of "polymultivalent" ligands combining several ligand clusters and a water-soluble biocompatible polymer is introduced. These original conjugates bear two levels of multivalency. They are prepared by covalent coupling of a controlled number of tetrameric cRGD peptide clusters along a well-defined copolymer synthesized by RAFT polymerization. The presence of multiple copies of peptide clusters on the same polymer backbone resulted in a much-higher relative potency than the free cluster reference. Thanks to the "polymultivalency", up to ∼2 orders of magnitude potency enhancement was reached in a competitive cell adhesion assay (nanomolar-range IC values). In addition, confocal microscopy and flow cytometry demonstrated that fluorescent "polymultivalent" conjugates (emitting in the far-red/near-infrared region) were able to specifically and selectively label cells expressing α ß -integrin, the natural receptor of cRGD. [Mh] Termos MeSH primário: Integrina alfaVbeta3/metabolismo Peptídeos Cíclicos/metabolismo Peptídeos/metabolismo Polímeros/metabolismo [Mh] Termos MeSH secundário: Adesão Celular Linhagem Celular Tumoral Sistemas de Liberação de Medicamentos Seres Humanos Integrina alfaVbeta3/análise Ligantes Microscopia Confocal Peptídeos/síntese química Peptídeos/química Peptídeos Cíclicos/síntese química Peptídeos Cíclicos/química Polímeros/síntese química Polímeros/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Integrin alphaVbeta3); 0 (Ligands); 0 (Peptides); 0 (Peptides, Cyclic); 0 (Polymers); 0 (cyclic arginine-glycine-aspartic acid peptide) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171009 [Lr] Data última revisão: 171009 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170803 [St] Status: MEDLINE [do] DOI: 10.1021/acs.bioconjchem.7b00362

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[PMID]: 28673932 [Au] Autor: Umemoto T; Matsuzaki Y; Shiratsuchi Y; Hashimoto M; Yoshimoto T; Nakamura-Ishizu A; Petrich B; Yamato M; Suda T [Ad] Endereço: International Research Center for Medical Science, Kumamoto University, Kumamoto, Japan umemoto@kumamoto-u.ac.jp csits@nus.edu.sg. [Ti] Título: Integrin αvß3 enhances the suppressive effect of interferon-γ on hematopoietic stem cells. [So] Source: EMBO J;36(16):2390-2403, 2017 Aug 15. [Is] ISSN: 1460-2075 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Hematopoietic homeostasis depends on the maintenance of hematopoietic stem cells (HSCs), which are regulated within a specialized bone marrow (BM) niche. When HSC sense external stimuli, their adhesion status may be critical for determining HSC cell fate. The cell surface molecule, integrin αvß3, is activated through HSC adhesion to extracellular matrix and niche cells. Integrin ß3 signaling maintains HSCs within the niche. Here, we showed the synergistic negative regulation of the pro-inflammatory cytokine interferon-γ (IFNγ) and ß3 integrin signaling in murine HSC function by a novel definitive phenotyping of HSCs. Integrin αvß3 suppressed HSC function in the presence of IFNγ and impaired integrin ß3 signaling mitigated IFNγ-dependent negative action on HSCs. During IFNγ stimulation, integrin ß3 signaling enhanced STAT1-mediated gene expression via serine phosphorylation. These findings show that integrin ß3 signaling intensifies the suppressive effect of IFNγ on HSCs, which indicates that cell adhesion via integrin αvß3 within the BM niche acts as a context-dependent signal modulator to regulate the HSC function under both steady-state and inflammatory conditions. [Mh] Termos MeSH primário: Proliferação Celular Células-Tronco Hematopoéticas/fisiologia Integrina alfaVbeta3/metabolismo Interferon gama/metabolismo [Mh] Termos MeSH secundário: Animais Regulação da Expressão Gênica Camundongos Fosforilação Processamento de Proteína Pós-Traducional Fator de Transcrição STAT1/metabolismo Transdução de Sinais [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (IFNG protein, mouse); 0 (Integrin alphaVbeta3); 0 (STAT1 Transcription Factor); 0 (Stat1 protein, mouse); 82115-62-6 (Interferon-gamma) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170828 [Lr] Data última revisão: 170828 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170705 [St] Status: MEDLINE [do] DOI: 10.15252/embj.201796771

