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1.
J Biol Regul Homeost Agents ; 24(3): 239-49, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20846472

RESUMO

The second half of the XX century saw a continuous improvement in the understanding of cellular immunology. The discovery of monoclonal antibodies permitted to identify several functional T-cell subpopulations, characterized by a specific pattern of cytokine secretion. According to their functions, cytokines have been divided into two main groups: pro- and anti- inflammatory. Cytokines are involved in several aspects of immunity and inflammation. Because of its importance in host defence, the cytokine system is redundant and therefore different cytokines may perform similar activities. Although cytokines and inflammatory processes have been studied widely in the peripheral blood, it is our opinion that the most important pathogenetic events occur at the tissue level, therefore the study of Tissue-infiltrating lymphocytes (TIL) is of foremost importance. In this review we therefore focus on the cytokine microenvironment; different local tissue cytokine-cocktails can modulate and regulate T-cell proliferation and differentiation. CD4+ T-cells are not characterized by irreversibly differentiated endpoints, but there is an evident plasticity of these cells with a large possibility of differentiation options. We will discuss the issue and give examples of the diseases where the study of TIL and their microenvironment are most significant, including tumors, primary immunodeficiencies, rheumathoid arthritis, inflammatory skin diseases and coronary disease. We also review the role of apoptosis and the environment of mucosal immunity.


Assuntos
Citocinas/fisiologia , Linfócitos/fisiologia , Animais , Apoptose , Autoimunidade , Diferenciação Celular , Dermatite/etiologia , Humanos , Imunidade nas Mucosas , Inflamação/etiologia , Linfócitos/citologia , Neoplasias/etiologia
2.
Amino Acids ; 36(4): 679-84, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18594942

RESUMO

Transglutaminase (TGs) enzymes and proteins crosslinking have for long time been implicated in the formation of hard tissue development, matrix maturation and mineralization. Among the TGs family members, in the context of connective tissue formation, TG2 and Factor XIII are expressed in cartilage by hypertrophic chondrocytes. Here, we analyse the morphological consequences of TG2 deficiency, during the development of skeletal elements. When TG2 is absent, there are not gross abnormalities in the development of the skeletal system, probably from compensatory mechanisms resulting in increased expression of FXIIIA and TGF-beta 1. In vivo other TGs may be involved in promoting chondrocytes and osteoblast differentiation and matrix mineralisation.


Assuntos
Fator XIIIa/biossíntese , Proteínas de Ligação ao GTP/deficiência , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/metabolismo , Fator de Crescimento Transformador beta1/biossíntese , Transglutaminases/deficiência , Animais , Fator XIIIa/genética , Proteínas de Ligação ao GTP/genética , Camundongos , Camundongos Knockout , Músculo Esquelético/enzimologia , Músculo Esquelético/crescimento & desenvolvimento , Fenótipo , Proteína 2 Glutamina gama-Glutamiltransferase , Fator de Crescimento Transformador beta1/genética , Transglutaminases/genética
3.
Oncogene ; 35(24): 3114-24, 2016 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-26522723

RESUMO

Epidermal homeostasis depends on the coordinated control of keratinocyte cell cycle. Differentiation and the alteration of this balance can result in neoplastic development. Here we report on a novel DLX3-dependent network that constrains epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrate that DLX3 operates through a p53-regulated network. DLX3 and p53 physically interact on the p21 promoter to enhance p21 expression. Elevating DLX3 in keratinocytes produces a G1-S blockade associated with p53 signature transcriptional profiles. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK. DLX3 expression is lost in human skin cancers and is extinguished during progression of experimentally induced mouse squamous cell carcinoma (SCC). Reinstatement of DLX3 function is sufficient to attenuate the migration of SCC cells, leading to decreased wound closure. Our data establish the DLX3-p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis.


