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1.
Food Chem Toxicol ; 135: 110924, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31672514

RESUMO

BACKGROUND: Allergic conjunctivitis (AC) resulting from conjunctival reactive inflammation is a common ocular surface disease. Quercetin is known for its anti-allergic properties but its effects on conjunctivitis are less well understood. PURPOSE: In this study, we evaluated the anti-allergic effects of quercetin in animal models of conjunctivitis, and explored its molecular mechanism(s) of action in cultured human mast cells (MCs). KEY RESULTS: Quercetin inhibited the ovalbumin (OVA) induced expression of IgE, HA, IL-4, TNF-α and substance-P in the peripheral blood of AC mouse models. Quercetin also attenuated OVA induced MC degranulation, eosinophil number, substance P concentrations, and mRNA IL-4/TNF-α expression in the conjunctival tissue of AC models. In vitro analysis showed that quercetin reduced DNP-HSA/IgE induced calcium (Ca2+) influx, and suppressed degranulation and chemokine release in LAD2 cells (human primary mast cell). Quercetin also inhibited DNP-HSA/IgE induced Lyn/PLCγ/IP3R-Ca2+ activation, Lyn/ERK1/2 signaling, and Lyn/NF-κB activation in LAD2 cells, all of which promote inflammation. When added alone, quercetin had no effect on PLCγ1 phosphorylation or expression, but potently inhibited Lyn and phosphorylation-Lyn. Quercetin (200 µM) and Lyn inhibitors (Bafetinib, 10 µM) inhibit the activity of Lyn kinase, and quercetin can reduce the activation of Lyn kinase by Lyn agonist (Tolimidone, 10 µM). These data can be preliminarily determined that quercetin can inhibit allergic conjunctivitis as a Lyn kinase inhibitor. CONCLUSIONS AND IMPLICATIONS: This study illustrated the use of quercetin for the treatment of allergic conjunctivitis, which might act through its ability to inhibit Lyn/PLCγ/IP3R-Ca2+, Lyn/ERK1/2, and Lyn/NF-κB signaling. The inhibition of Lyn likely represents a major mechanism by which quercetin dampens the inflammatory response in AC disease models.


Assuntos
Antialérgicos/uso terapêutico , Conjuntivite Alérgica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quercetina/uso terapêutico , Quinases da Família src/antagonistas & inibidores , Animais , Linhagem Celular , Quimiocinas/metabolismo , Conjuntivite Alérgica/induzido quimicamente , Conjuntivite Alérgica/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Humanos , Imunoglobulina E/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos Endogâmicos C57BL , Ovalbumina , Transdução de Sinais/efeitos dos fármacos , Pele/patologia
2.
Braz J Med Biol Res ; 53(1): e8659, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31859912

RESUMO

Eosinophils are abundant in the reproductive tract, contributing to the remodeling and successful implantation of the embryo. However, the mechanisms by which eosinophils migrate into the uterus and their relationship to edema are still not entirely clear, since there are a variety of chemotactic factors that can cause migration of these cells. Therefore, to evaluate the role of CCR3 in eosinophil migration, ovariectomized C57BL/6 mice were treated with CCR3 antagonist SB 328437 and 17ß-estradiol. The hypothesis that the CCR3 receptor plays an important role in eosinophil migration to the mouse uterus was confirmed, because we observed reduction in eosinophil peroxidase activity in these antagonist-treated uteruses. The antagonist also influenced uterine hypertrophy, inhibiting edema formation. Finally, histological analysis of the orcein-stained uteruses showed that the antagonist reduced eosinophil migration together with edema. These data showed that the CCR3 receptor is an important target for studies that seek to clarify the functions of these cells in uterine physiology.


