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1.
Pain ; 161(6): 1381-1398, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028334

RESUMO

Headache disorders are highly prevalent and debilitating, with limited treatment options. Previous studies indicate that many proinflammatory immune cells contribute to headache pathophysiology. Given the well-recognized role of regulatory T (Treg) cells in maintaining immune homeostasis, we hypothesized that enhancing Treg function may be effective to treat multiple headache disorders. In a mouse model of chronic migraine, we observed that repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration doubled the number of CD3 T cells in the trigeminal ganglia without altering the number of Treg cells, suggesting a deficiency in Treg-mediated immune homeostasis. We treated mice with low-dose interleukin-2 (ld-IL2) to preferentially expand and activate endogenous Treg cells. This not only prevented the development of NTG-induced persistent sensitization but also completely reversed the established facial skin hypersensitivity resulting from repeated NTG administration. The effect of ld-IL2 was independent of mouse sex and/or strain. Importantly, ld-IL2 treatment did not alter basal nociceptive responses, and repeated usage did not induce tolerance. The therapeutic effect of ld-IL2 was abolished by Treg depletion and was recapitulated by Treg adoptive transfer. Furthermore, treating mice with ld-IL2 1 to 7 days after mild traumatic brain injury effectively prevented as well as reversed the development of behaviors related to acute and chronic post-traumatic headache. In a model of medication overuse headache, Ld-IL2 completely reversed the cutaneous hypersensitivity induced by repeated administration of sumatriptan. Collectively, this study identifies ld-IL2 as a promising prophylactic for multiple headache disorders with a mechanism distinct from the existing treatment options.


Assuntos
Transtornos da Cefaleia , Interleucina-2/farmacologia , Transtornos de Enxaqueca , Animais , Camundongos , Nitroglicerina , Sumatriptana
2.
Environ Monit Assess ; 175(1-4): 315-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20577797

RESUMO

A cell line (FG cells) derived from a gill of the flounder, Paralichthys olivaceus were used to determine the cytotoxic effects of nonylphenol (NP). Cytotoxicity was measured by three endpoint systems: neutral red (NR) uptake assay, methyl thiazolyl tetrazolium (MTT) assay and cell protein assay. The result showed that NP was cytotoxic to FG cells at all tested concentrations, and toxicity increased as the concentration of NP was progressively increased. The 24 h-IC50 values of NP were 39.81, 37.76 and 38.22 µmol/L for NR uptake, MTT assay and cell protein assay, respectively. Moreover, the morphological changes of FG cells were also studied at the concentration of 30 µmol/L for 24 h. Cells morphology were markedly altered by NP observed under a scanning electron microscopy, as evidenced by swelling cells, two and more nucleolus and an increased number of lipid particles. This would suggest that the FG cell line is a suitable bioindicator for the screening of the acute toxicity of NP.


Assuntos
Brânquias/citologia , Fenóis/toxicidade , Animais , Linhagem Celular , Linguado , Microscopia Eletrônica de Varredura , Vermelho Neutro
3.
Mol Biol Rep ; 36(8): 2431-7, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19247802

RESUMO

The p8 protein is a transcription factor with a basic helix-loop-helix motif and a nuclear localization signal. In the present study, a common sea urchin (Paracentrotus lividus) homolog of p8 cDNA was cloned, sequenced and characterized. The full-length p8 cDNA consists of 896 bp and encodes 71 amino acids with a molecular mass of 8.238 kD. Homology alignments found that several phosphorylation sites and the most negative (Asp and Glu)/positive (Arg) propensities charged residues were well conserved between P. lividus and other species. Analysis by RT-PCR showed that there was no obvious difference in the patterns of expression during embryogenesis from unfertilization egg up to the pluteus stage, but p8 mRNA expression levels varied among tested adult tissues suggesting that p8 has a key function in embryogenesis but non-vital function under physiological conditions. Evolution relationships between P. lividus p8 and other species p8 homologs revealed in the phylogenetic tree were in agreement with the concept of traditional taxonomy.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , DNA Complementar/genética , Paracentrotus/fisiologia , Alinhamento de Sequência/métodos , Homologia de Sequência de Aminoácidos , Sequência de Aminoácidos , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Clonagem Molecular/métodos , DNA Complementar/análise , Regulação da Expressão Gênica no Desenvolvimento , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
J Biol Chem ; 279(37): 39085-93, 2004 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-15262961

