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1.
J Biol Chem ; 298(8): 102225, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35780836

RESUMO

Ephrin-B signaling has been implicated in many normal and pathological processes, including neural crest development and tumor metastasis. We showed previously that proteolysis of ephrin-B ligands by the disintegrin metalloprotease ADAM13 is necessary for canonical Wnt signal activation and neural crest induction in Xenopus, but it was unclear if these mechanisms are conserved in mammals. Here, we report that mammalian ADAM9 cleaves ephrin-B1 and ephrin-B2 and can substitute for Xenopus ADAM13 to induce the neural crest. We found that ADAM9 expression is elevated in human colorectal cancer (CRC) tissues and that knockdown (KD) of ADAM9 inhibits the migration and invasion of SW620 and HCT116 CRC cells by reducing the activity of Akt kinase, which is antagonized by ephrin-Bs. Akt is a signaling node that activates multiple downstream pathways, including the Wnt and mTOR pathways, both of which can promote CRC cell migration/invasion. Surprisingly, we also found that KD of ADAM9 downregulates Wnt signaling but has negligible effects on mTOR signaling in SW620 cells; in contrast, mTOR activity is suppressed while Wnt signaling remains unaffected by ADAM9 KD in HCT116 cells. These results suggest that mammalian ADAM9 cleaves ephrin-Bs to derepress Akt and promote CRC migration and invasion; however, the signaling pathways downstream of Akt are differentially regulated by ADAM9 in different CRC cell lines, reflecting the heterogeneity of CRC cells in responding to manipulations of upstream Akt regulators.


Assuntos
Proteínas ADAM/metabolismo , Neoplasias Colorretais , Efrinas , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/patologia , Humanos , Ligantes , Mamíferos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Metaloproteases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Via de Sinalização Wnt
2.
Cell Rep ; 35(6): 109118, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979626

RESUMO

As a critical machinery for rapid pathogen removal, resident memory T cells (TRMs) are locally generated after the initial encounter. However, their development accompanying tumorigenesis remains elusive. Using a murine breast cancer model, we show that TRMs develop in the tumor, the contralateral mammary mucosa, and the pre-metastatic lung. Single-cell RNA sequencing of TRMs reveals two phenotypically distinct populations representing their active versus quiescent phases. These TRMs in different tissue compartments share the same TCR clonotypes and transcriptomes with a subset of intratumoral effector/effector memory T cells (TEff/EMs), indicating their developmental ontogeny. Furthermore, CXCL16 is highly produced by tumor cells and CXCR6- TEff/EMs are the major subset preferentially egressing the tumor to form distant TRMs. Functionally, releasing CXCR6 retention in the primary tumor amplifies tumor-derived TRMs in the lung and leads to superior protection against metastases. This immunologic fortification suggests a potential strategy to prevent metastasis in clinical oncology.


Assuntos
Células T de Memória/metabolismo , Neoplasias/genética , Animais , Humanos , Camundongos , Metástase Neoplásica , Transfecção
3.
Diseases ; 9(1)2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33804610

RESUMO

Several diseases originate via dysregulation of the actin cytoskeleton. The ARID3A/Bright transcription factor has also been implicated in malignancies, primarily those derived from hematopoietic lineages. Previously, we demonstrated that ARID3A shuttles between the nucleus and the plasma membrane, where it localizes within lipid rafts. There it interacts with components of the B-cell receptor (BCR) to reduce its ability to transmit downstream signaling. We demonstrate here that a direct component of ARID3A-regulated BCR signal strength is cortical actin. ARID3A interacts with actin exclusively within lipid rafts via the actin-binding protein EZRIN, which confines unstimulated BCRs within lipid rafts. BCR ligation discharges the ARID3A-EZRIN complex from lipid rafts, allowing the BCR to initiate downstream signaling events. The ARID3A-EZRIN interaction occurs almost exclusively within unpolymerized G-actin, where EZRIN interacts with the multifunctional ARID3A REKLES domain. These observations provide a mechanism by which a transcription factor directly regulates BCR signaling via linkage to the actin cytoskeleton with consequences for B-cell-related neoplasia.

4.
Biochem Mol Biol Educ ; 48(6): 646-647, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32919430

RESUMO

Readily available, free, computational approaches, adaptable for topics accessible for first to senior year classes and individual research projects, emphasizing contributions of noncovalent interactions to structure, binding and catalysis were used to teach Course-based Undergraduate Research Experiences that fulfil generally accepted main CURE components: Scientific Background, Hypothesis Development, Proposal, Experiments, Teamwork, Data Analysis of quantitative data, Conclusions, and Presentation.