Assuntos
Movimento Celular/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Estradiol/administração & dosagem , Estrogênios/administração & dosagem , Receptores CCR3/antagonistas & inibidores , Útero/citologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia
3.
Int J Cancer ; 146(6): 1730-1740, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31840816

RESUMO

Immune checkpoint blockade (ICB) has shown long-term survival benefits, but only in a small fraction of cancer patients. Recent studies suggest that improved vessel perfusion by ICB positively correlates with its therapeutic outcomes. However, the underlying mechanism of such a process remains unclear. Here, we show that anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) treatment-induced tumor vessel normalization was accompanied by an increased infiltration of eosinophils into breast tumors. Eosinophil accumulation was positively correlated with the responsiveness of a breast tumor to anti-CTLA4 therapy. Depletion of eosinophils subsequently negated vessel normalization, reduced antitumor immunity and attenuated tumor growth inhibition by anti-CTLA4 therapy. Moreover, intratumoral accumulation of eosinophils relied on T lymphocytes and interferon γ production. Together, these results suggest that eosinophils partially mediate the antitumor effects of CTLA4 blockade through vascular remodeling. Our findings uncover an unidentified role of eosinophils in anti-CTLA4 therapy, providing a potential new target to improve ICB therapy and to predict its efficacy.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores , Linhagem Celular Tumoral , Eosinófilos/imunologia , Feminino , Humanos , Imunidade , Imunomodulação/efeitos dos fármacos , Imunofenotipagem , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Depleção Linfocítica , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Exp Parasitol ; 205: 107735, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31381870

RESUMO

Two experiments were performed to determine whether oral administration of copper oxide capsules controlled helminthic infections in Lacaune sheep without acute collateral effects on animal health. In experiment 1, 48 multiparous lactating sheep (60.1 ±â€¯8.5 kg) were stratified according to initial number of eggs (Haemonchus contortus) per gram of feces (EPG) and were assigned randomly to 1 of two treatments (24 sheep/treatment): no oral administration (control) or oral administration of two copper capsules (treated; approximately 58 mg copper/kg body weight). Blood and fecal samples were collected on days 0, 15 and 45. Animals treated with copper capsules showed lower of EPG, eosinophils, acetylcholinesterase (AChE) in whole blood, and lower butyrylcholinesterase (BChE) activity in serum. Treated sheep had higher erythrocyte numbers, hemoglobin concentrations, hematocrit, and lymphocyte numbers. In experiment 2, 12 male lambs negative for helminths and coccidia were assigned randomly to one of two treatments (six lambs/treatment): control or treated (one copper capsule; approximately 58 mg copper/kg body weight); the experiment was designed to determine whether the results of experiment 1 were due to treatment or parasitism. Blood samples were collected on days 0, 5, 10 and 15 and fecal samples were collected on days 0, 7 and 15. Treated animals showed greater concentrations of lymphocytes; however, treatment had no effect on other hemogram variables, AChE and BChE activities, or levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, creatinine, urea, albumin, total protein, and reactive oxygen species. These data suggest that copper capsules in dairy sheep efficiently controlled H. contortus infections. Treatment was not harmful to lambs during the first 15 days, i.e. there were no signs of acute toxicity.


Assuntos
Cobre/administração & dosagem , Hemoncose/veterinária , Helmintíase Animal/tratamento farmacológico , Lactação , Doenças dos Ovinos/tratamento farmacológico , Acetilcolinesterase/sangue , Administração Oral , Animais , Butirilcolinesterase/sangue , Cápsulas , Cobre/uso terapêutico , Indústria de Laticínios , Resíduos de Drogas , Eosinófilos/efeitos dos fármacos , Contagem de Eritrócitos/veterinária , Fezes/parasitologia , Feminino , Hemoncose/tratamento farmacológico , Hemoncose/prevenção & controle , Helmintíase Animal/sangue , Helmintíase Animal/prevenção & controle , Hematócrito/veterinária , Hemoglobinas/análise , Contagem de Linfócitos/veterinária , Masculino , Leite/química , Contagem de Ovos de Parasitas/veterinária , Paridade , Distribuição Aleatória , Ovinos , Doenças dos Ovinos/sangue , Doenças dos Ovinos/parasitologia , Doenças dos Ovinos/prevenção & controle
5.
Mol Immunol ; 114: 362-368, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31450181