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[PMID]: 28650456 [Au] Autor: Hayek SS; Koh KH; Grams ME; Wei C; Ko YA; Li J; Samelko B; Lee H; Dande RR; Lee HW; Hahm E; Peev V; Tracy M; Tardi NJ; Gupta V; Altintas MM; Garborcauskas G; Stojanovic N; Winkler CA; Lipkowitz MS; Tin A; Inker LA; Levey AS; Zeier M; Freedman BI; Kopp JB; Skorecki K; Coresh J; Quyyumi AA; Sever S; Reiser J [Ad] Endereço: Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA. [Ti] Título: A tripartite complex of suPAR, APOL1 risk variants and α ß integrin on podocytes mediates chronic kidney disease. [So] Source: Nat Med;23(8):945-953, 2017 Aug. [Is] ISSN: 1546-170X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and α ß integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments α ß integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on α ß integrin activation is a mechanism for CKD. [Mh] Termos MeSH primário: Apolipoproteínas/genética Integrina alfaVbeta3/metabolismo Lipoproteínas HDL/genética Podócitos/metabolismo Proteinúria/genética Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo Insuficiência Renal Crônica/genética [Mh] Termos MeSH secundário: Adolescente Adulto Afroamericanos Idoso Alelos Animais Apolipoproteína L1 Apolipoproteínas/metabolismo Estudos de Coortes Feminino Predisposição Genética para Doença Genótipo Seres Humanos Lipoproteínas HDL/metabolismo Masculino Camundongos Meia-Idade Proteinúria/metabolismo Insuficiência Renal Crônica/metabolismo Ressonância de Plasmônio de Superfície Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (APOL1 protein, human); 0 (Apolipoprotein L1); 0 (Apolipoproteins); 0 (Integrin alphaVbeta3); 0 (Lipoproteins, HDL); 0 (Receptors, Urokinase Plasminogen Activator) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170627 [St] Status: MEDLINE [do] DOI: 10.1038/nm.4362

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[PMID]: 28646039 [Au] Autor: Brilha S; Wysoczanski R; Whittington AM; Friedland JS; Porter JC [Ad] Endereço: Department of Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom. [Ti] Título: Monocyte Adhesion, Migration, and Extracellular Matrix Breakdown Are Regulated by Integrin αVß3 in Infection. [So] Source: J Immunol;199(3):982-991, 2017 Aug 01. [Is] ISSN: 1550-6606 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: In tuberculosis (TB), the innate inflammatory immune response drives tissue destruction, morbidity, and mortality. Monocytes secrete matrix metalloproteinases (MMPs), which have key roles in local tissue destruction and cavitation. We hypothesized that integrin signaling might regulate monocyte MMP secretion in pulmonary TB during cell adhesion to the extracellular matrix (ECM). Adhesion to type I collagen and fibronectin by -stimulated monocytes increased MMP-1 gene expression by 2.6-fold and 4.3-fold respectively, and secretion by 60% (from 1208.1 ± 186 to 1934.4 ± 135 pg/ml; < 0.0001) and 63% (1970.3 ± 95 pg/ml; < 0.001). MMP-10 secretion increased by 90% with binding to type I collagen and 55% with fibronectin, whereas MMP-7 increased 57% with collagen. The ECM did not affect the secretion of tissue inhibitors of metalloproteinases-1 or -2. Integrin αVß3 surface expression was specifically upregulated in stimulated monocytes and was further increased after adhesion to type I collagen. Binding of either ß3 or αV integrin subunits increased MMP-1/10 secretion in -stimulated monocytes. In a cohort of TB patients, significantly increased integrin ß3 mRNA accumulation in induced sputum was detected, to our knowledge, for the first time, compared with control subjects ( < 0.05). Integrin αVß3 colocalized with areas of increased and functionally active MMP-1 on infected monocytes, and αVß3 blockade markedly decreased type I collagen breakdown, and impaired both monocyte adhesion and leukocyte migration in a transwell system ( < 0.0001). In summary, our data demonstrate that stimulation upregulates integrin αVß3 expression on monocytes, which upregulates secretion of MMP-1 and -10 on adhesion to the ECM. This leads to increased monocyte recruitment and collagenase activity, which will drive inflammatory tissue damage. [Mh] Termos MeSH primário: Adesão Celular Movimento Celular Matriz Extracelular/metabolismo Integrina alfaVbeta3/genética Monócitos/imunologia Mycobacterium tuberculosis/imunologia [Mh] Termos MeSH secundário: Colágeno Tipo I/metabolismo Colagenases/metabolismo Matriz Extracelular/efeitos dos fármacos Fibronectinas/metabolismo Regulação da Expressão Gênica Seres Humanos Integrina alfaVbeta3/antagonistas & inibidores Integrina alfaVbeta3/imunologia Metaloproteinase 1 da Matriz/genética Metaloproteinase 1 da Matriz/metabolismo Metaloproteinase 10 da Matriz/imunologia Metaloproteinase 10 da Matriz/metabolismo Metaloproteinase 7 da Matriz/imunologia Metaloproteinase 7 da Matriz/metabolismo Inibidores de Metaloproteinases de Matriz/farmacologia Monócitos/microbiologia Monócitos/fisiologia Transdução de Sinais Escarro/química Regulação para Cima [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Collagen Type I); 0 (Fibronectins); 0 (Integrin alphaVbeta3); 0 (Matrix Metalloproteinase Inhibitors); EC 3.4.24.- (Collagenases); EC 3.4.24.22 (Matrix Metalloproteinase 10); EC 3.4.24.23 (Matrix Metalloproteinase 7); EC 3.4.24.7 (Matrix Metalloproteinase 1) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171010 [Lr] Data última revisão: 171010 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170625 [St] Status: MEDLINE [do] DOI: 10.4049/jimmunol.1700128

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