Assuntos
Bioquímica/educação , Simulação por Computador , Proteínas , Software , Ensino , Humanos , Conformação Proteica , Relação Estrutura-Atividade
5.
Front Genet ; 11: 771, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849789

RESUMO

Recent progress in high throughput sequencing technologies has provided an opportunity to probe T cell receptor (TCR) repertoire, bringing about an explosion of TCR sequencing data and analysis tools. For easier and more heuristic analysis TCR sequencing data, we developed a client-based HTML program (VisTCR). It has a data storage module and a data analysis module that integrate multiple cutting-edge analysis algorithms in a hierarchical fashion. Researchers can group and re-group samples for different analysis purposes by customized "Experiment Design File." Moreover, the VisTCR provides a user-friendly interactive interface, by all the TCR analysis methods and visualization results can be accessed and saved as tables or graphs in the process of analysis. The source code is freely available at https://github.com/qingshanni/VisTCR.

6.
J Allergy Clin Immunol ; 146(5): 1016-1026, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32298699

RESUMO

BACKGROUND: Whether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown. OBJECTIVE: We sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma. METHODS: Bacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines. RESULTS: Sputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders. CONCLUSIONS: Novel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.


Assuntos
Corticosteroides/uso terapêutico , Asma/microbiologia , Hipersensibilidade Imediata/microbiologia , Microbiota/genética , Boca/microbiologia , Escarro/microbiologia , Células Th2/imunologia , Administração por Inalação , Adulto , Asma/tratamento farmacológico , Biomarcadores , Citocinas/metabolismo , Feminino , Humanos , Hipersensibilidade Imediata/tratamento farmacológico , Masculino , Resultado do Tratamento
7.
J Med Chem ; 63(1): 283-294, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31793781

RESUMO

Autoimmune diseases are chronic inflammatory diseases associated with high morbidity and mortality. Treatment options for autoimmune diseases have increased over the past several decades, but they are, in general, limited in their clinical efficacy due to high toxicity and lack of selectivity. Thus, efforts must be made to identify new immunomodulatory agents that are effective through a novel mechanism to circumvent existing side effects. To define the structural requirements of subglutinols for immunomodulatory activity and to provide guiding principles on future therapeutic development, we prepared and evaluated several subglutinol analogs for their immunomodulatory activities. Our efforts identified a subglutinol analog with reduced structural complexity as a potential lead compound for future autoimmune drug development. Our study will provide an important framework for the design of potent and nontoxic immunomodulating agents derived from subglutinols.


Assuntos
Diterpenos/uso terapêutico , Imunossupressores/uso terapêutico , Pironas/uso terapêutico , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/toxicidade , Imunossupressores/síntese química , Imunossupressores/toxicidade , Interferon gama/metabolismo , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Pironas/síntese química , Pironas/toxicidade , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos
8.
Microbiome ; 6(1): 104, 2018 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-29885665

RESUMO

BACKGROUND: Perturbations to the composition and function of bronchial bacterial communities appear to contribute to the pathophysiology of asthma. Unraveling the nature and mechanisms of these complex associations will require large longitudinal studies, for which bronchoscopy is poorly suited. Studies of samples obtained by sputum induction and nasopharyngeal brushing or lavage have also reported asthma-associated microbiota characteristics. It remains unknown, however, whether the microbiota detected in these less-invasive sample types reflect the composition of bronchial microbiota in asthma. RESULTS: Bacterial microbiota in paired protected bronchial brushings (BB; n = 45), induced sputum (IS; n = 45), oral wash (OW; n = 45), and nasal brushings (NB; n = 27) from adults with mild atopic asthma (AA), atopy without asthma (ANA), and healthy controls (HC) were profiled using 16S rRNA gene sequencing. Though microbiota composition varied with sample type (p < 0.001), compositional similarity was greatest for BB-IS, particularly in AAs and ANAs. The abundance of genera detected in BB correlated with those detected in IS and OW (r median [IQR] 0.869 [0.748-0.942] and 0.822 [0.687-0.909] respectively), but not with those in NB (r = 0.004 [- 0.003-0.011]). The number of taxa shared between IS-BB and NB-BB was greater in AAs than in HCs (p < 0.05) and included taxa previously associated with asthma. Of the genera abundant in NB, only Moraxella correlated positively with abundance in BB; specific members of this genus were shared between the two compartments only in AAs. Relative abundance of Moraxella in NB of AAs correlated negatively with that of Corynebacterium but positively with markers of eosinophilic inflammation in the blood and BAL fluid. The genus, Corynebacterium, trended to dominate all NB samples of HCs but only half of AAs (p = 0.07), in whom abundance of this genus was negatively associated with markers of eosinophilic inflammation. CONCLUSIONS: Induced sputum is superior to nasal brush or oral wash for assessing bronchial microbiota composition in asthmatic adults. Although compositionally similar to the bronchial microbiota, the microbiota in induced sputum are distinct, reflecting enrichment of oral bacteria. Specific bacterial genera are shared between the nasal and the bronchial mucosa which are associated with markers of systemic and bronchial inflammation.


