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1.
Pharm Res ; 37(2): 31, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915990

RESUMO

PURPOSE: To assess the efficacy of the novel clinical formulation of fenretinide (LAU-7b) for the treatment of allergic asthma. To study the association between LAU-7b treatment in allergic asthma and the modulation of very long chain ceramides (VLCC). METHODS: We used two allergens (OVA and HDM) to induce asthma in mouse models and we established a treatment protocol with LAU-7b. The severity of allergic asthma reaction was quantified by measuring the airway resistance, quantifying lung inflammatory cell infiltration (Haematoxylin and eosin stain) and mucus production (Periodic acid Schiff satin). IgE levels were measured by ELISA. Immunophenotyping of T cells was done using Fluorescence-activated cell sorting (FACS) analysis. The analysis of the specific species of lipids and markers of oxidation was performed using mass spectrometry. RESULTS: Our data demonstrate that 10 mg/kg of LAU-7b was able to protect OVA- and HDM-challenged mice against increase in airway hyperresponsiveness, influx of inflammatory cells into the airways, and mucus production without affecting IgE levels. Treatment with LAU-7b significantly increased percentage of regulatory T cells and CD4+ IL-10-producing T cells and significantly decreased percentage of CD4+ IL-4-producing T cells. Our data also demonstrate a strong association between the improvement in the lung physiology and histology parameters and the drug-induced normalization of the aberrant distribution of ceramides in allergic mice. CONCLUSION: 9 days of 10 mg/kg of LAU-7b daily treatment protects the mice against allergen-induced asthma and restores VLCC levels in the lungs and plasma.


Assuntos
Alérgenos/imunologia , Asma/tratamento farmacológico , Fenretinida/uso terapêutico , Ovalbumina/imunologia , Pyroglyphidae/imunologia , Animais , Asma/imunologia , Asma/metabolismo , Ceramidas/metabolismo , Protocolos Clínicos , Modelos Animais de Doenças , Composição de Medicamentos , Feminino , Masculino , Metilcelulose/química , Camundongos
2.
Life Sci ; 241: 117120, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31825792

RESUMO

AIMS: The present study explored the function and regulatory mechanism of High mobility group box 1 (HMGB1) in asthma. MAIN METHODS: OVA (ovalbumin)-induced asthmatic mice model and LPS-treated cellular model were established in this study. Airway inflammation was measured through detecting the expression of IL-4, IL-5, IL-13 and Interferon-γ (IFN-γ) in serum and BALF (bronchoalveolar lavage fluid) by ELISA kits. Bioinformatics predictive analysis, ChIP assays, Luciferase reporter assay and Western blotting were used to explore the relation between HMGB1 and HSF1 (Heat shock factor 1). KEY FINDINGS: HMGB1 expression was increased in OVA-induced asthmatic mice. Silencing HMGB1 attenuated the increasing of IgE, inflammatory factors (IL-4, IL-5 and IL-13), and airway hyperresponsiveness that induced by OVA. In addition, our study found that HSF1 directly bind with the HMGB1 promoter and negatively regulation of HMGB1. HSF-1 were upregulated in OVA-induced asthmatic mice, and knockdown of HSF1 aggravated the OVA-induced airway inflammation and airway hyperreactivity in mice may through promoting the expression of HMGB1 and the activation of the Toll-like receptor 4 (TLR4)/Myeloid differentiation primary response 88 (MyD88)/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signal pathway. SIGNIFICANCE: The expression of HMGB1 could be negatively regulated by HSF1, and the TLR4/MyD88/NF-κB signal pathway was involved in HSF1/HMGB1-mediated regulation of asthma.


Assuntos
Asma/patologia , Proteína HMGB1/metabolismo , Fatores de Transcrição de Choque Térmico/fisiologia , Inflamação/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Asma/induzido quimicamente , Asma/genética , Asma/metabolismo , Sequência de Bases , Hiper-Reatividade Brônquica/etiologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Citocinas/metabolismo , Células HEK293 , Proteína HMGB1/genética , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , Ovalbumina/toxicidade , Regiões Promotoras Genéticas , Transdução de Sinais , Receptor 4 Toll-Like/genética
3.
Toxicol Lett ; 321: 146-154, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31836503

RESUMO

BACKGROUND: Exposure to particulate matters (PMs) can lead to an acute exacerbation of allergic airway diseases, increasing the severity of symptoms and mortality. However, little is known about the underlying molecular mechanism. This study aimed to investigate the effects of PMs on acute exacerbation of allergic airway inflammation and seek potential therapeutic targets. METHODS: Non-allergic control and ovalbumin (OVA)-allergic wide-type (WT) and Toll-like receptor 2 knockout (Tlr2-/-) mice were exposed to 100 µg of PM (diameter 5.85 µm) or saline by the oropharyngeal instillation. The responses were examined three days after exposure. In the RAW264.7 macrophage cell line, Tlr2 was knocked down by small-interfering RNA or the NF-κB inhibitor JSH-23 was used, and then the cells were stimulated with PMs for 12 h before comparison of the inflammatory responses. RESULTS: PM exposure led to increased inflammatory cell recruitment and airway intensity of PAS + staining in OVA-allergic WT mice, accompanied with an accumulation of inflammatory cells and elevated inflammatory cytokines, such as IL-6 and IL-18, in the bronchoalveolar lavage fluid (BALF). Furthermore, the protein levels of TLR2 and the NLRP3 inflammasome were elevated concomitantly with the airway inflammation post-OVA/PMs challenge. Tlr2 deficiency effectively inhibited the airway inflammation, including pulmonary inflammatory cell recruitment, mucus secretion, serum OVA-specific immunoglobulin E (IgE), and BALF inflammatory cytokine production. Additionally, the P-induced NLRP3 activation in the RAW 264.7 cell line was diminished by the knockdown of Tlr2 or JSH-23 treatment in vitro. CONCLUSION: Our results indicated that PMs exacerbate the allergic airway inflammation mediated by the TLR2/ NF-κB/NLRP3 signaling pathway. Inhibition of NF-κB seems to be a possible treatment.


