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1.
Nat Commun ; 10(1): 3031, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292453

RESUMO

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.


Assuntos
Acetatos/sangue , Feto/imunologia , Pré-Eclâmpsia/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Linfócitos T Reguladores/imunologia , Acetatos/administração & dosagem , Acetatos/imunologia , Acetatos/metabolismo , Adulto , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Desenvolvimento Infantil , Pré-Escolar , Suplementos Nutricionais , Feminino , Feto/citologia , Feto/diagnóstico por imagem , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes/imunologia , Humanos , Tolerância Imunológica/imunologia , Lactente , Recém-Nascido , Estudos Longitudinais , Troca Materno-Fetal/imunologia , Camundongos , Tamanho do Órgão/imunologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Estudos Prospectivos , Timo/citologia , Timo/diagnóstico por imagem , Timo/crescimento & desenvolvimento , Timo/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Ultrassonografia Pré-Natal , Adulto Jovem
2.
J Agric Food Chem ; 67(24): 6725-6735, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31117506

RESUMO

Jasmonic acid (JA)- and ethylene-mediated signaling pathways are reported to have synergistic effects on inhibiting gray mold. The present study aimed to explain the role of ethylene perception in methyl jasmonate (MeJA)-mediated immune responses. Results showed that exogenous MeJA enhanced disease resistance, accompanied by the induction of endogenous JA biosynthesis and ethylene production, which led to the activation of the phenolic metabolism pathway. Blocking ethylene perception using 1-methylcyclopropene (1-MCP) either before or after MeJA treatment could differently weaken the disease responses induced by MeJA, including suppressing the induction of ethylene production and JA contents and reducing activities of lipoxygenase and allene oxide synthase compared to MeJA treatment alone. Consequently, MeJA-induced elevations in the total phenolic content and the activities of phenylalanine ammonia-lyase, cinnamate 4-hydroxylase, 4-coumarate:coenzyme A ligase, and peroxidase were impaired by 1-MCP. These results suggested that ethylene perception participated in MeJA-mediated immune responses in tomato fruit.


Assuntos
Acetatos/imunologia , Botrytis/fisiologia , Ciclopentanos/imunologia , Etilenos/imunologia , Lycopersicon esculentum/imunologia , Oxilipinas/imunologia , Doenças das Plantas/imunologia , Reguladores de Crescimento de Planta/imunologia , Resistência à Doença , Frutas/imunologia , Frutas/microbiologia , Regulação da Expressão Gênica de Plantas , Lycopersicon esculentum/genética , Lycopersicon esculentum/microbiologia , Fenilalanina Amônia-Liase/genética , Fenilalanina Amônia-Liase/imunologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Transcinamato 4-Mono-Oxigenase/genética , Transcinamato 4-Mono-Oxigenase/imunologia
3.
Ann Rheum Dis ; 76(2): 399-407, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27323772

RESUMO

OBJECTIVE: To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy. METHODS: Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0-1/10, 2-5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0-3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse. RESULTS: Patients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0-1/10 reactivities) to 34% (2-5/10) and 55% (>5/10). With respect to specificity groups (0-3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively. CONCLUSIONS: The data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy. TRIAL REGISTRATION NUMBER: 2009-015740-42; Results.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Acetatos/imunologia , Acetilação , Artrite Reumatoide/tratamento farmacológico , Carbamatos/imunologia , Citrulina/análogos & derivados , Citrulina/imunologia , Humanos , Modelos Logísticos , Lisina/imunologia , Análise Multivariada , Ornitina/imunologia , Peptídeos/imunologia , Peptídeos Cíclicos/imunologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Vimentina/imunologia
4.
Mucosal Immunol ; 10(4): 946-956, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27966553

RESUMO

Intestinal IgA, which is regulated by gut microbiota, has a crucial role in maintenance of intestinal homeostasis and in protecting the intestines from inflammation. However, the means by which microbiota promotes intestinal IgA responses remain unclear. Emerging evidence suggests that the host can sense gut bacterial metabolites in addition to pathogen-associated molecular patterns and that recognition of these small molecules influences host immune response in the intestines and beyond. We reported here that microbiota metabolite short-chain fatty acid acetate promoted intestinal IgA responses, which was mediated by "metabolite-sensing" GPR43. GPR43-/- mice demonstrated lower levels of intestinal IgA and IgA+ gut bacteria compared with those in wild type (WT) mice. Feeding WT but not GPR43-/- mice acetate but not butyrate promoted intestinal IgA response independent of T cells. Acetate promoted B-cell IgA class switching and IgA production in vitro in the presence of WT but not GPR43-/- dendritic cells (DCs). Mechanistically, acetate-induced DC expression of Aldh1a2, which converts Vitamin A into its metabolite retinoic acid (RA). Moreover, blockade of RA signaling inhibited the acetate induction of B-cell IgA production. Our studies thus identified a new pathway by which microbiota promotes intestinal IgA response through its metabolites.


