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Pesquisa : D08.811.913.696.620.682.725.400.003 [Categoria DeCS]
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[PMID]:28450389
[Au] Autor:Triantafyllou E; Pop OT; Possamai LA; Wilhelm A; Liaskou E; Singanayagam A; Bernsmeier C; Khamri W; Petts G; Dargue R; Davies SP; Tickle J; Yuksel M; Patel VC; Abeles RD; Stamataki Z; Curbishley SM; Ma Y; Wilson ID; Coen M; Woollard KJ; Quaglia A; Wendon J; Thursz MR; Adams DH; Weston CJ; Antoniades CG
[Ad] Endereço:Institute of Liver Studies, King's College Hospital, King's College London, London, UK.
[Ti] Título:MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure.
[So] Source:Gut;67(2):333-347, 2018 02.
[Is] ISSN:1468-3288
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. DESIGN: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer ) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. RESULTS: We demonstrate a significant expansion of resolution-like MerTK+HLA-DR cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCII macrophages during the resolution phase in ALF, APAP-treated Mer mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DR phenotype which promotes neutrophil apoptosis and their subsequent clearance. CONCLUSIONS: We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.
[Mh] Termos MeSH primário: Falência Hepática Aguda/imunologia
Falência Hepática Aguda/metabolismo
Macrófagos/metabolismo
Inibidor Secretado de Peptidases Leucocitárias/farmacologia
c-Mer Tirosina Quinase/metabolismo
[Mh] Termos MeSH secundário: Acetaminofen
Adulto
Idoso
Animais
Estudos de Casos e Controles
Feminino
Expressão Gênica
Genes MHC Classe II
Antígenos HLA-DR/metabolismo
Seres Humanos
Macrófagos do Fígado/imunologia
Macrófagos do Fígado/metabolismo
Falência Hepática Aguda/induzido quimicamente
Falência Hepática Aguda/patologia
Macrófagos/imunologia
Masculino
Camundongos
Meia-Idade
Monócitos/imunologia
Monócitos/metabolismo
Neutrófilos/fisiologia
Fenótipo
Inibidor Secretado de Peptidases Leucocitárias/metabolismo
Inibidor Secretado de Peptidases Leucocitárias/uso terapêutico
Transcriptoma
c-Mer Tirosina Quinase/deficiência
c-Mer Tirosina Quinase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (HLA-DR Antigens); 0 (Secretory Leukocyte Peptidase Inhibitor); 362O9ITL9D (Acetaminophen); EC 2.7.10.1 (MERTK protein, human); EC 2.7.10.1 (Mertk protein, mouse); EC 2.7.10.1 (c-Mer Tyrosine Kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1136/gutjnl-2016-313615


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[PMID]:29286859
[Au] Autor:Otulakowski G; Engelberts D; Post M; Masterson C; Kavanagh BP
[Ad] Endereço:1 Hospital for Sick Children Toronto, Ontario, Canada and.
[Ti] Título:Hypercapnic Acidosis Regulates Mer Tyrosine Kinase Receptor Shedding and Activity.
[So] Source:Am J Respir Cell Mol Biol;58(1):132-134, 2018 01.
[Is] ISSN:1535-4989
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Acidose Respiratória/metabolismo
Hipercapnia/metabolismo
c-Mer Tirosina Quinase/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAM17/metabolismo
Acidose Respiratória/patologia
Animais
Linhagem Celular
Hipercapnia/patologia
Camundongos
[Pt] Tipo de publicação:LETTER; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.10.1 (Mertk protein, mouse); EC 2.7.10.1 (c-Mer Tyrosine Kinase); EC 3.4.24.86 (ADAM17 Protein); EC 3.4.24.86 (Adam17 protein, mouse)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171230
[St] Status:MEDLINE
[do] DOI:10.1165/rcmb.2017-0316LE


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[PMID]:29277773
[Au] Autor:Koda Y; Itoh M; Tohda S
[Ad] Endereço:Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
[Ti] Título:Effects of MERTK Inhibitors UNC569 and UNC1062 on the Growth of Acute Myeloid Leukaemia Cells.