Assuntos
Pulmão/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Material Particulado/toxicidade , Hipersensibilidade Respiratória/induzido quimicamente , Receptor 2 Toll-Like/metabolismo , Alérgenos , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Pulmão/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Tamanho da Partícula , Células RAW 264.7 , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética
4.
Life Sci ; 241: 117172, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843529

RESUMO

AIMS: Allergic airway inflammation is one of the major pathological events involved in asthma, and dysregulation of regulatory T cells (Treg) plays a crucial role in the development of allergic airway inflammation. Here, we attempted to investigate the regulatory effects of B cell-activating factor (BAFF) on Tregs in allergic airway inflammation. MAIN METHODS: BAFF expression was analyzed by ELISA, quantitative reverse transcription PCR (RT-PCR) and Western blot assays. The levels of IL-4, TGF-ß, IL-2, and IL-10 were tested using ELISA kits. Flow cytometry was conducted to analyze the populations of CTLA4+ Foxp3+ Tregs. KEY FINDINGS: BAFF was found to be aberrantly expressed in sputum and lungs in patients with asthma as well as OVA sensitized mice. BAFF silencing by lentiviral BAFF shRNA reduced the number of eosinophils and levels of IL-4 in the BAL fluid, as well as the Fizz1 expression in the lungs of OVA mice. Additionally, the population of CTLA4+ Foxp3+ Tregs were significantly decreased in OVA mice and had a negative correlation to BAFF levels in asthmatic patients and OVA mice. BAFF silencing in vivo increased levels of CTLA4+ Foxp3+ Tregs and the secretion of IL-10, and improved the regulatory phenotype and suppressor function of Tregs in vitro. Furthermore, BAFF can affect Tregs generation by regulating the production of the pro-Treg cytokines IL-2 and TGF-ß. SIGNIFICANCE: BAFF has an inhibitory effect on the generation and suppressor function of Tregs by affecting pro-Tregs cytokines, thereby contributing to the development of allergic airway inflammation.


Assuntos
Asma/prevenção & controle , Fator Ativador de Células B/antagonistas & inibidores , Citocinas/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Inflamação/prevenção & controle , Linfócitos T Reguladores/imunologia , Adulto , Animais , Asma/etiologia , Asma/imunologia , Asma/patologia , Fator Ativador de Células B/genética , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Ovalbumina/toxicidade
5.
Life Sci ; 242: 117222, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881223

RESUMO

BACKGROUND: Asthma is a complex inflammatory disease which affects multiple individuals worldwide especially pediatric ages. AIMS: This study aimed to assess the possible protective effect of carvacrol, as natural antioxidant anti-inflammatory drug, against bronchial asthma induced experimentally in rats. MAIN METHODS: Rats were randomly allocated into 5 groups; a normal control group, control drug group received only carvacrol, an asthma control group, a standard treatment group receiving dexamethasone (DEXA) and carvacrol treatment group. Bronchial asthma was induced by sensitization with i.p dose followed by challenge with intranasal dose of ovalbumin (OVA). 24 h after the last challenge, absolute eosinophil count (AEC) were determined in bronchoalveolar lavage fluids (BALF). Immunoglobulin E (IgE) was determined in serum. Inflammatory biomarkers like Interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin 13 (IL-13), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were also measured in BALF. Nitrosative stress biomarker namely inducible nitric oxide synthase (iNOS) was determined in BALF as well as oxidative stress biomarkers namely superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) were determined in lung tissue. Additionally, histopathological study, immunohistochemical study of UCN and western blot analysis of SP-D were performed. KEY FINDINGS: Carvacrol administration significantly reduced the values of AEC, IgE, IL-4, IL-5, IL-13, TNF-α, IFN-γ, iNOS and MDA, while it significantly increased the values of SOD and GSH as compared to the asthmatic group. Histopathological, immunohistochemical and western blot study reinforced the biochemical results. SIGNIFICANCE: Carvacrol may be a promising protective agent against bronchial asthma induced experimentally in rats.