Assuntos
Asma/microbiologia , Asma/fisiopatologia , Brônquios/microbiologia , Corynebacterium/isolamento & purificação , Moraxella/isolamento & purificação , Adulto , Corynebacterium/classificação , Corynebacterium/genética , Eosinófilos/imunologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Masculino , Microbiota/genética , Pessoa de Meia-Idade , Moraxella/classificação , Moraxella/genética , Mucosa Bucal/microbiologia , Nariz/microbiologia , RNA Ribossômico 16S/genética , Escarro/microbiologia
9.
Development ; 145(7)2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29540504

RESUMO

During vertebrate gastrulation, canonical Wnt signaling induces the formation of neural plate border (NPB). Wnt is also thought to be required for the subsequent specification of neural crest (NC) lineage at the NPB, but the direct evidence is lacking. We found previously that the disintegrin metalloproteinase ADAM13 is required for Wnt activation and NC induction in Xenopus Here, we report that knockdown of ADAM13 or its close paralog ADAM19 severely downregulates Wnt activity at the NPB, inhibiting NC specification without affecting earlier NPB formation. Surprisingly, ADAM19 functions nonproteolytically in NC specification by interacting with ADAM13 and inhibiting its proteasomal degradation. Ectopic expression of stabilized ADAM13 mutants that function independently of ADAM19 can induce the NC marker/specifier snail2 in the future epidermis via Wnt signaling. These results unveil the essential roles of a novel protease-protease interaction in regulating a distinct wave of Wnt signaling, which directly specifies the NC lineage.


Assuntos
Proteínas ADAM/metabolismo , Padronização Corporal/fisiologia , Crista Neural/metabolismo , Proteínas Wnt/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Membrana/metabolismo , Crista Neural/embriologia , Placa Neural/metabolismo , Transdução de Sinais , Via de Sinalização Wnt/fisiologia , Xenopus/embriologia
10.
Nat Commun ; 9(1): 179, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29330524

RESUMO

NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE.


Assuntos
Linfócitos B/efeitos dos fármacos , Rim/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/imunologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Animais , Linfócitos B/imunologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocina TWEAK/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Inflamação/genética , Subunidade p40 da Interleucina-12/efeitos dos fármacos , Subunidade p40 da Interleucina-12/imunologia , Rim/imunologia , Rim/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos NZB , Terapia de Alvo Molecular , Proteinúria/imunologia , Receptores OX40/metabolismo , Transdução de Sinais , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/imunologia , Quinase Induzida por NF-kappaB
11.
Sci Rep ; 7: 43173, 2017 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-28256591

RESUMO

Malignant glioma is a formidable disease that commonly leads to death, mainly due to the invasion of tumor cells into neighboring tissues. Therefore, inhibition of tumor cell invasion may provide an effective therapy for malignant glioma. Here we report that nicotinic acid (NA), an essential vitamin, inhibits glioma cell invasion in vitro and in vivo. Treatment of the U251 glioma cells with NA in vitro results in reduced invasion, which is accompanied by a loss of mesenchymal phenotype and an increase in cell-cell adhesion. At the molecular level, transcription of the adherens junction protein E-cadherin is upregulated, leading to accumulation of E-cadherin protein at the cell-cell boundary. This can be attributed to NA's ability to facilitate the ubiquitination and degradation of Snail1, a transcription factor that represses E-cadherin expression. Similarly, NA transiently inhibits neural crest migration in Xenopus embryos in a Snail1-dependent manner, indicating that the mechanism of action for NA in cell migration is evolutionarily conserved. We further show that NA injection blocks the infiltration of tumor cells into the adjacent brain tissues and improves animal survival in a rat model of glioma. These results suggest that NA treatment may be developed into a potential therapy for malignant glioma.