Assuntos
Carcinoma de Células Escamosas/patologia , Proteínas de Homeodomínio/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Carcinogênese , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Pontos de Checagem do Ciclo Celular , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Progressão da Doença , Feminino , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Transfecção , Proteína Supressora de Tumor p53/genética
4.
Transplant Proc ; 46(7): 2350-3, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25242785

RESUMO

INTRODUCTION: Safety in conducting a clinical trial is a prerequisite for patients who will be enrolled into that study. The aim of the present study was to evaluate retrospectively if patient and graft survival were similar among patients who participated in clinical trials versus those who did not. PATIENTS AND METHODS: We evaluated pretransplant and posttransplant characteristics of 245 kidney transplant (KT) patients who were selected to participate in at least one Phase II/Phase III clinical trial. We compared them with 361 KT patients who were not enrolled or refused to participate in those clinical trials; all studies were conducted at a single transplant center. Inclusion/exclusion criteria were as noted for each individual protocol. Only studies with enrollment at time of graft implant were considered. RESULTS: Selection of patients participating in clinical trials in general exclude high-risk patients. In our experience, only 36% of transplanted patients were selected for a multicenter, prospective, randomized, international study that included changes to the strategies in the administration of immunosuppressive drugs already on the market or development of a new immunosuppressant. After 5 years, graft and patient survival rates were similar between those who participated and those who did not participate in a clinical study. Although our data were collected retrospectively, an alternative design to achieve these conclusions would be a noninferiority study. CONCLUSIONS: Our results demonstrated similar rates of graft and patient survival among enrolled patients versus nonenrolled patients. Outcome surveillance offers safety in participating in clinical trials that involve changes in standard immunosuppression therapy and are part of the research necessary to develop patient-centered medical interventions.


Assuntos
Transplante de Rim , Sujeitos da Pesquisa , Adulto , Causas de Morte , Ensaios Clínicos como Assunto , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Humanos , Itália/epidemiologia , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes
5.
Neurology ; 64(11): 1931-7, 2005 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-15955946

RESUMO

BACKGROUND: Dominant mutations in COL6A1, COL6A2, and COL6A3, the three genes encoding collagen type VI, a ubiquitous extracellular matrix protein, are associated with Bethlem myopathy (BM) and Ullrich scleroatonic muscular dystrophy. METHODS: The authors devised a method to screen the entire coding sequence of the three genes by reverse transcriptase-PCR amplification of total RNA from skin fibroblasts and direct sequencing of the resulting 25 overlapping cDNA fragments covering 107 exons. RESULTS: Four splicing and four missense mutations were identified in 16 patients with BM, six of which are novel mutations in COL6A1. Both common and private mutations are localized in the alpha1 (VI) chain between the regions corresponding to the 3' end of the NH2-globular domain and the 5' end of the triple helix, encoded by exons 3 through 14. CONCLUSIONS: The clustering of the mutations in a relatively narrow area of the three collagen type VI chains in patients with Bethlem myopathy (BM) suggests that mutations in different regions could result in different phenotypes or in no phenotype at all. Moreover, the detection of mutations in only 60% of the patients suggests the existence of at least another gene associated with BM. The authors propose the direct sequencing of COL6 cDNAs as the first mutation screening analysis in BM, given the high number of exon-skipping events.


Assuntos
Colágeno Tipo VI/genética , Doenças Musculares/genética , Mutação/genética , Adolescente , Adulto , Processamento Alternativo/genética , Substituição de Aminoácidos/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons/genética , Feminino , Testes Genéticos , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologia , Mutação de Sentido Incorreto/genética , Linhagem , Subunidades Proteicas/genética , RNA Mensageiro/análise , RNA Mensageiro/genética
6.
Amino Acids ; 26(4): 405-8, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15290346

RESUMO

Transglutaminases are a class of nine different proteins involved in many biological phenomena such as differentiation, tissue repair, endocytosis. Transglutaminase 5 was originally cloned from skin keratinocytes, and a partial biochemical characterization showed its involvement in skin differentiation. Here we demonstrate that transglutaminase 5 is able to induce cell death when intracellularly overexpressed. Transfected cells show enzymatic activity, as demonstrated by fluoresceincadaverine staining. Transfected cells died due to the formation of hypodiploid DNA content, indicating the induction of cell death under these pharmacological conditions. We also show that the primary sequence of transglutaminase 5 contains GTP binding domains which are similar to those in transglutaminase 2. This raises the possibility that transglutaminase 5 is regulated by GTP in a similar fashion to transglutaminase 2.


Assuntos
Morte Celular/fisiologia , Transglutaminases/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular , Guanosina Trifosfato/metabolismo , Humanos , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Alinhamento de Sequência , Transglutaminases/química , Transglutaminases/genética
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