Assuntos
Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Fatores Imunológicos/farmacologia , Animais , Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/induzido quimicamente , Asma/patologia , Western Blotting , Modelos Animais de Doenças , Fatores Imunológicos/uso terapêutico , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Ovalbumina/farmacologia , Proteína D Associada a Surfactante Pulmonar/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
6.
Food Chem ; 303: 125407, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31466032

RESUMO

Theaflavin (TF), which is the key pigment in black tea, is a health-promoting food component with beneficial effects on humans. However, the interactions by which these effects are transferred and exerted into protein-rich foods are unclear. Here, egg ovalbumin (OVA) was selected as a representative dietary protein to ascertain their binding mechanism. Steady-state, time-resolved fluorescence and isothermal titration calorimetric results showed that TF can interact well with OVA with an affinity magnitude of 104. The noncovalent binding was mainly driven by hydrophobic interaction and hydrogen bonds. Structural analysis displayed that the TF binding pocket significantly overlapped with one of the surrounding specific IgE-binding epitopes, thereby causing a subtle structural adjustment on the secondary conformation of OVA. The biological complexation model that was delineated here will help understand how black tea dyes egg white in tea egg products and for the development of protein-rich carriers in functional foods.


Assuntos
Biflavonoides/química , Camellia sinensis/química , Catequina/química , Clara de Ovo/química , Ovalbumina/química , Pigmentos Biológicos/química , Extratos Vegetais/química , Animais , Galinhas , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Ligação Proteica , Chá/química
7.
Ecotoxicol Environ Saf ; 188: 109867, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31689658

RESUMO

BACKGROUND: Accumulating epidemiological studies showed that prenatal and early life exposure to ambient air pollution was important contributor to the development of childhood asthma. However, the effects and mechanisms of prenatal exposure to ozone (O3), a type of ambient air pollution, on the progression of asthma in offspring remain unclear. OBJECTIVE: This study aimed to determine the effects and mechanism of asthma in offspring after prenatal O3 exposure. METHODS: Pregnant BALB/c mice were exposed to O3 or air on gestational days (GDs) 13-18. Their offspring were sensitized and challenged to ovalbumin (OVA) to establish asthma model, and the asthma features were evaluated. The splenic natural killer (NK) cells in the offspring were measured to explore the mechanism on the effects of asthma in the offspring. The responses of the pregnant mice and dams after O3 exposure were evaluated. RESULTS: Airway inflammation, mucus secretion, OVA-specific immunoglobulin (Ig) E, T helper (Th) 2-skewed response, the frequency of CD3ε-CD49b+ splenic NK cells, the expression of tumor necrosis factor (TNF)-α, and IL (interleukin)-17 were significantly exacerbated in the OVA-induced asthma offspring after prenatal O3 exposure. In addition, airway inflammation, a lower number of CD3ε-CD49b+ splenic NK cells, and systemic oxidative stress were caused at the end of pregnancy after O3 exposure, which did not recover at the end of lactation for the first two responses. CONCLUSIONS: Prenatal O3 exposure increased the severity of OVA-induced asthma in the offspring, which might be directly induced by CD3ε-CD49b+ splenic NK cells in the offspring and indirectly related to the damaged maternal immune system.


Assuntos
Poluentes Atmosféricos/toxicidade , Asma/induzido quimicamente , Asma/patologia , Ovalbumina , Ozônio/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Asma/imunologia , Feminino , Células Matadoras Naturais/imunologia , Masculino , Camundongos Endogâmicos BALB C , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Equilíbrio Th1-Th2
8.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(12): 1223-1228, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31874664

RESUMO

OBJECTIVE: To establish and evaluate an ovalbumin (OVA)-induced bronchial asthma model in mice with intrauterine growth retardation (IUGR), and to explore the molecular mechanism of relationship between IUGR and asthma. METHODS: A total of 16 pregnant BALB/c female mice were divided into a low-protein diet group (n=8) and a normal-protein diet group (n=8), which were fed with low-protein (8%) diet and normal-protein (20%) diet respectively. The neonatal mice were weighed 6 hours after birth. Sixteen male neonatal mice with IUGR were randomly chosen from the low-protein diet group and enrolled in the IUGR group, and 16 male neonatal mice from the normal-protein diet group were enrolled in the control group. Blood samples were collected from the mice in both groups for testing of blood glucose. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum insulin level. The mice in the control group were randomized into a control + PBS group and a control + OVA group (n=8 each). The mice in the IUGR group were randomized into an IUGR + PBS group and an IUGR + OVA group (n=8 each). Six-week-old mice in the control + OVA and IUGR + OVA groups were subjected to intraperitoneal injection of 2 mg/mL OVA for sensitization and aerosol inhalation of 1% OVA for challenge. Mice in the control + PBS group and the IUGR + PBS group were treated with an equivalent amount of PBS. ELISA was used to determine serum IgE level in the mice in each group. Bronchoalveolar lavage fluid (BLF) was collected from the mice in each group for cell counting. The lung tissue of the mice in each group was stained with hematoxylin and eosin to observe pathological changes. RESULTS: The body weight at 6 hours after birth was significantly lower for neonatal mice in the low-protein diet group compared with those in the normal-protein diet group (P<0.01). The IUGR group had a significantly lower serum insulin level than the control group (P<0.01). The IUGR + PBS group had a significantly lower IgE level than the control + PBS group (P<0.01). Compared with the control + PBS and IUGR + PBS groups, the control + OVA and IUGR + OVA groups had a significantly increased IgE level, and the IgE level was significantly higher in the IUGR + OVA group than in the control + OVA group (P<0.01). Compared with the control + PBS and IUGR + PBS groups, the control + OVA and IUGR + OVA groups had significantly increased counts of leukocytes, eosinophils, lymphocytes, and macrophages in the BLF (P<0.01). The pulmonary alveoli of OVA-induced IUGR mice showed massive inflammatory cell infiltration and damage of intercellular continuity. Meanwhile, airway epithelial cell proliferation, bronchial wall thickening, bronchial lumen narrowing, and massive inflammatory cell infiltration around the bronchi and the vascular wall were observed. CONCLUSIONS: An OVA-induced bronchial asthma model has been successfully established in the mice with IUGR induced by low-protein diet, which provides a basis for further study of the molecular mechanism of relationship between IUGR and airway inflammation.


