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1.
Medicina (Kaunas) ; 59(10)2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37893495

RESUMO

Background and Objectives: Hypertension and vascular damage can begin in adolescents affected by Autosomal Dominant Polycystic Kidney Disease (ADPKD). This study aimed to evaluate markers of vascular damage and left ventricular geometry in a sample of children with ADPKD. Materials and Methods: Several vascular measurements were obtained: ambulatory blood pressure monitoring (ABPM), carotid intima-media thickness (cIMT), carotid distensibility coefficient (cDC), pulse wave velocity (PWV), and echocardiographic measurements (relative wall thickness (RWT) and left ventricular mass index (LVMI)). Results: Eleven ADPKD children were recruited (four females and seven males, mean age 9.5 ± 3.2 years). Four children were hypertensive at the ABPM, five were normotensive, and for two ABPM was not available. RWT was tendentially high (mean 0.47 ± 0.39). Eight patients had concentric cardiac remodeling, while one patient had cardiac hypertrophy. cIMT was above the 95° percentile for sex and height in 80% of the children (0.5 ± 0.005 mm). The average PWV and cDC were between the normal range (5.5 ± 4.6 m/s and 89.6 ± 16.1 × 10-3/KPa, respectively). We observed a positive correlation between the PWV and RWT (r = 0.616; p = 0.044) and a negative correlation between cDC and RWT (r = -0.770; p = 0.015). Cardiovascular damages (cIMT > 95° percentile) were found in normotensive patients. Conclusions: Increased RWT and high cIMT, indicating subclinical organ damage, are already present in ADPKD children. RWT was significantly correlated to that of cDC and PWV, implying that vascular stiffening is associated with cardiac remodeling. None of the children had an alteration in renal function. Subclinical cardiovascular damage preceded the decline in glomerular filtration rate.


Assuntos
Hipertensão , Rim Policístico Autossômico Dominante , Masculino , Feminino , Adolescente , Humanos , Criança , Rim Policístico Autossômico Dominante/complicações , Projetos Piloto , Espessura Intima-Media Carotídea , Monitorização Ambulatorial da Pressão Arterial , Análise de Onda de Pulso , Remodelação Ventricular , Hipertensão/complicações , Pressão Sanguínea , Hipertrofia Ventricular Esquerda/etiologia
2.
Am J Pathol ; 174(3): 1037-47, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19179604

RESUMO

The growth factor proepithelin has recently emerged as an important regulator of transformation in several physiological and pathological systems. In this study, we determined the biological roles of proepithelin in prostate cancer cells using purified human recombinant proepithelin as well as proepithelin-depletion strategies. Proepithelin promoted the migration of androgen-dependent and -independent human prostate cancer cells; androgen-independent DU145 cells were the more responsive. In these cells, proepithelin additionally stimulated wound closure, invasion, and promotion of cell growth in vitro. These effects required the activation of both the Akt and mitogen-activated protein kinase pathways. We have analyzed proepithelin expression levels in different available prostate cancer microarray studies using the Oncomine database and found a statistically significant increase in proepithelin mRNA expression levels in prostate cancers compared with nonneoplastic controls. Notably, depletion of endogenous proepithelin by siRNA and antisense strategies impaired the ability of DU145 cells to grow and migrate after serum withdrawal and inhibited anchorage-independent growth. Our results provide the first evidence for a role of proepithelin in stimulating the migration, invasion, proliferation, and anchorage-independent growth of prostate cancer cells. This study supports the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and initial progression of prostate cancer. Furthermore, proepithelin may prove to be a useful clinical marker for the diagnosis of prostate tumors.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Neoplasias da Próstata/patologia , Divisão Celular , Linhagem Celular Tumoral , Movimento Celular , Inativação Gênica , Granulinas , Homeostase , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Invasividade Neoplásica , Progranulinas , Neoplasias da Próstata/genética , Precursores de Proteínas/genética , Precursores de Proteínas/fisiologia , Transdução de Sinais , Cicatrização
3.
J Cell Physiol ; 216(2): 426-37, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18286479

RESUMO

The adaptor protein Grb10 is an interacting partner of the IGF-I receptor (IGF-IR) and the insulin receptor (IR). Previous work from our laboratory has established the role of Grb10 as a negative regulator of IGF-IR-dependent cell proliferation. We have shown that Grb10 binds the E3 ubiquitin ligase Nedd4 and promotes IGF-I-stimulated ubiquitination, internalization, and degradation of the IGF-IR, thereby giving rise to long-term attenuation of signaling. Recent biochemical evidence suggests that tyrosine-kinase receptors (RTK) may not be polyubiquitinated but monoubiquitinated at multiple sites (multiubiquitinated). However, the type of ubiquitination of the IGF-IR is still not defined. Here we show that the Grb10/Nedd4 complex upon ligand stimulation mediates multiubiquitination of the IGF-IR, which is required for receptor internalization. Moreover, Nedd4 by promoting IGF-IR ubiquitination and internalization contributes with Grb10 to negatively regulate IGF-IR-dependent cell proliferation. We also demonstrate that the IGF-IR is internalized through clathrin-dependent and-independent pathways. Grb10 and Nedd4 remain associated with the IGF-IR in early endosomes and caveosomes, where they may participate in sorting internalized receptors. Grb10 and Nedd4, unlike the IGF-IR, which is targeted for lysosomal degradation are not degraded and likely directed into recycling endosomes. These results indicate that Grb10 and Nedd4 play a critical role in mediating IGF-IR down-regulation by promoting ligand-dependent multiubiquitination of the IGF-IR, which is required for receptor internalization and regulates mitogenesis.