RESUMO

Madi-Ryuk (MDR) is a traditional Korean medicine and it has been widely used in Korea to treat arthritis and we previously reported the anti-allergic inflammatory effect of MDR in vitro model. However, therapeutic evidence of MDR on in vivo model of allergic inflammatory reaction has not yet been demonstrated. The research purpose was to investigate the efficacy of MDR and its active ingredient tannic acid (TA) in ovalbumin (OVA)-induced AR mice model. OVA-challenged AR mice orally medicated MDR or its active ingredient TA daily for ten days. In mice having a AR, MDR and TA prominently diminished number of rubs and levels of histamine, IgE, thymic stromal lymphopoietin, interleukin (IL)-1ß, IL-4, IL-5, IL-13, IL-33, and tumor necrosis factor-α. In addition, protein expression levels and activities of caspase-1 were declined by oral medication of MDR and TA. Decline in levels of macrophage inflammatory protein-2 and intercellular adhesion molecules-1 and reduction in penetrations of inflammatory cells into inflamed tissue were also noted in MDR and TA groups. Taken together, identification of MDR effect in preclinical models suggests that MDR may be a therapeutic drug for the treatment and prevention of AR.


Assuntos
Anti-Inflamatórios/farmacologia , Rinite Alérgica/tratamento farmacológico , Taninos/farmacologia , Animais , Caspase 1/metabolismo , Quimiocina CXCL2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Histamina/metabolismo , Imunoglobulina E/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Medicina Tradicional Coreana/métodos , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Ovalbumina/farmacologia , Rinite Alérgica/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Drugs ; 79(13): 1419-1434, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31352605

RESUMO

Eosinophilic esophagitis (EoE), a chronic allergic disorder of the esophagus, is characterized by symptoms of esophageal dysfunction and eosinophil-predominant inflammation. The incidence of EoE has increased substantially over the past two decades, coinciding with the so-called allergy epidemic. Current treatment options consist of dietary intervention, endoscopic dilatation, and pharmacotherapy. Given that EoE is a chronic progressive disease that is prone to relapse after cessation of therapy, these treatment options are suboptimal for long-term management. Persistent, uncontrolled esophageal inflammation is associated with esophageal remodeling and stricture formation, thus, the creation and/or discovery of alternative treatments is of paramount importance. The pathogenesis of EoE is currently under intense investigation, and recent insights concerning cellular and molecular etiology have led to the development of therapies that target specific pathophysiological pathways. This article provides an overview of established EoE pharmacotherapies, which include proton pump inhibitors and swallowed topical steroids. Additionally, anti-allergic targets, immunosuppressives, and monoclonal antibodies (such as mepolizumab, reslizumab, QAX576, RPC4046, dupilumab, omalizumab, and infliximab) that have been evaluated as treatments for EoE are summarized. Finally, several promising therapeutic agents (e.g., sialic acid-binding immunoglobulin-like lectin 8 antibodies, the transforming growth factor-ß1 signal blocker losartan, CC chemokine receptor type 3 antagonists, thymic stromal lymphopoietin antibodies, antibodies targeting the α4ß7 integrin, anti-interleukin-9 antibodies, and anti-interleukin-15 antibodies) that target specific molecules or cells implicated in the pathogenesis of EoE are proposed.


Assuntos
Esofagite Eosinofílica/tratamento farmacológico , Eosinófilos/efeitos dos fármacos , Animais , Antialérgicos/uso terapêutico , Humanos , Hipersensibilidade/tratamento farmacológico
7.
Nat Commun ; 10(1): 3371, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358760