Assuntos
Acetatos/metabolismo , Células Dendríticas/imunologia , Ácidos Graxos Voláteis/metabolismo , Intestinos/imunologia , Microbiota/imunologia , Receptores Acoplados a Proteínas-G/metabolismo , Acetatos/química , Acetatos/imunologia , Animais , Butiratos/química , Butiratos/imunologia , Butiratos/metabolismo , Células Cultivadas , Ácidos Graxos Voláteis/química , Ácidos Graxos Voláteis/imunologia , Feminino , Imunidade nas Mucosas , Imunoglobulina A/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Acoplados a Proteínas-G/genética , Retinal Desidrogenase/metabolismo , Tretinoína/metabolismo , Vitamina A/metabolismo
5.
ChemMedChem ; 11(6): 562-74, 2016 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-26898175

RESUMO

People suffering from allergies can be treated with repeated injections of increasing amounts of a specific allergen. This type of specific immunotherapy is currently the only way to treat the underlying pathological immune response associated with an allergy. The approach can afford long-lasting protection, but the process takes 3-5 years, can produce allergic reactions, and in severe cases treatment is often aborted due to anaphylaxis. However, treatment can be optimized with the use of specific adjuvants that modify the immune response, its duration, and that increase the production of the correct type of antibodies. In the pursuit of such adjuvants, two new trivalent acetylated ß-(1→2)-linked mannobioses based on a previously discovered lead molecule were prepared. The new molecules, along with the previously developed lead, were investigated by rigorous NMR and molecular modeling experiments in order to elucidate their behavior and preferred conformations in solution. Furthermore, the molecules were subjected to a biological investigation in which their immunostimulatory properties were evaluated by assessing their effect on the production of TH 2-type cytokine interleukin-4 (IL-4) and Treg pro-inflammatory cytokine tumor necrosis factor (TNF). Treatment of peripheral mononuclear blood cell cultures from patients suffering from birch allergy with birch allergen Bet v induced a strong IL-4 response, whereas the same treatment together with the trivalent acetylated mannobioses caused significant suppression of the induced IL-4.


Assuntos
Adjuvantes Imunológicos/síntese química , Dissacarídeos/síntese química , Interleucina-4/metabolismo , Mananas/síntese química , Acetatos/síntese química , Acetatos/química , Acetatos/imunologia , Acetatos/farmacologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Química Click , Cobre , Dissacarídeos/química , Dissacarídeos/imunologia , Células HEK293 , Humanos , Espectroscopia de Ressonância Magnética , Mananas/química , Mananas/imunologia , Mananas/farmacologia , Conformação Molecular , Receptores Toll-Like/metabolismo
6.
Sci Rep ; 6: 21934, 2016 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-26902398

RESUMO

Dutch elm disease (DED), caused by three fungal species in the genus Ophiostoma, is the most devastating disease of both native European and North American elm trees. Although many tolerant cultivars have been identified and released, the tolerance mechanisms are not well understood and true resistance has not yet been achieved. Here we show that the expression of disease-responsive genes in reactions leading to tolerance or susceptibility is significantly differentiated within the first 144 hours post-inoculation (hpi). Analysis of the levels of endogenous plant defense molecules such as jasmonic acid (JA) and salicylic acid (SA) in tolerant and susceptible American elm saplings suggested SA and methyl-jasmonate as potential defense response elicitors, which was further confirmed by field observations. However, the tolerant phenotype can be best characterized by a concurrent induction of JA and disease-responsive genes at 96 hpi. Molecular investigations indicated that the expression of fungal genes (i.e. cerato ulmin) was also modulated by endogenous SA and JA and this response was unique among aggressive and non-aggressive fungal strains. The present study not only provides better understanding of tolerance mechanisms to DED, but also represents a first, verified template for examining simultaneous transcriptomic changes during American elm-fungus interactions.


Assuntos
Ciclopentanos/metabolismo , Proteínas Fúngicas/genética , Ophiostoma/genética , Oxilipinas/metabolismo , Doenças das Plantas/genética , Proteínas de Plantas/genética , Ulmus/genética , Acetatos/imunologia , Acetatos/metabolismo , Ciclopentanos/imunologia , Suscetibilidade a Doenças , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Interações Hospedeiro-Patógeno , Tolerância Imunológica , Anotação de Sequência Molecular , Ophiostoma/crescimento & desenvolvimento , Ophiostoma/patogenicidade , Oxilipinas/imunologia , Fenótipo , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/imunologia , Ácido Salicílico/imunologia , Ácido Salicílico/metabolismo , Fatores de Tempo , Ulmus/imunologia , Ulmus/microbiologia , Virulência
7.
Biol Trace Elem Res ; 152(1): 117-24, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23377609