Assuntos
Asma , Retardo do Crescimento Fetal , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Feminino , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina
9.
Life Sci ; 239: 117017, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678284

RESUMO

Saxagliptin (Saxa), a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, is widely used for the treatment of type 2 diabetes mellitus. It has been documented to have immunomodulatory and anti-inflammatory actions. Our objective was to delineate the protective effect and the underlying mechanism of Saxa-in comparison with Dexamethasone (Dexa) - in airway inflammation induced by ovalbumin (OVA) in mice. METHODS: Mice were OVA-sensitized and challenged for the induction of acute asthma. Mice were orally administrated Saxa or Dexa. Total and differential cell counts, lactate dehydrogenase (LDH) and total protein concentrations were assessed in bronchoalveolar lavage fluid (BALF). The toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-kB), reduced glutathione (GSH), and total nitrate/nitrite products (NOx) levels as well as myeloperoxidase (MPO) activity in lung tissues were measured. Histopathological examination of the lung specimens was carried out using the hematoxylin and eosin (H & E) staining. RESULTS: Histopathological examination revealed that both Saxa and Dexa ameliorated OVA-induced inflammatory changes and significantly reduced total and differential leukocyte counts, LDH and total protein level in BALF upon comparison with OVA group. In addition, both treatments significantly mitigated OVA-induced oxidative stress as evidenced by diminished lung NOx level and MPO activity and elevated GSH level. The elevation of TLR4 and NF-kB levels in lung tissue were ameliorated by Saxa and Dexa administration. CONCLUSION: Saxa had marked antiasthmatic effect in OVA-induced allergic asthma through modulation of TLR4 and NF-κB signaling. Also, Saxa may represent a promising therapeutic agent for acute allergic asthma.


Assuntos
Adamantano/análogos & derivados , Asma/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , NF-kappa B/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Doença Aguda , Adamantano/uso terapêutico , Animais , Asma/induzido quimicamente , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Dexametasona/uso terapêutico , L-Lactato Desidrogenase/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Ovalbumina , Peroxidase/metabolismo
10.
J Environ Pathol Toxicol Oncol ; 38(3): 229-238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679310

RESUMO

Asthma has affected more than 300 million people worldwide and is considered one of the most debilitating global public health problems based on a recent statistical report from the Global Initiative for Asthma. Inflammation of the airways leads to the various interrelated mechanisms of innate and adaptive immunity acting mutually with the epithelium of the respiratory organ. Fucoxanthin is an orange or brown pigment which is naturally found in various seaweeds. To the best of our knowledge, there are no scientific claims or evidence of the curative effects of fucoxanthin against asthma. Hence, this present research was designed to investigate the curative activity of fucoxanthin against ovalbumin-induced asthma in a mouse model. Fucoxanthin (50 mg/kg) showed significant (P < 0.001) antiasthma activity. It effectively decreased intracellular secretion of reactive oxygen species and increased antioxidant enzyme activity. Fucoxanthin also decreased inflammatory cytokine markers in bronchoalveolar lavage fluid. Because fucoxanthin showed effective antiasthma activity against ovalbumin-induced asthma in experimental animals, further research on this natural antioxidant could lead to development of a novel drug for the treatment of asthma in humans.


Assuntos
Antiasmáticos/farmacologia , Antioxidantes/metabolismo , Asma/tratamento farmacológico , Citocinas/imunologia , Inflamação/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Xantofilas/farmacologia , Animais , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/química , Citocinas/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Camundongos , Ovalbumina/toxicidade
11.
Pathologe ; 40(Suppl 3): 259-264, 2019 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-31720747

RESUMO

Hyperosmolar micromilieu has been observed in physiologic (kidney medulla, lymphatic tissue) and pathologic (renal allorejection, solid tumors) conditions. Hyperosmolarity can modulate gene expression and alter the stimulatory profile of macrophages and dendritic cells. We have reported that dendritic cells upon exposure to hypertonic stimuli shift their profile towards a macrophage-M2-like phenotype, resulting in attenuated local alloreactivity during acute kidney graft rejection. Moreover, we showed that a hyperosmotic microenvironment affects the cross-priming capacity of dendritic cells. Using ovalbumin as a model antigen, we showed that exposure of dendritic cells to hyperosmolarity strongly inhibits activation of antigen-specific T cells despite enhancement of antigen uptake, processing, and presentation; it can reduce dendritic cell-T cell contact time. We have identified TRIF as key mediator of this phenomenon. Moreover, we detected a hyperosmolarity-triggered, TRIF-dependent clustering of MHC class I­antigen complexes, but not of unloaded MHCI molecules, providing a possible explanation for a reduced T cell activation. Our findings identify dendritic cells as important players in hyperosmolarity-triggered immune imbalance and suggest that targeting local hyperosmolarity in tumor micromilieu may contribute to an enhanced specific anti-tumor immune response.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Células Dendríticas , Antígenos de Histocompatibilidade Classe I , Apresentação Cruzada , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ativação Linfocitária , Osmorregulação , Ovalbumina/imunologia , Linfócitos T
12.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(11): 845-851, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31694095