RESUMO

TNF-like ligand 1 A (TL1A) and death receptor 3 (DR3) are a ligand-receptor pair involved in the pathogenesis of inflammatory bowel disease. Group 3 innate lymphoid cells (ILC3s) regulate intestinal immunity and highly express DR3. Here, we report that activation of DR3 signaling by an agonistic anti-DR3 antibody increases GM-CSF production from ILC3s through the p38 MAPK pathway. GM-CSF causes accumulation of eosinophils, neutrophils and CD11b+CD11c+ myeloid cells, resulting in loss of ILC3s from the intestine in an IL-23-dependent manner and exacerbating colitis. Blockade of GM-CSF or IL-23 reverses anti-DR3 antibody-driven ILC3 loss, whereas overexpression of IL-23 induces loss of ILC3s in the absence of GM-CSF. Neutralization of TL1A by soluble DR3 ameliorates both DSS and anti-CD40 antibody-induced colitis. Moreover, ILC3s are required for the deleterious effect of anti-DR3 antibodies on innate colitis. These findings clarify the process and consequences of DR3 signaling-induced intestinal inflammation through regulation of ILC3s.


Assuntos
Colite/imunologia , Doenças Inflamatórias Intestinais/imunologia , Linfócitos/imunologia , Membro 25 de Receptores de Fatores de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Células Cultivadas , Colite/genética , Colite/metabolismo , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-23/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética
8.
Cells ; 8(6)2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226782

RESUMO

Licochalcone A was isolated from Glycyrrhiza uralensis and previously reported to have antitumor and anti-inflammatory effects. Licochalcone A has also been found to inhibit the levels of Th2-associated cytokines in the bronchoalveolar lavage fluid (BALF) of asthmatic mice. However, the molecular mechanism underlying airway inflammation and how licochalcone A regulates oxidative stress in asthmatic mice are elusive. In this study, we investigated whether licochalcone A could attenuate inflammatory and oxidative responses in tracheal epithelial cells, and whether it could ameliorate oxidative stress and airway inflammation in asthmatic mice. Inflammatory human tracheal epithelial (BEAS-2B) cells were treated with licochalcone A to evaluate oxidative responses and inflammatory cytokine levels. In addition, BALB/c mice were sensitized with ovalbumin (OVA) and injected intraperitoneally with licochalcone A (5 or 10 mg/kg). Licochalcone A significantly inhibited reactive oxygen species, eotaxin, and proinflammatory cytokines in BEAS-2B cells. Licochalcone A also decreased intercellular adhesion molecule 1 levels in inflammatory BEAS-2B cells, blocking monocyte cell adherence. We also found that licochalcone A significantly decreased oxidative responses, reduced malondialdehyde levels, and increased glutathione levels in the lungs of OVA-sensitized mice. Furthermore, licochalcone A decreased airway hyper-responsiveness, eosinophil infiltration, and Th2 cytokine production in the BALF. These findings suggest that licochalcone A alleviates oxidative stress, inflammation, and pathological changes by inhibiting Th2-associated cytokines in asthmatic mice and human tracheal epithelial cells. Thus, licochalcone A demonstrated therapeutic potential for improving asthma.


Assuntos
Asma/complicações , Asma/tratamento farmacológico , Chalconas/uso terapêutico , Estresse Oxidativo , Substâncias Protetoras/uso terapêutico , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/tratamento farmacológico , Animais , Especificidade de Anticorpos , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Adesão Celular/efeitos dos fármacos , Chalconas/farmacologia , Quimiocinas/metabolismo , Colágeno/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dano ao DNA , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Feminino , Glutationa/metabolismo , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Humanos , Hiperplasia , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Ovalbumina , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células THP-1
9.
Int Immunopharmacol ; 73: 581-589, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31234092