RESUMO

The detection of cadmium ions using enzyme-linked immunosorbent assays (ELISA) has been reported by several research groups. Because cadmium ions are too small to stimulate the immune system, high molecular weight immunogens of cadmium are constructed using bifunctional chelators. At present, the most commonly used bifunctional chelator for the preparation of antigens for heavy metal ions is 1-(4-isothiocyanobenzyl) ethylenediamine N,N,N',N'-tetraacetic acid (ITCBE). However, the price of ITCBE is high. So we are interested in a cheaper bifunctional chelator, 1-(4-aminobenzyl) ethylenediamine N,N,N',N'-tetraacetic acid (aminobenzyl-EDTA). Here, cadmium ions were conjugated to carrier proteins using aminobenzyl-EDTA to make artificial antigens. Then, several mice were immunized with the antigen. And monoclonal antibodies (MAbs) against cadmium were produced. Spleen cells of immunized mice were fused with myeloma cells. The resulting hybridomas were screened using protein conjugates which were covalently bound to metal-free EDTA or cadmium. Three hybridoma cell lines (A3, E4 and B5) that produced MAbs with high selectivity and sensitivity were expanded for further study. Cross-reactivities with other metals were below 1 %. These antibodies were used to construct competitive ELISAs. The IC50 for A3 was 8.4 µg/l. The detection range and the lowest detection limit using the antibody A3 was 0.394-64.39 and 0.051 µg/l, respectively. Spike-recovery studies in tap water showed that the antibody A3 could be used for cadmium detection in drinking water.


Assuntos
Acetatos/imunologia , Anticorpos Monoclonais/imunologia , Cádmio/imunologia , Ácido Edético/análogos & derivados , Etilenodiaminas/imunologia , Soroalbumina Bovina/imunologia , Acetatos/química , Animais , Anticorpos Monoclonais/metabolismo , Antígenos/química , Antígenos/imunologia , Cádmio/análise , Cádmio/química , Bovinos , Água Potável/análise , Água Potável/química , Ácido Edético/química , Ácido Edético/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Etilenodiaminas/química , Hibridomas/citologia , Hibridomas/metabolismo , Imunização , Camundongos , Estrutura Molecular , Reprodutibilidade dos Testes , Soroalbumina Bovina/química , Espectrofotometria Ultravioleta
8.
Rev. esp. enferm. dig ; 102(7): 421-425, jul. 2010. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-80482

RESUMO

Objective: the aim is to determine immunopathological modifications in rectal mucosa from rabbits after local challenge in ovalbumin (OVA) sensitized animals previously treated with montelukast. Material and methods: experimental design: thirty two rabbits divided into four groups: G1: normal; G2: subcutaneously OVA sensitized; G3: sensitized, locally OVA challenged and sampled 4 hours after challenge; and G4: sensitized, locally OVA challenged and treated 4 hours before challenge with montelukast (0.15 mg/kg). Specific anti-OVA IgE levels were evaluated by passive cutaneous anaphylaxis test (PCA). In each group 200 high microscopical power fields (HPF) were counted. Results were expressed as arithmetic mean and SE. Anti -CD4, CD5, micro chain monoclonal antibodies were used. Avidin biotin horseradish peroxidase system was used. Results: CD 4: G1: 8.3 ± 0.06; G2: 13.4 ± 0.08, G3: 8.25 ± 0.06, G4: 11.8 ± 0.02. CD 5: G1: 7.3 ± 0.05; G2: 9.4 ± 0.05, G3: 11.3 ± 0.06, G4: 8.1 ± 0.06. ì chain: G1: 10.4 ± 0.06; G2: 3.8 ± 0.02, G3: 6.0 ± 0.10, G4: 2.2 ± 0.10. In all cases, experimental groups (G3 vs. G4) presented statistical significant differences (p < 0.05). CD4+, CD5+ cells and micro chain+ decrease in experimental group (G4), probably due to lymphocyte migration inhibition to challenged mucosa. micro chain+ cell decrease could be based on B cell activation and expression of different surface immunoglobulins. Cells expressing micro chain decreased in G2 and G3 likely due to activation of B cells and subsequent expression of other immunoglobulin chains in cell surface. Conclusions: we conclude that obtained data are important to elucidate immunopathology of local anaphylactic reaction in rectal mucosa from systemic sensitized animals after treatment with montelukast(AU)


Assuntos
Animais , Masculino , Feminino , Coelhos , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/patologia , Ovalbumina/análise , Antagonistas de Leucotrienos/análise , Antagonistas de Leucotrienos/imunologia , Imuno-Histoquímica , Anticorpos Monoclonais/imunologia , Acetatos/análise , Acetatos/imunologia , Antagonistas de Leucotrienos/metabolismo , Anticorpos Monoclonais/análise , Ovalbumina/imunologia , Imuno-Histoquímica/instrumentação , Imuno-Histoquímica/veterinária , Anticorpos Monoclonais , Acetatos , Acetatos/metabolismo
9.
J Biomed Biotechnol ; 2010: 525291, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20445752