RESUMO

Objective: To explore the role of S100A8, the receptor for advanced glycation endproducts (RAGE) and Caveolin-1 in neutrophilic asthmatic rats, and to further study the intervention of roxithromycin and the possible mechanisms. Methods: Male Brown Norway rats were randomly assigned to a control group, an asthma group and a Roxithromycin group. The asthmatic rat model was established by intraperitoneal injection of ovalbumin (OVA) and Freund's complete adjuvant (FCA) mixture, and aerosol inhalation of OVA. Rats in the Roxithromycin group were given roxithromycin injection 30 mg/kg 30 minutes before each challenge. Rats in the control and the asthma groups were replaced with equal volumes of saline, respectively. Bronchoalveolar lavage fluid (BALF) neutrophil percentage (Neu%) and pathological changes of pulmonary tissue (hematoxylin-eosin, HE staining) were measured to confirm the establishment of asthmatic models. The concentration of inflammatory cytokines and S100A8 were quantified by enzyme-linked immunosorbent assay (ELISA), and the expression of Caveolin-1 and RAGE at protein levels were detected by immunohistochemistry and Western blot. Results: Neu% in BALF of the asthma group was significantly higher than those of the control group, and Neu% in the Roxithromycin group was lower than the asthma group (all P<0.01). Pulmonary histology revealed that there were a large number of inflammatory cells infiltrated in the bronchial and perivascular, pulmonary interstitial and alveolar spaces, and the bronchial wall and smooth muscles were thickened obviously in the asthma group. Rats in the Roxithromycin group showed milder inflammation and airway remodeling change than the asthma group. There was no obvious pathological damage in the control group. The concentration of IL-6 and IL-17 in BALF and serum of rats in the asthma group were significantly higher than those in the control group (P<0.01), and Roxithromycin inhibited the high expression of these cytokines (P<0.05). The expression of S100A8 and RAGE in the asthma group were significantly higher than those in the control group [(20.6±4.4) vs (7.1±2.0) ng/L; (885±118) vs (462±102) ng/L; (14.2±1.7) vs (7.6±1.8) ng/L; (774±166) vs (406±69) ng/L, all P<0.05], and Roxithromycin inhibited the high expression of these proteins [(14.3±3.7) vs (20.6±4.4) ng/L; (650±53) vs (885±118) ng/L; (10.4±1.2) vs (14.2±1.7) ng/L; (560±64) vs (728±72) ng/L] (all P<0.05). Meanwhile, the expression of Caveolin-1 in the asthma group was significantly lower than that in the control group (P<0.01), and Roxithromycin up-regulated its expression (P<0.01). Correlation analysis showed that there was a significantly positive correlation between the expression of S100A8 and RAGE (r=0.706, P<0.01), while there was a significantly negative correlation between the expression of S100A8 and Caveolin-1 (r=-0.775, P<0.01), and between the expression of Caveolin-1 and RAGE (r=-0.919, P<0.01). Conclusion: S100A8 and Caveolin-1 may play an important role in neutrophilic asthma via RAGE, and Roxithromycin may exerts anti-inflammatory effects and inhibition of airway remodeling partly through this signaling pathway.


Assuntos
Antibacterianos/farmacologia , Asma/tratamento farmacológico , Calgranulina A/efeitos dos fármacos , Caveolina 1/efeitos dos fármacos , Roxitromicina/farmacologia , Remodelação das Vias Aéreas , Animais , Antibacterianos/administração & dosagem , Western Blotting , Líquido da Lavagem Broncoalveolar , Calgranulina A/metabolismo , Caveolina 1/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Pulmão/fisiopatologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ovalbumina , Ratos , Receptor para Produtos Finais de Glicação Avançada , Roxitromicina/administração & dosagem
13.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 31(5): 504-509, 2019 Oct 14.
Artigo em Chinês | MEDLINE | ID: mdl-31713379