[So] Source:Anticancer Res;38(1):199-204, 2018 01.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase that affects cancer cell proliferation. This study evaluated the effects of the synthetic MERTK inhibitors UNC569 and UNC1062 on in vitro growth of acute myeloid leukaemia (AML) cells. MATERIALS AND METHODS: Four AML cell lines expressing MERTK were treated with UNC569 and UNC1062 and analyzed for cell proliferation, immunoblotting, and gene expression. The effects of MERTK knockdown were also evaluated. RESULTS: Treatment with the inhibitors suppressed cell growth and induced apoptosis in all cell lines. OCI/AML5 and TMD7 cells, in which MERTK was constitutively phosphorylated by autocrine mechanisms, were highly susceptible to these inhibitors. The treatment reduced the phosphorylation of MERTK and its down-stream signalling molecules, v-akt murine thymoma viral oncogene homolog 1 (AKT) and extracellular signal-regulated kinase (ERK). Similar effects were observed after MERTK knockdown. The inhibitors and the knockdown caused similar changes in mRNA expression. CONCLUSION: These MERTK inhibitors are potential molecular-targeted drugs for treating AML expressing constitutively phosphorylated MERTK.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Leucemia Mieloide Aguda/tratamento farmacológico
Morfolinas/farmacologia
Inibidores de Proteínas Quinases/farmacologia
Pirazóis/farmacologia
Pirimidinas/farmacologia
Sulfonamidas/farmacologia
c-Mer Tirosina Quinase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Linhagem Celular
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Leucemia Mieloide Aguda/genética
Leucemia Mieloide Aguda/metabolismo
Fosforilação/efeitos dos fármacos
RNA Interferente Pequeno/genética
c-Mer Tirosina Quinase/genética
c-Mer Tirosina Quinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Morpholines); 0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 0 (Pyrimidines); 0 (RNA, Small Interfering); 0 (Sulfonamides); 0 (UNC1062); 0 (UNC569); EC 2.7.10.1 (MERTK protein, human); EC 2.7.10.1 (c-Mer Tyrosine Kinase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status:MEDLINE


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[PMID]:28462455
[Au] Autor:Al-Khersan H; Shah KP; Jung SC; Rodriguez A; Madduri RK; Grassi MA
[Ad] Endereço:Pritzker School of Medicine, The University of Chicago, Chicago, IL, 60637, USA.
[Ti] Título:A novel MERTK mutation causing retinitis pigmentosa.
[So] Source:Graefes Arch Clin Exp Ophthalmol;255(8):1613-1619, 2017 Aug.
[Is] ISSN:1435-702X
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous inherited retinal dystrophy. To date, over 80 genes have been implicated in RP. However, the disease demonstrates significant locus and allelic heterogeneity not entirely captured by current testing platforms. The purpose of the present study was to characterize the underlying mutation in a patient with RP without a molecular diagnosis after initial genetic testing. METHODS: Whole-exome sequencing of the affected proband was performed. Candidate gene mutations were selected based on adherence to expected genetic inheritance pattern and predicted pathogenicity. Sanger sequencing of MERTK was completed on the patient's unaffected mother, affected brother, and unaffected sister to determine genetic phase. RESULTS: Eight sequence variants were identified in the proband in known RP-associated genes. Sequence analysis revealed that the proband was a compound heterozygote with two independent mutations in MERTK, a novel nonsense mutation (c.2179C > T) and a previously reported missense variant (c.2530C > T). The proband's affected brother also had both mutations. Predicted phase was confirmed in unaffected family members. CONCLUSION: Our study identifies a novel nonsense mutation in MERTK in a family with RP and no prior molecular diagnosis. The present study also demonstrates the clinical value of exome sequencing in determining the genetic basis of Mendelian diseases when standard genetic testing is unsuccessful.
[Mh] Termos MeSH primário: DNA/genética
Mutação
Retinite Pigmentosa/genética
c-Mer Tirosina Quinase/genética
[Mh] Termos MeSH secundário: Análise Mutacional de DNA
Exoma
Feminino
Seres Humanos
Masculino
Oftalmoscopia
Linhagem
Retina/patologia
Retinite Pigmentosa/diagnóstico
Retinite Pigmentosa/metabolismo
c-Mer Tirosina Quinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 2.7.10.1 (MERTK protein, human); EC 2.7.10.1 (c-Mer Tyrosine Kinase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1007/s00417-017-3679-9


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[PMID]:28916522
[Au] Autor:Cross SN; Potter JA; Aldo P; Kwon JY; Pitruzzello M; Tong M; Guller S; Rothlin CV; Mor G; Abrahams VM
[Ad] Endereço:Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510; and.
[Ti] Título:Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation.