RESUMO

The industrial use of elicitors as alternative tools for disease control needs the identification of abundant sources of them. We report on an elicitor obtained from the green algae Ulva spp. A fraction containing most exclusively the sulfated polysaccharide known as ulvan-induced expression of a GUS gene placed under the control of a lipoxygenase gene promoter. Gene expression profiling was performed upon ulvan treatments on Medicago truncatula and compared to phytohormone effects. Ulvan induced a gene expression signature similar to that observed upon methyl jasmonate treatment (MeJA). Involvement of jasmonic acid (JA) in ulvan response was confirmed by detecting induction of protease inhibitory activity and by hormonal profiling of JA, salicylic acid (SA) and abscisic acid (ABA). Ulvan activity on the hormonal pathway was further consolidated by using Arabidopsis hormonal mutants. Altogether, our results demonstrate that green algae are a potential reservoir of ulvan elicitor which acts through the JA pathway.


Assuntos
Acetatos/metabolismo , Arabidopsis/imunologia , Ciclopentanos/metabolismo , Medicago truncatula/imunologia , Oxilipinas/metabolismo , Polissacarídeos/farmacologia , Ulva/química , Acetatos/imunologia , Análise de Variância , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Cromatografia em Gel , Ciclopentanos/imunologia , Expressão Gênica/efeitos dos fármacos , Glucuronidase/metabolismo , Medicago truncatula/efeitos dos fármacos , Medicago truncatula/metabolismo , Nucleotidiltransferases/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Oxilipinas/imunologia , Reguladores de Crescimento de Planta/metabolismo , Polissacarídeos/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier
10.
Eur Respir J ; 33(6): 1302-8, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19164343

RESUMO

Montelukast and desloratadine synergistically inhibit the allergen-induced early asthmatic response. Montelukast also suppresses the allergen-induced late asthmatic response, but there are no reports on the effect of desloratadine or the combination on the allergen-induced late asthmatic response. Atopic asthmatics (n = 10) completed a multicentric randomised double-blind crossover study comparing single-dose placebo, 5 mg desloratadine, 10 mg montelukast and the combination administered 2 h prior to allergen inhalation challenge. Methacholine challenges were performed 24 h before and after allergen challenge. Exhaled nitric oxide measurements and sputum inflammatory cell counts were also carried out. All active treatments significantly decreased the late asthmatic response area under the curve. Combination therapy provided the greatest inhibition compared to desloratadine and montelukast. Montelukast was nonsignificantly better than desloratadine but not as effective as the combination. There was a trend towards a decrease in airway responsiveness following montelukast and combination. Montelukast, but not desloratadine or the combination, decreased exhaled NO levels 24 h after allergen. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed at 7 h with desloratadine and combination therapy, and at 24 h with montelukast and combination therapy. Single-dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment.


Assuntos
Acetatos/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H1 não Sedativos/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Loratadina/análogos & derivados , Quinolinas/uso terapêutico , Acetatos/administração & dosagem , Acetatos/imunologia , Adulto , Alérgenos/imunologia , Análise de Variância , Antiasmáticos/administração & dosagem , Antiasmáticos/imunologia , Asma/imunologia , Testes de Provocação Brônquica , Estudos Cross-Over , Método Duplo-Cego , Quimioterapia Combinada , Eosinófilos , Feminino , Humanos , Antagonistas de Leucotrienos/administração & dosagem , Antagonistas de Leucotrienos/imunologia , Loratadina/administração & dosagem , Loratadina/imunologia , Loratadina/uso terapêutico , Masculino , Cloreto de Metacolina , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Placebos , Quinolinas/administração & dosagem , Quinolinas/imunologia , Testes de Função Respiratória , Escarro/citologia , Resultado do Tratamento
11.
J Agric Food Chem ; 56(8): 2581-8, 2008 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-18373349

RESUMO

High-affinity and selective monoclonal antibodies have been produced against the strobilurin fungicide trifloxystrobin. A battery of functionalized haptens has been synthesized, and conjugate-coated enzyme-linked immunosorbent assays following different procedures have been developed. On the one hand, a two-step conjugate-coated immunoassay was optimized using extended or short incubation times, with limits of detection of 0.10 ng/mL for the extended assay and 0.17 ng/mL for the rapid assay. On the other hand, an immunoassay in the conjugate-coated format was optimized following a procedure consisting of just one incubation step. This one-step assay had a limit of detection of 0.21 ng/mL. All of these assays showed detection limits for trifloxystrobin in the low parts per billion range, well below the common maximum residue limits for this pesticide in foodstuffs (50 microg/kg).