RESUMO

Inhaled terbutaline is commercially available ß2-agonist which consists of equivalent amount of R- and S-enantiomer. In this study, we aimed to investigate the effects of single enantiomers of terbutaline and its racemate in an ovalbumin (OVA)-induced mouse model of asthma via. seven days inhalation and the potential mechanisms involved. In a standard experimental asthma model, BALB/c mice were sensitized and challenged with OVA. R-terbutaline (R-ter), S-terbutaline (S-ter) or racemic terbutaline (rac-ter) was given via. nose-only inhalation for one week. Airway responsiveness to methacholine was measured by the plethysmography in conscious mice. Eosinophils counts in blood and bronchoalveolar (BAL) fluid were determined. The OVA-sIgE in plasma and inflammatory cytokines and mediators in BAL fluid or lung tissue were analyzed by ELISA, qRT-PCR or western blotting. Airway inflammation and remodeling were evaluated with hematoxylin and eosin (HE), periodic acid-Schiff (PAS), and Masson staining. Drug distribution and deposition after inhalation were determined by LC-MS/MS. Our data showed that R-ter efficiently ameliorated asthma responses, including airway hyperresponsiveness, eosinophils influx and IL-5 in BALF, plasma OVA-sIgE and significantly reduced pulmonary inflammation, peribronchial smooth muscle layer thickness, goblet cell hyperplasia, and deposition of collagen fibers, as well as downregulation of p38 MAPK phosphorylation and NF-κB expression. Racemic mixture exhibited diminished effects while S-ter enhanced airway responsiveness to methacholine and exerted pro-asthmatic effects.


Assuntos
Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Terbutalina/uso terapêutico , Administração por Inalação , Animais , Asma/imunologia , Asma/patologia , Asma/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Citocinas/imunologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Imunoglobulina E/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Ovalbumina , Estereoisomerismo , Terbutalina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
10.
Int J Chron Obstruct Pulmon Dis ; 14: 1045-1051, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190789

RESUMO

Many patients with chronic obstructive pulmonary disease (COPD) continue to experience exacerbations despite receiving standard-of-care treatments. Novel approaches to COPD treatment focus on understanding and targeting molecular mechanisms of airway inflammation, airway obstruction, remodeling and lung destruction. Several identified phenotypes and endotypes of COPD will pave the future path for a more personalized approach to therapy. Although well known to be associated with neutrophilic inflammation, COPD may also be driven by eosinophilic inflammation both at stable states and during exacerbation. Targeting eosinophilic inflammation has been successful in managing severe eosinophilic asthma and may hold promise in certain phenotypes of COPD. The most promising biologic treatments at an advanced stage of development are agents blocking interleukin (IL)-5 or its receptor. This review examines our current understanding of the eosinophilic inflammation in COPD and the rationale for IL-5 targeting agents.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Eosinófilos/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-5/antagonistas & inibidores , Interleucina-5/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Eosinófilos/metabolismo , Interleucina-5/metabolismo , Subunidade alfa de Receptor de Interleucina-5/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Terapia de Alvo Molecular , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
11.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(6): 426-431, 2019 Jun 12.
Artigo em Chinês | MEDLINE | ID: mdl-31189228

RESUMO

Objective: To compare the clinical characteristics of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) by different levels of blood eosinophil (EOS) count and to investigate the predictive value of the response to glucocorticoid treatment and the readmission rate in the patients with higher blood eosinophils. Methods: A total of 120 patients with AECOPD were admitted to the Department of Pulmonary and Critical Care Medicine in The Second Xiangya Hospital of Central South University from January 01, 2017 to December 31, 2017. Patients were divided into two groups according to their admission blood eosinophil fractions. Patients with EOS%≥2% were in the EOS group (n=56) , while patients with EOS%<2% were in the Non-EOS group (n=64) . The clinical characteristics, hospitalization treatments especially the glucocorticoid treatment response were compared, and the risk of severe acute exacerbation of the two groups including the 12-month COPD-related readmission, and time to first COPD-related readmission were also compared. Results: Compared with the Non-EOS group, the EOS group had lower values of white blood cell (WBC) , neutrophil fraction (N%) , blood neutrophil-to-lymphocyte ratio (NLR) , and C-reactive protein (CRP) . The EOS group also required shorter course of antibiotic treatment [8 (6-10) and 9 (7-11) , P=0.033]. In glucocorticoid-treated patients (n=82) , the EOS group had significantly alleviated symptoms than the Non-EOS group (patients withδCAT≥2 were 86.8% and 68.2%, respectively, P=0.046) , and the duration of hospitalization of the EOS group was shorter [9 (7-11) and 10 (9 to 13) , P=0.042]. Patients with glucocorticoid treatment in the EOS group had significantly alleviated symptoms than those without glucocorticoid treatment (patients with δCAT ≥ 2 were 86.8% and 61.1%, respectively, P=0.040) . The follow-up one year after discharge showed a higher risk of severe acute exacerbation in the EOS group [Adjust OR 2.67 (1.10-6.46), P=0.030; HR: 1.57 (1.02-2.40), P=0.040]. Conclusion: The blood eosinophil levels were useful in predicting the AECOPD patients' response to glucocorticoid treatment and the risk of severe acute exacerbations.


