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1.
Cell Death Differ ; 23(8): 1322-30, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26990660

RESUMO

Establishment of cell-cell adhesion is crucial in embryonic development as well as within the stem cell niches of an adult. Adhesion between macrophages and erythroblasts is required for the formation of erythroblastic islands, specialized niches where erythroblasts proliferate and differentiate to produce red blood cells throughout life. The Eph family is the largest known family of receptor tyrosine kinases (RTKs) and controls cell adhesion, migration, invasion and morphology by modulating integrin and adhesion molecule activity and by modifying the actin cytoskeleton. Here, we identify the proteoglycan agrin as a novel regulator of Eph receptor signaling and characterize a novel mechanism controlling cell-cell adhesion and red cell development within the erythroid niche. We demonstrate that agrin induces clustering and activation of EphB1 receptors on developing erythroblasts, leading to the activation of α5ß1 integrins. In agreement, agrin knockout mice display severe anemia owing to defective adhesion to macrophages and impaired maturation of erythroid cells. These results position agrin-EphB1 as a novel key signaling couple regulating cell adhesion and erythropoiesis.


Assuntos
Agrina/metabolismo , Adesão Celular/fisiologia , Transdução de Sinais/fisiologia , Agrina/deficiência , Agrina/genética , Animais , Sobrevivência Celular , Eritrócitos/citologia , Eritrócitos/metabolismo , Receptores de Hialuronatos/metabolismo , Integrina alfa5beta1/metabolismo , Proteínas Relacionadas a Receptor de LDL , Células Progenitoras de Megacariócitos/citologia , Células Progenitoras de Megacariócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Fosforilação , Receptor EphB1/metabolismo , Receptores de LDL/metabolismo , Baço/patologia
2.
Leukemia ; 30(5): 1143-54, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26898191

RESUMO

Mesenchymal stem cells (MSC) represent a promising therapeutic approach in many diseases in view of their potent immunomodulatory properties, which are only partially understood. Here, we show that the endothelium is a specific and key target of MSC during immunity and inflammation. In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC, and increasing TIMP-1 concentrations delivered by an Adeno Associated Virus (AAV) vector recapitulates the effects of MSC transplantation on draining LNs. Thus, this study discovers a new and highly efficient general mechanism through which MSC tune down immunity and inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.


Assuntos
Células Endoteliais/metabolismo , Linfonodos/citologia , Linfócitos/fisiologia , Células-Tronco Mesenquimais/fisiologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidores da Angiogênese , Animais , Técnicas de Transferência de Genes , Vetores Genéticos , Inflamação , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Camundongos , Inibidor Tecidual de Metaloproteinase-1/administração & dosagem , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/farmacologia
3.
Eur J Clin Invest ; 37(7): 552-7, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17576206

RESUMO

BACKGROUND: Macroprolactinaemia may represent a relevant cause of misdiagnosis, unnecessary investigation and inappropriate treatment. The aim of this study was to investigate the clinical and neuroradiological characteristics of patients with and without macroprolactinaemia and to evaluate the impact of macroprolactin determination on the diagnostic work-up of hyperprolactinaemic patients. MATERIALS AND METHODS: Retrospective analysis in 135 consecutive hyperprolactinaemic patients (111 women and 24 men; mean age 37 +/- 11.6 years) whose archived sera were subsequently tested for macroprolactin. Recoveries

Assuntos
Adenoma/sangue , Hiperprolactinemia/sangue , Hipófise/diagnóstico por imagem , Neoplasias Hipofisárias/sangue , Prolactina/análise , Adenoma/diagnóstico , Adenoma/diagnóstico por imagem , Adulto , Biomarcadores , Diagnóstico Diferencial , Feminino , Humanos , Hiperprolactinemia/diagnóstico , Hiperprolactinemia/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Hipófise/patologia , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/diagnóstico por imagem , Prolactina/sangue , Radiografia , Estudos Retrospectivos
4.
Eur J Endocrinol ; 154(1): 83-6, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16381995

RESUMO

OBJECTIVE: In vitro and in vivo models indicate that all-trans retinoic acids influence glucose and lipid metabolism. We aimed to evaluate the effects of chronic treatment with acitretin, an all-trans retinoic acid, on glucose metabolism, lipid profile and adiponectin and resistin levels. DESIGN: Ten normoglycemic, normolipemic patients affected with psoriasis vulgaris were studied before and after 1 and 3 months of oral treatment with 35 microg of acitretin. METHODS: Glucose metabolism, lipid profile, and adiponectin and resistin levels were evaluated in basal conditions and after acitretin treatment. Ten healthy subjects matched for age, body mass index (BMI) and insulin sensitivity were studied as controls. RESULTS: One-month acitretin treatment reduced psoriasis activity, insulin sensitivity, evaluated as QUICKI values (0.364 +/- 0.034 versus 0.329 +/- 0.051; P < 0.05) and HOMA-IR index (1.53 +/- 0.73 versus 2.59 +/- 1.41; P < 0.05), and high-density lipoprotein (HDL)-cholesterol levels (45.2 +/- 11.7 versus 39.4 +/- 10.4 mg/dl; P = 0.01). The impairment in glucose and lipid homeostasis was transient and not associated to BMI variations. Adiponectin levels did not change during the treatment, while resistin levels, which were higher in untreated patients than in controls (9.4 +/- 4.4 versus 6.2 +/- 2.1 ng/ml; P = 0.05), fell within the normal range after 1 and 3 months of therapy. The normalization of resistin levels occurred without significant changes in circulating tumor necrosis factor alpha (TNFalpha) levels, which persisted elevated throughout the treatment. CONCLUSIONS: Treatment with a low dose of acitretin induced a mild, transient reduction of insulin sensitivity and HDL-cholesterol levels that was not related to modifications of adiponectin, resistin and TNFalpha levels. Although the role of resistin in humans remains elusive, the levels of this adipocytokine seem to be affected, at least in part, by retinoids.


Assuntos
Acitretina/uso terapêutico , Adiponectina/sangue , Resistência à Insulina/fisiologia , Lipídeos/sangue , Psoríase/tratamento farmacológico , Resistina/sangue , Adulto , Glicemia/metabolismo , HDL-Colesterol/sangue , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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