RESUMO

OBJECTIVE: To investigate the protective effect of excretory-secretory protein (AES) from adult Trichinella spiralis on ovalbumin (OVA)-induced allergic rhinitis in mice. METHODS: Eighteen female BALB/c mice were randomly divided into three groups, including the blank control group (Group A), OVA-induced rhinitis group (Group B) and AES treatment group (Group C). Mice in Group A were given PBS. Mice in Group B were intraperitoneally injected with antigen adjuvant suspension for systemic sensitization, once every other day for seven times; then, local excitation was intranasally induced with 5% OVA solution once a day for seven times to establish a mouse model of allergic rhinitis. In addition to induction of allergic rhinitis, mice in Group C were given 25 µg AES at baseline sensitization and local excitation. Following the final challenge, mice were observed for 30 min in each group, and the behavioral score was evaluated. The serum levels of IFN-γ, IL-4, IL-5, IL-10 and TGF-ß were determined using an enzyme-linked immunosorbent assay in mice, and the pathological changes of mouse nasal mucosa were observed under a microscope. RESULTS: There was a significant difference in the mouse behavioral scores among the three groups (F = 110.12, P < 0.01). The mouse behavioral score was significantly higher in Group B than in Group A (7.17 ± 0.75 vs. 1.33 ± 0.52, P < 0.01), and more remarkable pathological damages of mouse nasal mucosa were seen in Group B than in Group A, while the mouse behavioral score was significantly decreased in Group C than in Group B (P < 0.01), and the pathological damages of mouse nasal mucosa remarkably alleviated in Group C relative to Group B. There was a significant difference in serum IFN-γ level among the three groups (F = 7.50, P < 0.01) and the serum IFN-γ level in Group B was significantly lower than in group A and C (both P < 0.05). There were significant differences in serum IL-4 (F = 470.81, P < 0.01) and IL-5 levels (F =68.20, P < 0.01) among the three groups, and significantly greater serum IL-4 and IL-5 levels were detected in Group B than in Group A (P < 0.01), while significantly lower serum IL-4 and IL-5 levels were detected in Group C than in Group B (P < 0.01). There were significant differences in serum IL-10 (F = 174.91, P < 0.01) and TGF-ß levels (F = 9.39, P < 0.01) among the three groups, and significantly greater serum IL-10 and TGF-ß levels were seen in Group C than in Group B (both P < 0.05). CONCLUSIONS: T. spiralis AES has a remarkable protective activity against OVA-induced allergic rhinitis in mice.


Assuntos
Antígenos de Helmintos , Proteínas de Helminto , Rinite Alérgica , Trichinella spiralis , Animais , Antígenos de Helmintos/imunologia , Antígenos de Helmintos/farmacologia , Modelos Animais de Doenças , Feminino , Proteínas de Helminto/imunologia , Proteínas de Helminto/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/efeitos dos fármacos , Ovalbumina , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/imunologia , Rinite Alérgica/prevenção & controle
14.
Life Sci ; 236: 116790, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626791

RESUMO

AIMS: Although the bulk of research into the biology of serotonin 5-HT2A receptors has focused on its role in the CNS, selective activation of these receptors in peripheral tissues can produce profound anti-inflammatory effects. We previously demonstrated that the small molecule 5-HT2 receptor agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] inhibits TNF-α-mediated proinflammatory signaling cascades and inflammation via 5-HT2A receptor activation and prevents the development of, and inflammation associated with, acute allergic asthma in a mouse ovalbumin (OVA) model. Here, we investigated the ability of (R)-DOI to reverse inflammation and symptoms associated with established asthma in a newly developed model of chronic asthma. METHODS: An 18-week ovalbumin challenge period was performed to generate persistent, chronic asthma in BALB/c mice. Four once daily intranasal treatments of (R)-DOI were administered one week after allergen cessation, with respiratory parameters being measured by whole-body plethysmography (WBP). Cytokine and chemokine levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in homogenized lung tissue, bronchoalveolar (BALF) fluid was analyzed for chemokine modulation by multiplex assays, and Periodic Acid-Schiff and Masson's Trichrome staining was performed to determine goblet cell infiltration and overall changes to lung morphology. KEY FINDINGS: 5-HT2 activation via (R)-DOI attenuates elevated airway hyperresponsiveness to methacholine, reduces pulmonary inflammation and mucus production, and reduces airway structural remodeling and collagen deposition by nearly 70%. SIGNIFICANCE: Overall, these data provide support for the therapeutic potential of (R)-DOI and 5-HT2 receptor activation for the treatment of asthma, and identifies (R)-DOI as a novel therapeutic compound against pulmonary fibrosis.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Anfetaminas/farmacologia , Asma/tratamento farmacológico , Pneumonia/prevenção & controle , Receptores 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Remodelação das Vias Aéreas/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Doença Crônica , Feminino , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Hipersensibilidade/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Pneumonia/imunologia , Pneumonia/patologia
15.
Life Sci ; 238: 116953, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626793

RESUMO

AIMS: This study focused on investigating whether NS8593 reverses airway smooth muscle (ASM) contraction and the underlying mechanism. MAIN METHODS: ASM contraction in mouse tracheal rings and lung slices was measured. Currents mediated by voltage dependent Ca2+ channels (VDCCs) and ACH-activated channels were measured using the whole-cell patch-clamp technique in single tracheal smooth muscle cells (TSMCs). Intracellular Ca2+ level and cell length were measured using an LSM 700 laser confocal microscope and a Zen 2010 software. Mouse respiratory system resistance (Rrs) was assessed using a FlexiVent FX system. KEY FINDINGS: High K+ (80 mM K+) and ACH induced ASM contraction in mouse tracheal rings and lung slices, which was partially relaxed by nifedipine (blocker of L-type VDCCs, LVDCCs), YM-58483 (blocker of store-operated Ca2+ entry (SOCE), transient receptor potential C3 (TRPC3) and TRPC5 channels), respectively. However, the contraction was completely reversed by NS8593, whereas, slightly relaxed by formoterol. ACH activated inward currents, which displayed linear and reversed around 0 mV, indicating the currents were mediated by non-selective cation channels (NSCCs). Moreover, these currents were blocked by YM-58483. In addition, such currents were abolished by NS8593, implicating that NS8593 inhibits the same channels. Besides, NS8593 inhibited increases of intracellular Ca2+ and the associated cell shortening. Finally, NS8593 inhibited ACH-induced increases of mouse respirator system resistance (Rrs). SIGNIFICANCE: Our results indicate that NS8593 inhibits LVDCCs and NSCCs, resulting in decreases of intracellular Ca2+ and then leading to ASM relaxation. These data suggest that NS8593 might be a new bronchodilator.