Assuntos
Acetatos/análise , Anticorpos Monoclonais , Ensaio de Imunoadsorção Enzimática/métodos , Fungicidas Industriais/análise , Haptenos/química , Iminas/análise , Resíduos de Praguicidas/análise , Acetatos/imunologia , Especificidade de Anticorpos , Contaminação de Alimentos/análise , Haptenos/imunologia , Iminas/imunologia , Metacrilatos/análise , Estrobilurinas
12.
Eur Ann Allergy Clin Immunol ; 39(7): 232-6, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18236999

RESUMO

BACKGROUND: Moderately severe atopic dermatitis makes up nearly one-fifth of children with atopic dermatitis. OBJECTIVE: To determine the clinical and laboratory effects of montelukast in moderately severe atopic dermatitis. METHODS: Randomized, double-blind, placebo-controlled, crossover trial with washout period, conducted from May 2002 to February 2006. The study involved 25 patients, 2-16 years old with dermatitis. Patients received oral montelukast (9 patients, Group B) or placebo (16 patients, Group A) in phase 1, and were crossed over to placebo or montelukast, respectively, for phase 2. Patients included if > 10% of skin was involved and failed response to 2 week conventional treatment. Itching, sleep disturbance, frequency of use of oral antihistamines & topical steroids, severity scores were serially assessed. In addition, eosinophil and serum IgE were serially collected. RESULTS: Most of patients were 6-10 years of age. Both groups had comparable gender distribution. The patients in Group B were more likely to have a history of bronchial asthma (55.6%) or allergic rhinitis (33.3%) than patients in Group A, but were less likely to have a positive history of atopy. While on montelukast, there was a reduction of mean score for itching in phase 2, for sleep disturbance in phase 2, for antihistamines in phase 1, for extent-of-disease in phase 1 and 2, and for severity score in phase 2 and blood eosinophil & IgE in phase 2. CONCLUSION: Montelukast reduces itching, sleep disturbance, disease extent and severity, blood eosinophil count and serum IgE.


Assuntos
Acetatos/administração & dosagem , Acetatos/efeitos adversos , Dermatite Atópica/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Acetatos/imunologia , Administração Oral , Adolescente , Contagem de Células Sanguíneas , Criança , Pré-Escolar , Dermatite Atópica/sangue , Dermatite Atópica/imunologia , Dermatite Atópica/fisiopatologia , Esquema de Medicação , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Antagonistas dos Receptores Histamínicos H1/imunologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Masculino , Quinolinas/imunologia , Sono/efeitos dos fármacos , Resultado do Tratamento
13.
Toxicol Appl Pharmacol ; 216(2): 248-55, 2006 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-16806339

RESUMO

Dichloroacetyl chloride (DCAC) is formed from trichloroethene (TCE), which is implicated in inducing/accelerating autoimmune response. Due to its potent acylating activity, DCAC may convert proteins to neo-antigens and thus could induce autoimmune responses. Dichloroacetic anhydride (DCAA), which is a similar acylating agent, might also induce autoimmune responses. To evaluate if chloroacylation plays a role in the induction of autoimmunity, we have measured the autoimmune responses following treatment with DCAC or DCAA in autoimmune-prone MRL+/+ mice. Five-week-old female mice were injected intraperitoneally (twice weekly) with 0.2 mmol/kg of DCAC or DCAA in corn oil for 6 weeks. Total serum IgG, IgG1, and IgE levels were significantly increased in DCAC-treated mice as compared to controls. These increases corresponded with increases in DCAC-specific IgG and IgG1 levels. Total serum IgM was decreased in both DCAC- and DCAA-treated mice. Antinuclear antibodies, measured as an indication of systemic autoimmune responses, were increased in both DCAC- and DCAA-treated mice. Of eight Th1/Th2 cytokines measured in the serum, only IL-5 was significantly decreased in both treatment groups. The cytokine secretion patterns of splenic lymphocytes after stimulation with antibodies against CD3 (T cell receptor-mediated signal) and CD28 (costimulatory signal) differed between treatment and control groups. Levels of IL-1, IL-3, IL-6, IFN-gamma, G-CSF, and KC were higher in cultures of stimulated splenocytes from either DCAC- or DCAA-treated mice than from controls. The level of IL-17 was only increased in cultures from DCAC-treated mice. Increased lymphocytic populations were found in the red pulp of spleens following treatment with either DCAC or DCAA. In addition, thickening of the alveolar septa in the lungs of DCAC- or DCAA-treated mice was observed. The lung histopathology in exposed mice was consistent with the symptomology observed in welders exposed to DCAC/phosgene. Thickening was more pronounced in DCAC-treated mice. Our data suggest that DCAC and DCAA elicit autoimmune responses in MRL+/+ mice that might be reflective of their chloroacylation potential in vivo.