Assuntos
Antineoplásicos/metabolismo , Caderinas/metabolismo , Glioma/patologia , Niacina/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Animais , Antineoplásicos/administração & dosagem , Adesão Celular , Movimento Celular , Modelos Animais de Doenças , Humanos , Niacina/administração & dosagem , Proteólise , Ratos , Análise de Sobrevida , Resultado do Tratamento
12.
J Immunol ; 197(6): 2090-101, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27534551

RESUMO

Helper and cytotoxic T cells accomplish focused secretion through the movement of vesicles toward the microtubule organizing center (MTOC) and translocation of the MTOC to the target contact site. In this study, using Jurkat cells and OT-I TCR transgenic primary murine CTLs, we show that the dynein-binding proteins nuclear distribution E homolog 1 (NDE1) and dynactin (as represented by p150(Glued)) form mutually exclusive complexes with dynein, exhibit nonoverlapping distributions in target-stimulated cells, and mediate different transport events. When Jurkat cells expressing a dominant negative form of NDE1 (NDE1-enhanced GFP fusion) were activated by Staphylococcus enterotoxin E-coated Raji cells, NDE1 and dynein failed to accumulate at the immunological synapse (IS) and MTOC translocation was inhibited. Knockdown of NDE1 in Jurkat cells or primary mouse CTLs also inhibited MTOC translocation and CTL-mediated killing. In contrast to NDE1, knockdown of p150(Glued), which depleted the alternative dynein/dynactin complex, resulted in impaired accumulation of CTLA4 and granzyme B-containing intracellular vesicles at the IS, whereas MTOC translocation was not affected. Depletion of p150(Glued) in CTLs also inhibited CTL-mediated lysis. We conclude that the NDE1/Lissencephaly 1 and dynactin complexes separately mediate two key components of T cell-focused secretion, namely translocation of the MTOC and lytic granules to the IS, respectively.


Assuntos
Complexo Dinactina/fisiologia , Dineínas/fisiologia , Proteínas Associadas aos Microtúbulos/fisiologia , Linfócitos T/fisiologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/fisiologia , Sinalização do Cálcio , Citotoxicidade Imunológica , Humanos , Células Jurkat , Centro Organizador dos Microtúbulos/metabolismo , Vesículas Secretórias/fisiologia , Sinapses/metabolismo , Linfócitos T Citotóxicos/imunologia
13.
Proc Natl Acad Sci U S A ; 113(31): 8765-70, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27432971

RESUMO

Type 2 inflammation occurs in a large subgroup of asthmatics, and novel cytokine-directed therapies are being developed to treat this population. In mouse models, interleukin-33 (IL-33) activates lung resident innate lymphoid type 2 cells (ILC2s) to initiate airway type 2 inflammation. In human asthma, which is chronic and difficult to model, the role of IL-33 and the target cells responsible for persistent type 2 inflammation remain undefined. Full-length IL-33 is a nuclear protein and may function as an "alarmin" during cell death, a process that is uncommon in chronic stable asthma. We demonstrate a previously unidentified mechanism of IL-33 activity that involves alternative transcript splicing, which may operate in stable asthma. In human airway epithelial cells, alternative splicing of the IL-33 transcript is consistently present, and the deletion of exons 3 and 4 (Δ exon 3,4) confers cytoplasmic localization and facilitates extracellular secretion, while retaining signaling capacity. In nonexacerbating asthmatics, the expression of Δ exon 3,4 is strongly associated with airway type 2 inflammation, whereas full-length IL-33 is not. To further define the extracellular role of IL-33 in stable asthma, we sought to determine the cellular targets of its activity. Comprehensive flow cytometry and RNA sequencing of sputum cells suggest basophils and mast cells, not ILC2s, are the cellular sources of type 2 cytokines in chronic asthma. We conclude that IL-33 isoforms activate basophils and mast cells to drive type 2 inflammation in chronic stable asthma, and novel IL-33 inhibitors will need to block all biologically active isoforms.