[So] Source:J Immunol;199(8):2885-2895, 2017 Oct 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chorioamnionitis, premature rupture of fetal membranes (FMs), and subsequent preterm birth are associated with local infection and inflammation, particularly IL-1ß production. Although bacterial infections are commonly identified, other microorganisms may play a role in the pathogenesis. Because viral pandemics, such as influenza, Ebola, and Zika, are becoming more common, and pregnant women are at increased risk for associated complications, this study evaluated the impact that viral infection had on human FM innate immune responses. This study shows that a herpes viral infection of FMs sensitizes the tissue to low levels of bacterial LPS, giving rise to an exaggerated IL-1ß response. Using an ex vivo human FM explant system and an in vivo mouse model of pregnancy, we report that the mechanism by which this aggravated inflammation arises is through the inhibition of the TAM receptor, MERTK, and activation of the inflammasome. The TAM receptor ligand, growth arrest specific 6, re-establishes the normal FM response to LPS by restoring and augmenting TAM receptor and ligand expression, as well as by preventing the exacerbated IL-1ß processing and secretion. These findings indicate a novel mechanism by which viruses alter normal FM immune responses to bacteria, potentially giving rise to adverse pregnancy outcomes.
[Mh] Termos MeSH primário: Membranas Extraembrionárias/imunologia
Gammaherpesvirinae/imunologia
Infecções por Herpesviridae/imunologia
Herpesvirus Humano 2/imunologia
Inflamassomos/metabolismo
Nascimento Prematuro/imunologia
Proteínas Proto-Oncogênicas/metabolismo
Receptores Proteína Tirosina Quinases/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Corioamnionite
Feminino
Infecções por Herpesviridae/complicações
Seres Humanos
Imunização
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Interleucina-1beta/metabolismo
Lipopolissacarídeos/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Gravidez
Nascimento Prematuro/etiologia
Proteínas Proto-Oncogênicas/genética
Receptores Proteína Tirosina Quinases/genética
c-Mer Tirosina Quinase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Inflammasomes); 0 (Intercellular Signaling Peptides and Proteins); 0 (Interleukin-1beta); 0 (Lipopolysaccharides); 0 (Proto-Oncogene Proteins); 0 (growth arrest-specific protein 6); EC 2.7.10.1 (MERTK protein, human); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (c-Mer Tyrosine Kinase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700870


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[PMID]:28851810
[Au] Autor:DeBerge M; Yeap XY; Dehn S; Zhang S; Grigoryeva L; Misener S; Procissi D; Zhou X; Lee DC; Muller WA; Luo X; Rothlin C; Tabas I; Thorp EB
[Ad] Endereço:From the Department of Pathology and Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL (M.D., X.Y.Y., S.D., S.Z., L.G., S.M., D.P., X.Z., D.C.Le., W.A.M., X.L., E.B.T.); Division of Molecular Medicine at Columbia University, New York (I.T.)
[Ti] Título:MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury.
[So] Source:Circ Res;121(8):930-940, 2017 Sep 29.
[Is] ISSN:1524-4571
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Clinical benefits of reperfusion after myocardial infarction are offset by maladaptive innate immune cell function, and therapeutic interventions are lacking. OBJECTIVE: We sought to test the significance of phagocytic clearance by resident and recruited phagocytes after myocardial ischemia reperfusion. METHODS AND RESULTS: In humans, we discovered that clinical reperfusion after myocardial infarction led to significant elevation of the soluble form of MerTK (myeloid-epithelial-reproductive tyrosine kinase; ie, soluble MER), a critical biomarker of compromised phagocytosis by innate macrophages. In reperfused mice, macrophage deficiency led to decreased cardiac wound debridement, increased infarct size, and depressed cardiac function, newly implicating MerTK in cardiac repair after myocardial ischemia reperfusion. More notably, ) mice, which are resistant to cleavage, showed significantly reduced infarct sizes and improved systolic function. In contrast to other cardiac phagocyte subsets, resident cardiac MHCII CCR2 (major histocompatibility complex II/C-C motif chemokine receptor type 2) macrophages expressed higher levels of MerTK and, when exposed to apoptotic cells, secreted proreparative cytokines, including transforming growth factor-ß. deficiency compromised the accumulation of MHCII phagocytes, and this was rescued in ) mice. Interestingly, blockade of CCR2-dependent monocyte infiltration into the heart reduced soluble MER levels post-ischemia reperfusion. CONCLUSIONS: Our data implicate monocyte-induced MerTK cleavage on proreparative MHCII cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury.