Assuntos
Acetatos/toxicidade , Anidridos Acéticos/toxicidade , Autoimunidade/efeitos dos fármacos , Ácido Dicloroacético/toxicidade , Camundongos Endogâmicos MRL lpr , Acetatos/imunologia , Anidridos Acéticos/imunologia , Animais , Anticorpos Antinucleares/sangue , Anticorpos Bloqueadores/farmacologia , Autoimunidade/imunologia , Antígenos CD28/imunologia , Complexo CD3/imunologia , Células Cultivadas , Citocinas/sangue , Ácido Dicloroacético/imunologia , Feminino , Homozigoto , Imunoglobulinas/sangue , Imunoglobulinas/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Camundongos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia
14.
Methods ; 36(4): 368-75, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16111893

RESUMO

To achieve its full biological activity, NF-kappaB must undergo a variety of post-translational modifications, including acetylation. Acetylation plays a prominent role in regulating the nuclear action of NF-kappaB. The RelA subunit of NF-kappaB forms the major target of acetylation at several different sites. Acetylation of discrete lysine residues in RelA modulates distinct functions of NF-kappaB, including transcriptional activation, DNA binding, and assembly with its inhibitor IkappaBalpha. Here, we describe the experimental methods that have allowed the detection and functional analysis of acetylated forms of NF-kappaB. Acetylation of NF-kappaB can be studied both in vivo and in vitro. In vivo [3H]acetate labeling assays provides a useful, albeit rather insensitive, method for initial verification of acetylation of either over-expressed or endogenous subunits of NF-kappaB. A second valuable in vivo approach involves the use of anti-acetylated lysine antibodies for immunoblotting. However, the success of this approach varies with the specific antibody employed and the target protein studied. In vitro acetylation assays provide a rapid and sensitive method to validate the involvement of candidate histone acetyltransferases and to map the sites of acetylation. Anti-RelA antibodies that selectively react with site-specific acetylated forms of RelA are a singularly powerful tool for the study of NF-kappaB acetylation both in vivo and in vitro.


Assuntos
Técnicas de Laboratório Clínico , NF-kappa B/metabolismo , Processamento de Proteína Pós-Traducional , Acetatos/imunologia , Acetatos/metabolismo , Acetilação , Acetiltransferases/imunologia , Acetiltransferases/metabolismo , Animais , Anticorpos/imunologia , Proteínas de Ciclo Celular/imunologia , Proteínas de Ciclo Celular/metabolismo , Extratos Celulares/isolamento & purificação , Linhagem Celular , Histona Acetiltransferases , Humanos , Imunoprecipitação/métodos , Lisina/imunologia , Lisina/metabolismo , Radioisótopos/química , Fator de Transcrição RelA , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Transfecção/métodos , Fatores de Transcrição de p300-CBP
15.
Immunology ; 113(2): 246-52, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15379985

RESUMO

The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through a receptor (cysLT1-R) which can be targeted in rhinitis and asthma. We investigated the effects of cysLT1-R antagonism in experimental allergic rhinitis, focusing on bone marrow eosinophil progenitor responses. BALB/c mice were sensitized, then given daily intranasal ovalbumin for 2 weeks, with montelukast sodium (5 mg/kg or 2.5 mg/kg) or placebo by gavage. Bone marrow eosinophil/basophil colonies were enumerated, and colony cells were morphologically assessed as indices of eosinophil differentiation and maturation. Montelukast treatment resulted in a significant decrease of eosinophils in the nasal mucosa, and in either bone marrow interleukin (IL)-5-, but not IL-3-, or granulocyte-macrophage colony-stimulating factor-responsive eosinophil/basophil colony-forming units, and IL-5-stimulated eosinophil maturation. These results indicate that cysLT1-R antagonism in vivo limits both IL-5-responsive eosinophilopoiesis, acting at several stages of eosinophil differentiation and maturation. The anti-allergic effects of cysLT1-R antagonists are consistent with the concept that cysLTs and IL-5 act together in the recruitment of eosinophils and eosinophil progenitors from the marrow during upper airway allergic inflammation.