Assuntos
Processamento Alternativo , Asma/genética , Inflamação/genética , Interleucina-33/genética , Adulto , Asma/metabolismo , Basófilos/metabolismo , Linhagem Celular , Células Epiteliais/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Masculino , Mastócitos/metabolismo , Pessoa de Meia-Idade , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Escarro/citologia , Escarro/metabolismo , Adulto Jovem
14.
Am J Respir Crit Care Med ; 193(11): 1281-91, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26649486

RESUMO

RATIONALE: Pulmonary sarcoidosis is classically defined by T-helper (Th) cell type 1 inflammation (e.g., IFN-γ production by CD4(+) effector T cells). Recently, IL-17A-secreting cells have been found in lung lavage, invoking Th17 immunity in sarcoidosis. Studies also identified IL-17A-secreting cells that expressed IFN-γ, but their abundance as a percentage of total CD4(+) cells was either low or undetermined. OBJECTIVES: Based on evidence that Th17 cells can be polarized to Th17.1 cells to produce only IFN-γ, our goal was to determine whether Th17.1 cells are a prominent source of IFN-γ in sarcoidosis. METHODS: We developed a single-cell approach to define and isolate major Th-cell subsets using combinations of chemokine receptors and fluorescence-activated cell sorting. We subsequently confirmed the accuracy of subset enrichment by measuring cytokine production. MEASUREMENTS AND MAIN RESULTS: Discrimination between Th17 and Th17.1 cells revealed very high percentages of Th17.1 cells in lung lavage in sarcoidosis compared with controls in two separate cohorts. No differences in Th17 or Th1 lavage cells were found compared with controls. Lung lavage Th17.1-cell percentages were also higher than Th1-cell percentages, and approximately 60% of Th17.1-enriched cells produced only IFN-γ. CONCLUSIONS: Combined use of surface markers and functional assays to study CD4(+) T cells in sarcoidosis revealed a marked expansion of Th17.1 cells that only produce IFN-γ. These results suggest that Th17.1 cells could be misclassified as Th1 cells and may be the predominant producer of IFN-γ in pulmonary sarcoidosis, challenging the Th1 paradigm of pathogenesis.


Assuntos
Interferon gama/imunologia , Sarcoidose Pulmonar/imunologia , Células Th1/imunologia , Células Th17/imunologia , Adulto , Idoso , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Células Th1/metabolismo , Células Th17/metabolismo
15.
Crit Rev Biochem Mol Biol ; 48(6): 544-60, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24066766

RESUMO

The neural crest (NC) is a population of migratory stem/progenitor cells that is found in early vertebrate embryos. NC cells are induced during gastrulation, and later migrate to multiple destinations and contribute to many types of cells and tissues, such as craniofacial structures, cardiac tissues, pigment cells and the peripheral nervous system. Recently, accumulating evidence suggests that many extracellular metalloproteinases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs), play important roles in various stages of NC development. Interference with metalloproteinase functions often causes defects in craniofacial structures, as well as in other cells and tissues that are contributed by NC cells, in humans and other vertebrates. In this review, we summarize the current state of the field concerning the roles of these three families of metalloproteinases in NC development and related tissue morphogenesis, with a special emphasis on craniofacial morphogenesis.


Assuntos
Proteínas ADAM/metabolismo , Cabeça/embriologia , Metaloproteinases da Matriz/metabolismo , Crista Neural/embriologia , Proteínas ADAMTS , Proteína ADAMTS9 , Animais , Anormalidades Craniofaciais/embriologia , Transição Epitelial-Mesenquimal , Humanos , Camundongos , Morfogênese , Inibidores Teciduais de Metaloproteinases
16.
Fly (Austin) ; 6(1): 30-4, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22513479

RESUMO

Notch signaling is integral to a large number of developmental and homeostasis events, and either gain or loss of Notch signaling results in a wide range of defects. Notch must be processed by several proteases, including a member of the ADAM (a disintegrin and metalloprotease) family to mediate downstream signaling. Until recently, interactions of Notch with specific ADAMs in different contexts were unclear. ADAM10 is now known to be specifically essential for development and homeostasis of mouse epidermis and cardiovascular structures, and ADAM17 may not be able to fully replace ADAM10 in these contexts. However, Notch from T-cell acute lymphoblastic leukemia (T-ALL) patients can be cleaved by both ADAMs 10 and 17. Studies have revealed that ADAM10 is necessary for Notch processing when Notch is activated by a ligand, while ADAM17 is the major protease for processing Notch that is activated independently of ligand in both flies and mammals.


Assuntos
Proteínas ADAM/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Animais , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores Notch/metabolismo
17.
Mol Cancer ; 7: 63, 2008 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-18637170

RESUMO

By nature, scientists contribute to our understanding of nature and ourselves. As communities undergo significant changes, new challenges are presented. Here, we offer alternative views on recent changes in society.


Assuntos
Apoio à Pesquisa como Assunto , Pessoal de Laboratório Médico , Natureza , Revisão da Pesquisa por Pares , Publicações Periódicas como Assunto , Pesquisa/normas , Ciência/economia , Ciência/normas
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