[Mh] Termos MeSH primário: Macrófagos/enzimologia
Traumatismo por Reperfusão Miocárdica/enzimologia
Miocárdio/enzimologia
Proteínas Proto-Oncogênicas/metabolismo
Receptores Proteína Tirosina Quinases/metabolismo
Infarto do Miocárdio com Supradesnível do Segmento ST/enzimologia
[Mh] Termos MeSH secundário: Animais
Apoptose
Citocinas/imunologia
Citocinas/metabolismo
Modelos Animais de Doenças
Feminino
Predisposição Genética para Doença
Antígenos de Histocompatibilidade Classe II/imunologia
Antígenos de Histocompatibilidade Classe II/metabolismo
Seres Humanos
Imunidade Inata
Macrófagos/imunologia
Macrófagos/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Meia-Idade
Monócitos/enzimologia
Monócitos/imunologia
Traumatismo por Reperfusão Miocárdica/imunologia
Traumatismo por Reperfusão Miocárdica/patologia
Traumatismo por Reperfusão Miocárdica/fisiopatologia
Miocárdio/imunologia
Miocárdio/patologia
Fagocitose
Fenótipo
Proteólise
Proteínas Proto-Oncogênicas/deficiência
Proteínas Proto-Oncogênicas/genética
Proteínas Proto-Oncogênicas/imunologia
Receptores Proteína Tirosina Quinases/deficiência
Receptores Proteína Tirosina Quinases/genética
Receptores Proteína Tirosina Quinases/imunologia
Receptores CCR2/genética
Receptores CCR2/imunologia
Receptores CCR2/metabolismo
Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia
Infarto do Miocárdio com Supradesnível do Segmento ST/patologia
Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia
Transdução de Sinais
Fatores de Tempo
c-Mer Tirosina Quinase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ccr2 protein, mouse); 0 (Cytokines); 0 (Histocompatibility Antigens Class II); 0 (Proto-Oncogene Proteins); 0 (Receptors, CCR2); EC 2.7.10.1 (MERTK protein, human); EC 2.7.10.1 (Mertk protein, mouse); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (c-Mer Tyrosine Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170831
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCRESAHA.117.311327


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[PMID]:28801233
[Au] Autor:Baratin M; Simon L; Jorquera A; Ghigo C; Dembele D; Nowak J; Gentek R; Wienert S; Klauschen F; Malissen B; Dalod M; Bajénoff M
[Ad] Endereço:Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France. Electronic address: baratin@ciml.univ-mrs.fr.
[Ti] Título:T Cell Zone Resident Macrophages Silently Dispose of Apoptotic Cells in the Lymph Node.
[So] Source:Immunity;47(2):349-362.e5, 2017 Aug 15.
[Is] ISSN:1097-4180
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In lymph nodes (LNs), dendritic cells (DCs) are thought to dispose of apoptotic cells, a function pertaining to macrophages in other tissues. We found that a population of CX3CR1 MERTK cells located in the T cell zone of LNs, previously identified as DCs, are efferocytic macrophages. Lineage-tracing experiments and shield chimeras indicated that these T zone macrophages (TZM) are long-lived macrophages seeded in utero and slowly replaced by blood monocytes after birth. Imaging the LNs of mice in which TZM and DCs express different fluorescent proteins revealed that TZM-and not DCs-act as the only professional scavengers, clearing apoptotic cells in the LN T cell zone in a CX3CR1-dependent manner. Furthermore, similar to other macrophages, TZM appear inefficient in priming CD4 T cells. Thus, efferocytosis and T cell activation in the LN are uncoupled processes designated to macrophages and DCs, respectively, with implications to the maintenance of immune homeostasis.
[Mh] Termos MeSH primário: Linfonodos/imunologia
Macrófagos/imunologia
Fagocitose
[Mh] Termos MeSH secundário: Animais
Apresentação do Antígeno
Apoptose
Linfócitos T CD4-Positivos/imunologia
Receptor 1 de Quimiocina CX3C
Diferenciação Celular
Linhagem da Célula
Células Cultivadas
Células Dendríticas/imunologia
Tolerância Imunológica
Ativação Linfocitária
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Proteínas Proto-Oncogênicas/metabolismo
Receptores Proteína Tirosina Quinases/metabolismo
Receptores de Quimiocinas/metabolismo
c-Mer Tirosina Quinase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CX3C Chemokine Receptor 1); 0 (Cx3cr1 protein, mouse); 0 (Proto-Oncogene Proteins); 0 (Receptors, Chemokine); EC 2.7.10.1 (Mertk protein, mouse); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (c-Mer Tyrosine Kinase)
[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:170813
[St] Status:MEDLINE


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[PMID]:28727830
[Au] Autor:Uribe DJ; Mandell EK; Watson A; Martinez JD; Leighton JA; Ghosh S; Rothlin CV
[Ad] Endereço:Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America.