Assuntos
Eosinofilia/complicações , Eosinófilos/metabolismo , Glucocorticoides/uso terapêutico , Readmissão do Paciente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Biomarcadores/sangue , Progressão da Doença , Eosinofilia/tratamento farmacológico , Eosinófilos/efeitos dos fármacos , Humanos , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Estudos Retrospectivos , Resultado do Tratamento
12.
Respir Res ; 20(1): 83, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053134

RESUMO

BACKGROUND: An inverse relationship between oral corticosteroid (OCS) dose and peripheral blood eosinophil (PBE) count is widely recognized in patients with severe eosinophilic asthma; however, there are limited data available to quantify this relationship. This post hoc analysis of the SIRIUS study (NCT01691508) examined the impact of weekly incremental OCS dose reductions on PBE counts during the 3-8-week optimization phase of the study. METHODS: SIRIUS was a randomized, double-blind study involving patients with severe asthma (≥12 years old), which included an initial OCS dose optimization phase prior to randomization. Regression analysis assuming a linear relationship between change in OCS dose and change in log (PBE count) during the optimization phase was used to estimate the changes in PBE count following specific decreases in OCS dose. RESULTS: All 135 patients from the SIRIUS intent-to-treat population were included in this analysis. During the optimization period, 44% (60/135) of patients reduced their OCS dose, with an increase in geometric mean PBE count of 110 cells/µL (200 to 310 cells/µL; geometric mean ratio from beginning to end of the optimization phase: 1.52) recorded in these patients. The model estimated that reduction of daily OCS dose by 5 mg/day led to a 41% increase in PBE count (mean ratio to beginning of optimization phase: 1.41 [95% confidence interval (CI); 1.22, 1.63]). CONCLUSION: These data confirmed and quantified the inverse association between OCS dose and PBE count. These insights will help to inform clinicians when tapering OCS doses in patients with severe eosinophilic asthma.


Assuntos
Corticosteroides/administração & dosagem , Asma/sangue , Asma/tratamento farmacológico , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Índice de Gravidade de Doença , Administração Oral , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino
13.
Phytomedicine ; 62: 152942, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31102886

RESUMO

BACKGROUND: The roots of Korean red ginseng (Panax ginseng C.A.Mey.; KGC) have been used as an herbal supplement to enhance vital energy and immune capacity. Salvia plebeia R.Br. has been used to treat inflammatory diseases. PURPOSE: The aim of this study was to examine the anti-asthmatic effects of a mixture of Korean red ginseng and Salvia plebeia R.Br. (KGC3P), its component nepetin, and their modes of action in alleviating ovalbumin (OVA)-induced asthma in mice. METHOD: BALB/c mice were sensitized with OVA then subjected to intratracheal, intraperitoneal, and aerosol challenges. KGC3P and nepetin were administered orally for four weeks. Airway hyperresponsiveness (AHR), OVA-specific IgE levels, and Th2 cytokine- and gene expression levels in bronchoalveolar lavage fluid (BALF) and splenocytes were measured. Histological and immune cell subtype analyses were performed. PTEN and Akt phosphorylation levels were also evaluated. RESULTS: KGC3P reduced OVA-induced AHR, serum IgE levels, histological changes, and eosinophils infiltration but also the absolute number of immune cell subtypes including CD3+/CD4+, CD3+/CD8+, CD4+/CD69+, and Gr-1+/CD11b+ in the lungs, BALF, and mesenteric lymph nodes (MLN). KGC3P also lowered the Th2 cytokines IL-4, IL-5, and IL-13 in the BALF and splenocytes and downregulated the IL-4, IL-13, IL-17, TNF-α, and MUC5AC genes in the lung. KGC3P upregulated the peroxisome proliferator-activated receptor (PPAR)γ gene but downregulated the p-Akt and p-PTEN phosphorylation. Similar results were obtained with nepetin treatment. CONCLUSION: KGC3P and nepetin are anti-asthmatic because they reduce various immune cells such as eosinophils and Th2 cell as well as Th2 cytokines. These mechanisms may be accompanied by the regulation of PPARγ expression and the PTEN pathway. Taken together, our results indicate that KGC3P and nepetin may potentially prevent and treat asthma.