Assuntos
1-Naftilamina/análogos & derivados , Asma/tratamento farmacológico , Canais de Cálcio Tipo L/química , Cálcio/metabolismo , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , 1-Naftilamina/farmacologia , Animais , Antialérgicos/farmacologia , Asma/induzido quimicamente , Asma/patologia , Canais de Cálcio Tipo L/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso/metabolismo , Músculo Liso/patologia , Ovalbumina/toxicidade
16.
Anal Bioanal Chem ; 411(27): 7055-7059, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31598742

RESUMO

A new perspective on the relevant problem-creating simple, rapid, and efficient protein sensors based on microstructured optical fibers using a simple homogeneous analysis format-was proposed. Commercially available long-period grating hollow core microstructured optical fibers (LPG HCMOF) were used to determine bovine serum albumin (BSA) and albumin from chicken eggs (OVA) in binary mixtures as well as immunoglobulin G (IgG) in the presence of BSA and OVA. LPG HCMOF transmission spectra allowed the detection of both BSA and OVA up to 10 mg/mL with LOD as low as 0.1 and 0.8 µg/mL, respectively. Partial least squares regression (PLS) was utilized for modeling of LPG HCMOF spectral data and quantitative analysis of BSA, OVA, total protein, and IgG in binary and ternary mixtures. Rather high coefficients of determination (R2) and low root mean square error for the calibration (RMSEC) (15%) and prediction (RMSEP) (20%) were obtained for all PLS models. The proposed approach was tested in the analysis of BSA in spiked horse blood hemolyzed (HBH). The results demonstrated the functionality of the proposed approach and offered the opportunity for the creation of a wide range of sensors for protein determination in complex mixtures. Graphical abstract.


Assuntos
Imunoglobulina G/análise , Ovalbumina/análise , Soroalbumina Bovina/análise , Animais , Análise Química do Sangue/métodos , Bovinos , Galinhas , Cavalos , Análise dos Mínimos Quadrados , Camundongos , Modelos Moleculares , Fibras Ópticas
17.
Life Sci ; 236: 116901, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610206

RESUMO

AIMS: Allergic rhinitis is a global cause of disability, characterized by airway inflammation. Sumatriptan is a 5-hydroxytryptamine 1B/1D (5HT1B/1D) agonist used as a treatment for migraine headaches. Activation of 5HT1B/1D receptors can inhibit the release of neuropeptides and inhibit the inflammation cascades. This study investigated the effect of sumatriptan on ovalbumin-induced allergic rhinitis model in mice and the role of nitric oxide. METHODS: Female Balb/c mice were sensitized by intraperitoneal ovalbumin and challenged by intranasal ovalbumin. Mice received sumatriptan in doses 3, 10, 30 µg/kg intraperitoneally, 30 min before the last ovalbumin challenge. KEY FINDINGS: Intraperitoneal injection of sumatriptan significantly decreased the nasal scratching, IL-4 and serum IgE levels of allergic mice, but it increased IFNγ levels. Histopathological analysis showed that the number of eosinophils was significantly elevated in nasal mucosa of ovalbumin-induced allergic mice, while sumatriptan treatment significantly reduced the number of eosinophils. GR-127935, a selective 5-HT1B/1D-receptor antagonist, reversed the anti-allergic effects of sumatriptan. Acute administration of l-NAME, a non-specific inhibitor of nitric oxide synthase, along with sumatriptan attenuated the anti-allergic effects of sumatriptan but chronic administration of l-NAME did not affect the influences of sumatriptan. Furthermore, sumatriptan decreased the inducible nitric oxide synthase (iNOS) protein expression in allergic mice, but it did not change the concentration of eNOS protein. SIGNIFICANCE: This study shows that sumatriptan administration is associated with anti-allergic effects which are through 5HT1B/1D receptors. Decrease in iNOS expression and changes in T-helper 1&2 cytokines levels may indicate the involvement of inducible NOS and inflammation.


Assuntos
Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo , Ovalbumina/toxicidade , Rinite Alérgica/prevenção & controle , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sumatriptana/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/metabolismo , Rinite Alérgica/patologia
18.
Exp Parasitol ; 206: 107767, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520603

RESUMO

Schistosoma mansoni eggs can influence immune responses directed at them, and the mechanisms by which this is achieved are being unravelled. Going towards, developing effective tools for the study of how S. mansoni influences naïve T cells, we have developed S. mansoni eggs expressing chicken ovalbumin (OVA), using a lentiviral transduction system. Indeed, such a parasite could be used in conjunction with cells from OT-II transgenic mice as a source of naïve, antigen-specific T cells. The expression of the transgenic protein was confirmed by real-time RT-PCR of OVA-specific mRNA and western blotting using polyclonal antibodies specific for OVA. T cells from OT-II transgenic mice expressing a T cell receptor specific for the OVA323-339 peptide recognised the OVA-transduced S. mansoni eggs. Using flow cytometry on CFSE-labelled OT-II splenocytes, we demonstrated that OVA-transduced eggs elicit higher OT-II proliferative responses than untransduced eggs. The OT-II T cells also produced TNF-α and IFN-γ following exposure to OVA-transduced eggs. In addition, moderate amounts of IL-6 and IL-17A were also detected. In contrast, no IL-10, IL-4 and IL-2 were detected in cultures, whether the cells were stimulated with transduced or untransduced eggs. Thus, the cytokine signatures showed the transfected eggs induced predominantly a Th1 response, with a small amount of IL-6 and IL-17.