[Ti] Título:The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer.
[So] Source:PLoS One;12(7):e0179979, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The receptor tyrosine kinases (RTKs) TYRO3, AXL and MERTK (TAM) have well-described oncogenic functions in a number of cancers. Notwithstanding, TAM RTKs are also potent and indispensable inhibitors of inflammation. The combined deletion of Axl and Mertk in mice enhances chronic inflammation and autoimmunity, including increased inflammation in the gut and colitis-associated cancer. On the other hand, deletion of Tyro3 increases the risk of allergic responses. Therefore, the indiscriminate inhibition of these TAM RTKs could result in undesirable immunological diseases. Here we show that AXL, but not MERTK or TYRO3 expression is enhanced in late stage colorectal cancer (CRC) and AXL expression associates with a cell migration gene signature. Silencing AXL or the inhibition of AXL kinase activity significantly inhibits tumor cell migration and invasion. These results indicate that the selective inhibition of AXL alone might confer sufficient therapeutic benefit in CRC, while preserving at least some of the beneficial, anti-inflammatory effects of MERTK and TYRO3 RTKs.
[Mh] Termos MeSH primário: Carcinoma/genética
Movimento Celular/fisiologia
Proliferação Celular/fisiologia
Neoplasias Colorretais/genética
Invasividade Neoplásica/genética
Proteínas Proto-Oncogênicas/genética
Receptores Proteína Tirosina Quinases/genética
[Mh] Termos MeSH secundário: Carcinoma/metabolismo
Carcinoma/patologia
Linhagem Celular Tumoral
Neoplasias Colorretais/metabolismo
Neoplasias Colorretais/patologia
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Invasividade Neoplásica/patologia
Proteínas Proto-Oncogênicas/metabolismo
Receptores Proteína Tirosina Quinases/metabolismo
c-Mer Tirosina Quinase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proto-Oncogene Proteins); EC 2.7.10.1 (MERTK protein, human); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (TYRO3 protein, human); EC 2.7.10.1 (axl receptor tyrosine kinase); EC 2.7.10.1 (c-Mer Tyrosine Kinase)
[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:170721
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179979


  9 / 355 MEDLINE  
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[PMID]:28668213
[Au] Autor:Ochodnicky P; Lattenist L; Ahdi M; Kers J; Uil M; Claessen N; Leemans JC; Florquin S; Meijers JCM; Gerdes VEA; Roelofs JJTH
[Ad] Endereço:Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
[Ti] Título:Increased Circulating and Urinary Levels of Soluble TAM Receptors in Diabetic Nephropathy.
[So] Source:Am J Pathol;187(9):1971-1983, 2017 Sep.
[Is] ISSN:1525-2191
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:TAM receptors (Tyro3, Axl, and Mer) have been implicated in innate immunity. Circulating TAM receptor soluble forms (sTyro3, sAxl, sMer) are related to autoimmune disorders. We investigated TAM and their ligand protein S in patients with diabetes. Urinary and plasma levels of protein S, sTyro3, sAxl, and sMer were determined in 126 patients with diabetes assigned to a normoalbuminuric or macroalbuminuric (urinary albumin excretion <30 mg/24 hours and >300 mg/24 hours, respectively) study group and 18 healthy volunteers. TAM and protein S immunostaining was performed on kidney biopsy specimens from patients with diabetic nephropathy (n = 9) and controls (n = 6). TAM expression and shedding by tubular epithelial cells were investigated by PCR and enzyme-linked immunosorbent assay in an in vitro diabetes model. Patients with macroalbuminuria diabetes had higher circulating levels of sMer and more urinary sTyro3 and sMer than normoalbuminuric diabetics. Increased clearance of sTyro3 and sMer was associated with loss of tubular Tyro3 and Mer expression in diabetic nephropathy tissue and glomerular depositions of protein S. During in vitro diabetes, human kidney cells had down-regulation of Tyro3 and Mer mRNA and increased shedding of sTyro3 and sMer. Renal injury in diabetes is associated with elevated systemic and urine levels of sMer and sTyro3. This is the first study reporting excretion of sTAM receptors in urine, identifying the kidney as a source of sTAM.