Assuntos
Eosinófilos/imunologia , Antagonistas de Leucotrienos , Proteínas de Membrana/antagonistas & inibidores , Rinite Alérgica Perene/imunologia , Acetatos/imunologia , Animais , Basófilos/imunologia , Medula Óssea/imunologia , Diferenciação Celular , Técnicas de Cultura , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Hematopoese/imunologia , Interleucina-3/análise , Interleucina-5/análise , Contagem de Leucócitos , Antagonistas de Leucotrienos/imunologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/imunologia , Quinolinas/imunologia , Receptores de Leucotrienos/imunologia , Células-Tronco/imunologia
16.
Ann Allergy Asthma Immunol ; 92(2): 250-4, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14989395

RESUMO

BACKGROUND: Butterbur or Petasites hybridus is an herbal remedy that exhibits antihistamine and antileukotriene activity and has been shown to attenuate the response to adenosine monophosphate challenge in patients with allergic rhinitis and asthma. However, no data are available regarding its effects on the histamine and allergen cutaneous response. OBJECTIVE: To evaluate the effects of butterbur compared with fexofenadine and montelukast on the histamine and allergen wheal and flare cutaneous responses. METHODS: Atopic patients were randomized into a double-blind, double-dummy, crossover study to receive for 1 week butterbur, 50 mg twice daily (8 AM and 10 PM); fexofenadine, 180 mg once daily (10 PM), and placebo once daily (8 AM); montelukast, 10 mg once daily (10 PM), and placebo once daily (8 AM); or placebo twice daily (8 AM and 10 PM). Patients attended the department at 10 AM and had measurements of the cutaneous wheal and flare responses to histamine, allergen, and saline control at 10-minute intervals for 60 minutes. RESULTS: Twenty patients completed the study. The mean +/- SE histamine wheal and flare responses, respectively, were significantly attenuated (P < .05) by fexofenadine (9.4 +/- 1.8 mm2 and 13.5 +/- 3.2 mm2) compared with placebo (15.5 +/- 3.3 mm2 and 179.8 +/- 74.3 mm2) but not by butterbur (16.4 +/- 2.1 mm2 and 297.7 +/- 121.2 mm2) or montelukast (19 +/- 1.9 mm2 and 240.2 +/- 66.6 mm2). The allergen wheal and flare responses, respectively, were also significantly attenuated (P < .05) by fexofenadine (31.1 +/- 6.3 mm2 and 256.9 +/- 86.5 mm2) compared with placebo (65.4 +/- 15.2 mm2 and 1,014.5 +/- 250.0 mm2) but not by butterbur (50.4 +/- 9.2 mm2 and 1,110.3 +/- 256.1 mm2) or montelukast (58.8 +/- 9.1 mm2 and 1,463.6 +/- 295.6 mm2). CONCLUSIONS: Butterbur did not produce any significant effects on the histamine and allergen cutaneous response compared with placebo, whereas mediator antagonism with fexofenadine but not montelukast produced significant attenuation. This finding would suggest that butterbur may not be effective in allergic skin disease.


Assuntos
Dermatite Atópica/tratamento farmacológico , Histamina/imunologia , Petasites , Fitoterapia/métodos , Terfenadina/análogos & derivados , Acetatos/imunologia , Acetatos/farmacologia , Adulto , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacologia , Estudos Cross-Over , Dermatite Atópica/imunologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Quinolinas/imunologia , Quinolinas/farmacologia , Testes Cutâneos , Terfenadina/imunologia , Terfenadina/farmacologia
17.
Shi Yan Sheng Wu Xue Bao ; 37(5): 359-66, 2004 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-15636363

RESUMO

A monoclonal antibody (McAb) against methyl jasmonate (MeJA) was prepared and characterized. The McAb, J2-4B, was derived from an immunogen in which the C1-COOH of jasmonic acid (JA) was conjugated to the -NH2 of keyhole limpet hemocyanin (KLH). The McAb showed a higher recognition ability to methyl esters of JA than to its free acids. The integrity of a pentenyl in JA molecule was necessary for the recognition of McAb. Hydrogenation at C-9 and C-10 (dihydrojasmonic acid, 2H-JA) or eliminating the methyl group at C-12 (JAS-25) significantly abolished the binding force of JA molecule with the McAb. Some structural or functional analogues or precursor of JA, such as cucurbic acid, theobroxide, coronatine, and linolenic acid, could not be recognized by the McAb. The McAb has been used to set up a competitive enzyme-linked immunosorbent assay (ELISA) with a linearity range from 2.06 to 500 pmol of MeJA. Using this method, the fluctuations of JA content in florets during anthesis of wheat and Italian ryegrass were analyzed. Results showed that JA level increased obviously as the florets approaching to opening, arrived at a "peak" value at full opening and decreased sharply afterwards.