Assuntos
Proteína Adaptadora GRB10/metabolismo , Poliubiquitina/metabolismo , Receptor IGF Tipo 1/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Caveolina 1/genética , Caveolina 1/metabolismo , Linhagem Celular , Proliferação de Células , Clatrina/genética , Clatrina/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte , Endossomos/metabolismo , Proteína Adaptadora GRB10/genética , Lisossomos/metabolismo , Camundongos , Complexos Multiproteicos/metabolismo , Ubiquitina-Proteína Ligases Nedd4 , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
4.
J Cell Sci ; 119(Pt 21): 4574-84, 2006 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17074837

RESUMO

The detection of EMILIN1, a connective tissue glycoprotein associated with elastic fibers, at the level of the ectoplacental cone and trophoblast giant cells of developing mouse embryos (Braghetta et al., 2002) favored the idea of a structural as well as a functional role for this protein in the process of placentation. During the establishment of human placenta, a highly migratory subpopulation of extravillous trophoblasts (EVT), originating from anchoring chorionic villi, penetrate and invade the uterine wall. In this study we show that EMILIN1, produced by decidual stromal and smooth muscle uterine cells, is expressed in the stroma and in some instances as a gradient of increasing concentration in the perivascular region of modified vessels. This distribution pattern is consistent with the haptotactic directional migration observed in in vitro functional studies of freshly isolated EVT and of the immortalized HTR-8/SVneo cell line of trophoblasts. Function-blocking monoclonal antibodies against alpha4-integrin chain and against EMILIN1 as well as the use of EMILIN1-specific short interfering RNA confirmed that trophoblasts interact with EMILIN1 and/or its functional gC1q1 domain via alpha4beta1 integrin. Finally, membrane type I-matrix metalloproteinase (MT1-MMP) and MMP-2 were upregulated in co-cultures of trophoblast cells and stromal cells, suggesting a contributing role in the haptotactic process towards EMILIN1.


Assuntos
Movimento Celular , Glicoproteínas de Membrana/metabolismo , Invasividade Neoplásica/patologia , Células Estromais/patologia , Trofoblastos/fisiologia , Útero/patologia , Adesão Celular , Vilosidades Coriônicas/metabolismo , Decídua/citologia , Decídua/metabolismo , Feminino , Humanos , Integrina alfa4beta1/metabolismo , Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz Associadas à Membrana/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Placenta/citologia , Placenta/metabolismo , Gravidez , Primeiro Trimestre da Gravidez , RNA Interferente Pequeno/farmacologia , Células Estromais/metabolismo
5.
Cancer Res ; 66(14): 7103-10, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16849556

RESUMO

The growth factor proepithelin (also known as progranulin, acrogranin, PC-derived growth factor, or granulin-epithelin precursor) is a secreted glycoprotein that functions as an important regulator of cell growth, migration, and transformation. Proepithelin is overexpressed in a great variety of cancer cell lines and clinical specimens of breast, ovarian, and renal cancer as well as glioblastomas. In this study, we have investigated the effects of proepithelin on bladder cancer cells using human recombinant proepithelin purified to homogeneity from 293-EBNA cells. Although proepithelin did not appreciably affect cell growth, it did promote migration of 5637 bladder cancer cells and stimulate in vitro wound closure and invasion. These effects required the activation of the mitogen-activated protein kinase pathway and paxillin, which upon proepithelin stimulation formed a complex with focal adhesion kinase and active extracellular signal-regulated kinase. Our results provide the first evidence for a role of proepithelin in stimulating migration and invasion of bladder cancer cells, and support the hypothesis that this growth factor may play a critical role in the establishment of the invasive phenotype.


Assuntos
Carcinoma de Células de Transição/patologia , Movimento Celular/fisiologia , Quinase 1 de Adesão Focal/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Paxilina/metabolismo , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células de Transição/enzimologia , Ativação Enzimática , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Sistema de Sinalização das MAP Quinases , Invasividade Neoplásica , Progranulinas , Precursores de Proteínas/metabolismo , Precursores de Proteínas/farmacologia , Proteínas Recombinantes/farmacologia , Neoplasias da Bexiga Urinária/enzimologia
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