[Mh] Termos MeSH primário: Nefropatias Diabéticas/metabolismo
Proteína S/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
Receptores Proteína Tirosina Quinases/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Linhagem Celular
Nefropatias Diabéticas/sangue
Nefropatias Diabéticas/urina
Feminino
Seres Humanos
Glomérulos Renais/metabolismo
Masculino
Meia-Idade
Proteína S/urina
Proteínas Proto-Oncogênicas/sangue
Proteínas Proto-Oncogênicas/urina
Receptores Proteína Tirosina Quinases/sangue
Receptores Proteína Tirosina Quinases/urina
c-Mer Tirosina Quinase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein S); 0 (Proto-Oncogene Proteins); EC 2.7.10.1 (MERTK protein, human); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (TYRO3 protein, human); EC 2.7.10.1 (axl receptor tyrosine kinase); EC 2.7.10.1 (c-Mer Tyrosine Kinase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170703
[St] Status:MEDLINE


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[PMID]:28539349
[Au] Autor:Bellesi M; de Vivo L; Chini M; Gilli F; Tononi G; Cirelli C
[Ad] Endereço:Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin 53719.
[Ti] Título:Sleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex.
[So] Source:J Neurosci;37(21):5263-5273, 2017 May 24.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We previously found that and its ligand , astrocytic genes involved in phagocytosis, are upregulated after acute sleep deprivation. These results suggested that astrocytes may engage in phagocytic activity during extended wake, but direct evidence was lacking. Studies in humans and rodents also found that sleep loss increases peripheral markers of inflammation, but whether these changes are associated with neuroinflammation and/or activation of microglia, the brain's resident innate immune cells, was unknown. Here we used serial block-face scanning electron microscopy to obtain 3D volume measurements of synapses and surrounding astrocytic processes in mouse frontal cortex after 6-8 h of sleep, spontaneous wake, or sleep deprivation (SD) and after chronic (∼5 d) sleep restriction (CSR). Astrocytic phagocytosis, mainly of presynaptic components of large synapses, increased after both acute and chronic sleep loss relative to sleep and wake. MERTK expression and lipid peroxidation in synaptoneurosomes also increased to a similar extent after short and long sleep loss, suggesting that astrocytic phagocytosis may represent the brain's response to the increase in synaptic activity associated with prolonged wake, clearing worn components of heavily used synapses. Using confocal microscopy, we then found that CSR but not SD mice show morphological signs of microglial activation and enhanced microglial phagocytosis of synaptic elements, without obvious signs of neuroinflammation in the CSF. Because low-level sustained microglia activation can lead to abnormal responses to a secondary insult, these results suggest that chronic sleep loss, through microglia priming, may predispose the brain to further damage. We find that astrocytic phagocytosis of synaptic elements, mostly of presynaptic origin and in large synapses, is upregulated already after a few hours of sleep deprivation and shows a further significant increase after prolonged and severe sleep loss, suggesting that it may promote the housekeeping of heavily used and strong synapses in response to the increased neuronal activity of extended wake. By contrast, chronic sleep restriction but not acute sleep loss activates microglia, promotes their phagocytic activity, and does so in the absence of overt signs of neuroinflammation, suggesting that like many other stressors, extended sleep disruption may lead to a state of sustained microglia activation, perhaps increasing the brain's susceptibility to other forms of damage.
[Mh] Termos MeSH primário: Astrócitos/metabolismo
Córtex Cerebral/metabolismo
Microglia/metabolismo
Fagocitose
Privação do Sono/metabolismo
[Mh] Termos MeSH secundário: Animais
Córtex Cerebral/citologia
Córtex Cerebral/fisiopatologia
Feminino
Peptídeos e Proteínas de Sinalização Intercelular/genética
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Proteínas Proto-Oncogênicas/genética
Proteínas Proto-Oncogênicas/metabolismo
Receptores Proteína Tirosina Quinases/genética
Receptores Proteína Tirosina Quinases/metabolismo
Sinapses/metabolismo
c-Mer Tirosina Quinase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Intercellular Signaling Peptides and Proteins); 0 (Proto-Oncogene Proteins); 0 (growth arrest-specific protein 6); EC 2.7.10.1 (Mertk protein, mouse); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (c-Mer Tyrosine Kinase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3981-16.2017



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