Assuntos
Acetatos/imunologia , Anticorpos Monoclonais/biossíntese , Ciclopentanos/imunologia , Ciclopentanos/metabolismo , Lolium/metabolismo , Oxilipinas/imunologia , Oxilipinas/metabolismo , Triticum/metabolismo , Acetatos/química , Animais , Linhagem Celular Tumoral , Ciclopentanos/química , Ensaio de Imunoadsorção Enzimática , Flores/química , Camundongos , Estrutura Molecular , Oxilipinas/química
18.
Am J Respir Crit Care Med ; 167(9): 1232-8, 2003 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-12456382

RESUMO

We evaluated whether montelukast conferred additive effects in patients with asthma receiving fluticasone/salmeterol (FP/SM) combination and FP alone. Twenty-two patients with mild to moderate asthma completed a double-blind, placebo-controlled study. After a 2-week run-in using FP 250 microg/SM 50 microg 1 puff twice daily, patients entered a randomized crossover period to receive additional montelukast 10 mg daily or placebo for 3 weeks each. For the first 2 weeks, they received FP/SM 1 puff BID, and then they received FP 250 microg 1 puff BID for the 3rd week. The primary outcome was adenosine monophosphate challenge threshold and recovery time; secondary outcomes included surrogate inflammatory markers and lung function. Compared with FP/SM run-in, adding montelukast to FP/SM was better (p < 0.05) than placebo for inflammatory markers but not for lung function. For adenosine monophosphate threshold, recovery, exhaled nitric oxide, and blood eosinophils, there were 1.4 (95% confidence interval, 1.1-1.8) geometric mean fold, 10 minutes (3-17 minutes), 2.1 parts per billion (0.2-3.9 parts per billion), and 88 (34-172) x 10(6)/L differences, respectively. The combination of FP plus montelukast was superior to FP/SM for inflammatory markers but was inferior for lung function. Thus, in patients taking FP/SM or FP, montelukast conferred complimentary effects on surrogate inflammatory markers, which were dissociated from lung function. Further studies are required to evaluate whether these effects of montelukast translate into clinical benefits.


Assuntos
Acetatos/uso terapêutico , Albuterol/análogos & derivados , Albuterol/uso terapêutico , Androstadienos/uso terapêutico , Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Biomarcadores/sangue , Antagonistas de Leucotrienos/uso terapêutico , Quinolinas/uso terapêutico , Acetatos/imunologia , Monofosfato de Adenosina , Adolescente , Adulto , Idoso , Albuterol/imunologia , Androstadienos/imunologia , Antiasmáticos/imunologia , Anti-Inflamatórios/imunologia , Asma/sangue , Asma/imunologia , Testes de Provocação Brônquica , Estudos Cross-Over , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fluticasona , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Antagonistas de Leucotrienos/imunologia , Masculino , Pessoa de Meia-Idade , Quinolinas/imunologia , Xinafoato de Salmeterol , Índice de Gravidade de Doença , Resultado do Tratamento
20.
Am J Respir Crit Care Med ; 163(6): 1420-5, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11371412

RESUMO

We studied, separately, the effects of the histamine antagonist, fexofenadine hydrochloride, and the leukotriene antagonist, montelukast sodium, and their placebos on airway sensitivity to and recovery from inhaled mannitol in subjects with asthma. Two 180-mg doses of fexofenadine were taken over 14 h, and three 10-mg doses of montelukast over 36 h, with the last dose 5 h before challenge. Fexofenadine reduced sensitivity to mannitol and the PD(15) was (mean [95% confidence interval] 138 [95, 201]) mg versus placebo (51 [25, 106] mg) (p < 0.001). The final percent reduction in FEV(1) with fexofenadine was 20.8 +/- 5.4% and not different from placebo (20.1 +/- 5.3%) (p = 0.7); however, recovery was slower with fexofenadine compared with placebo (p < 0.001). By contrast, montelukast had no effect on sensitivity to mannitol and the PD(15) was 71 [36, 144] mg versus placebo (87 [51, 148] mg (p = 0.35). The total dose of mannitol delivered and the final percent reduction in FEV(1) with montelukast were 171 +/- 142 mg and 21 +/- 4% and for placebo were 182 +/- 144 mg and 20 +/- 5% (p = 0.35, p = 0.59, respectively). However, recovery of FEV(1) to baseline was faster with montelukast, with the area under the percent reduction FEV(1)-versus-time curve reduced (220 +/- 121% change.min) compared with placebo (513 +/- 182% change.min) (p < 0.001). We conclude that whereas histamine is important for the initial airway response, leukotrienes are important in sustaining the airway response to inhaled mannitol.


Assuntos
Acetatos/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/diagnóstico , Asma/imunologia , Hiper-Reatividade Brônquica/diagnóstico , Hiper-Reatividade Brônquica/imunologia , Testes de Provocação Brônquica/métodos , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Manitol , Quinolinas/uso terapêutico , Terfenadina/análogos & derivados , Terfenadina/uso terapêutico , Acetatos/imunologia , Administração por Inalação , Adolescente , Adulto , Idoso , Antiasmáticos/imunologia , Asma/tratamento farmacológico , Asma/fisiopatologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/fisiopatologia , Método Duplo-Cego , Interações de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/imunologia , Humanos , Antagonistas de Leucotrienos/imunologia , Masculino , Pessoa de Meia-Idade , Quinolinas/imunologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Terfenadina/imunologia , Fatores de Tempo
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