Assuntos
Ovalbumina/análise , Receptores de Antígenos de Linfócitos T/imunologia , Schistosoma mansoni/metabolismo , Linfócitos T/imunologia , Animais , Western Blotting , Galinhas , Citocinas/análise , Citocinas/metabolismo , Eletroforese em Gel de Ágar , Feminino , Citometria de Fluxo , Interleucina-17/análise , Interleucina-17/metabolismo , Interleucina-2/análise , Interleucina-2/metabolismo , Interleucina-6/análise , Interleucina-6/metabolismo , Fígado/parasitologia , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Ovalbumina/genética , Ovalbumina/imunologia , Ovalbumina/metabolismo , Óvulo/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/genética , Transcrição Reversa , Schistosoma mansoni/genética , Schistosoma mansoni/crescimento & desenvolvimento , Baço/citologia , Linfócitos T/citologia
19.
Toxicol Lett ; 316: 147-153, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520700

RESUMO

Asthma is a common chronic inflammatory disease which severely reduces the quality of life in patients. Studies have demonstrated that both PM2.5 and cold stress contribute to the development of asthma. However, the combined effects of these two risking factors are unknown. In this study, we investigated the combined effects of PM2.5 exposure and cold stress (PMCS) on asthma, as well as the underlying mechanisms by using a murine model. After different exposures, the immune-pathological changes and redox states in groups were evaluated. Besides, the balance of TH1/TH2 cells and the acetylation levels of H3K9 and H3K14 in IL-4 gene promotor were detected. Our results showed that, compared with other exposures, PMCS led to an increased inflammation and redox levels in mice. It also significantly increased the percentage of TH2 T cells, which was correlated with hyperacetylation of H3K9 and H3K14 in IL-4 gene promoter in CD4+T cells. Furthermore, a significantly increased P300 and decreased HDAC1 were detected in CD4 + T cells in PMCS group. In conclusion, our findings demonstrated that PMCS exacerbated asthma in mice by increasing H3K9 and H3K14 acetylation in IL-4 gene promoter in CD4 + T cells, and P300 and HDAC1 might contribute to their combined effects.


Assuntos
Asma/induzido quimicamente , Temperatura Baixa/efeitos adversos , Histonas/metabolismo , Interleucina-4/metabolismo , Pulmão/efeitos dos fármacos , Material Particulado/toxicidade , Regiões Promotoras Genéticas , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Acetilação , Animais , Asma/genética , Asma/imunologia , Asma/metabolismo , Modelos Animais de Doenças , Proteína p300 Associada a E1A/metabolismo , Histona Desacetilase 1/metabolismo , Interleucina-4/genética , Interleucina-4/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Ovalbumina , Tamanho da Partícula , Processamento de Proteína Pós-Traducional , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
20.
Immunology ; 158(2): 136-149, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31515801

RESUMO

Immune-checkpoint blockade antibodies have been approved for the treatment of cancer. However, poorly immunogenic tumours are less responsive to such therapies. Agonistic anti-Toll-like receptor 4 (TLR4) monoclonal antibodies (mAbs) activate only cell-surface TLR4; in contrast, lipopolysaccharide (LPS) activates both TLR4 and intracellular inflammatory caspases. In this study, we investigated the adjuvant activity of an anti-TLR4 mAb in T-cell-mediated antitumour immunity. The anti-TLR4 mAb induced the activation of antigen-specific T-cells in adoptive transfer studies. The growth of ovalbumin (OVA)-expressing tumours was significantly suppressed by administration of OVA and the anti-TLR4 mAb in combination, but not individually. The antitumour effect of anti-PD-1 mAb was enhanced in mice administered with OVA plus the anti-TLR4 mAb. The OVA-specific IFN-γ-producing CD8 T-cells were induced by administration of OVA and the anti-TLR4 mAb. The suppression of tumour growth was diminished by depletion of CD8, but not CD4, T-cells. The inflammatory response to the anti-TLR4 mAb was of significantly lesser magnitude than that to LPS, as assessed by NF-κB activation and production of TNF-α, IL-6 and IL-1ß. Administration of LPS (at a dose that elicited levels of proinflammatory cytokines comparable to those by the anti-TLR4 mAb) plus OVA induced no or less-marked activation of OVA-specific T-cells and failed to suppress tumour growth in mice. In conclusion, the agonistic anti-TLR4 mAb induces potent CD8 T-cell-dependent antitumour immunity and an inflammatory response of lesser magnitude than does LPS. The agonistic anti-TLR4 mAb has potential as an adjuvant for use in vaccines against cancer.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Melanoma Experimental/terapia , Neoplasias Cutâneas/terapia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Imunização , Imunoterapia/métodos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/imunologia , Ovalbumina/administração & dosagem , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/patologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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