RESUMO

In smokers' lungs, excessive mucus clogs small airways, impairing respiration and promoting recurrent infection. A breakthrough in understanding this pathology was the realization that smoke could directly stimulate mucin synthesis in lung epithelial cells and that this phenomenon was dependent on the cell surface receptor for epidermal growth factor, EGFR. Distal steps in the smoke-triggered pathway have not yet been determined. We report here that the predominant airway mucin (MUC5AC) undergoes transcriptional up-regulation in response to tobacco smoke; this is mediated by an AP-1-containing response element, which binds JunD and Fra-2. These transcription factors require phosphorylation by upstream kinases JNK and ERK, respectively. Whereas ERK activation results from the upstream activation of EGFR, JNK activation is chiefly EGFR-independent. Our experiments demonstrated that smoke activates JNK via a Src-dependent, EGFR-independent signaling cascade initiated by smoke-induced reactive oxygen species. Taken together with our earlier results, these data indicate that the induction of mucin by smoke is the combined effect of mutually independent, reactive oxygen species activation of both EGFR and JNK.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno , Pulmão/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mucinas/metabolismo , Nicotiana/efeitos adversos , Espécies Reativas de Oxigênio , Fumar , Fator de Transcrição AP-1/metabolismo , Animais , Western Blotting , Linhagem Celular , Linhagem Celular Transformada , Linhagem Celular Tumoral , Células Cultivadas , Clonagem Molecular , Proteínas de Ligação a DNA/metabolismo , Antígeno 2 Relacionado a Fos , Deleção de Genes , Genes Dominantes , Humanos , Hibridização In Situ , Luciferases/metabolismo , Pulmão/efeitos dos fármacos , MAP Quinase Quinase 4 , Masculino , Microscopia de Fluorescência , Modelos Biológicos , Mutação , Reação em Cadeia da Polimerase , Ligação Proteica , Transporte Proteico , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Regulação para Cima
5.
J Biol Chem ; 278(28): 26202-7, 2003 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-12711607

RESUMO

Cells dividing at the time of carcinogen exposure are at particular risk for neoplasia. Tobacco smoke contains numerous carcinogens, and we find that smoke, in the absence of exogenous growth factors, is capable of stimulating cell proliferation. The smoke-triggered mechanism includes the generation of oxygen radicals, which in turn stimulate tumor necrosis factor alpha-converting enzyme (a disintegrin and metalloproteinase (ADAM) 17) to cleave transmembrane amphiregulin, a ligand for the epidermal growth factor receptor (EGFR). The binding of amphiregulin to EGFR then stimulates proliferation of lung epithelial cells. These results shed light on the pathogenesis of lung cancer, suggest novel drug targets for the reduction of cancer risk in smokers, and provide insight into how EGFR integrates responses to diverse noxious stimuli.


Assuntos
Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pulmão/citologia , Pulmão/efeitos dos fármacos , Metaloendopeptidases/metabolismo , Fumar , Proteínas ADAM , Proteína ADAM17 , Anfirregulina , Animais , Carcinógenos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Família de Proteínas EGF , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Humanos , Immunoblotting , Ligantes , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Modelos Biológicos , Oligonucleotídeos Antissenso/farmacologia , Oxigênio/metabolismo , Fosforilação , Testes de Precipitina , Ligação Proteica , Espécies Reativas de Oxigênio , Células Tumorais Cultivadas
6.
Novartis Found Symp ; 248: 171-6; discussion 176-80, 277-82, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12568494

RESUMO

Mucin, the major macromolecular component of mucus, is generally considered to be a protective substance. When overproduced in a variety of lung diseases, however, mucin gives rise to clinical problems such as airway obstruction and recurrent infection. Our approach to identifying drug targets for the control of mucin overproduction is the analysis of cellular signalling pathways linking stimuli in the diseased lung to mucin transcription. Here we show that mucin transcription in response to both gram-positive bacteria and tobacco smoke is mediated through activation of the epidermal growth factor receptor (EGFR). The mode of activation of EGFR in response to bacterial lipoteichoic acid involves cleavage of the transmembrane ligand HBEGF by ADAM 10, whereas the activation of EGFR in response to smoke involves cleavage of amphiregulin by ADAM 17.


Assuntos
Receptores ErbB/fisiologia , Bactérias Gram-Positivas/fisiologia , Pulmão/metabolismo , Mucinas/biossíntese , Fumaça , Proteínas ADAM , Proteína ADAM17 , Anfirregulina , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Linhagem Celular , Família de Proteínas EGF , Endopeptidases/fisiologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores ErbB/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Glicoproteínas/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ligantes , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Metaloendopeptidases/fisiologia , Mucinas/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Receptores de Superfície Celular , Transdução de Sinais , Ácidos Teicoicos/farmacologia , Nicotiana , Transcrição Gênica , Domínios de Homologia de src
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