Assuntos
Antiasmáticos/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Panax/química , Salvia/química , Animais , Antiasmáticos/química , Asma/tratamento farmacológico , Asma/metabolismo , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Quimioterapia Combinada , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Eosinófilos/patologia , Flavonas/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Ovalbumina/efeitos adversos , Células Th2/efeitos dos fármacos , Células Th2/patologia
14.
Eur J Pharmacol ; 856: 172400, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31103630

RESUMO

Eosinophils and their granular proteins are crucial for combating allergic airway diseases. Eosinophils derived from HL-60 clone 15 (HC15) cells have been established as a feasible alternative cell model for human primary eosinophils. Simvastatin, a cholesterol-lowering agent, has been shown to exhibit anti-inflammatory and anti-allergic effects. Among the granular eosinophil proteins, eosinophil cationic protein (ECP) is the one best recognised in allergic airway diseases. The aim of our study is to investigate the effect and regulatory mechanisms of simvastatin on ECP levels derived from eosinophils. Both HC15 cell counts and ECP levels decreased after simvastatin treatment in the animal and cell models; however, after a cell count adjustment, simvastatin was not observed to exert a significantly inhibitory effect on ECP expression. Real-time polymerase chain reaction and Western blotting analyses demonstrated that simvastatin did not inhibit the intracellular formation or release of ECP. Cell cycle analysis showed that the percentage of HC15 cells in the G1 and S phases significantly increased and decreased, respectively, after simvastatin treatment. Simvastatin inhibited the proliferation of HC15-derived eosinophils by inducing G1/S cell cycle arrest in a dose-dependent manner. Its effect on the cell cycle involved the downregulation of cyclin A but without the presence of mevalonate; therefore, total ECP expression from eosinophils decreased, not by suppressing the actual formation or release of ECP but by arresting the G1/S cell cycle phase and inhibiting subsequent cell proliferation through the mevalonate pathway.


Assuntos
Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Sinvastatina/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Clonais/citologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Masculino , Ácido Mevalônico/farmacologia , Ratos , Ratos Sprague-Dawley , Sinvastatina/antagonistas & inibidores
15.
Int Immunopharmacol ; 72: 82-91, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30965222

RESUMO

We describe the potent effect of myriadenolide (Myr), a naturally occurring labdane diterpene, in promoting the production of eosinophils in cultured bone-marrow from several inbred mouse strains. This enhancing effect is lineage-selective and requires the eosinophil growth factors, Interleukin(IL)-5 or GM-CSF. Myr acts over a very low concentration range (10-10-10-14 M), if added at the beginning of the cell cultivation. Its enhancing effect increases between 24 h and 10 days of culture. We used both pharmacological and genetical tools to analyze its mechanism of action. Several lines of evidence show that the enhancing effect of Myr requires functional integrity of the 5-lipoxygenase (5-LO) pathway, and of CysLT1 receptors, which transduce the effects of cysteinyl-leukotrienes generated through this pathway. Myr also protects developing eosinophils from apoptosis induced by exogenous prostaglandin E2 (PGE2), but not by NO, indicating that it acts upstream of NO in the PGE2-initiated proapoptotic pathway which requires iNOS and CD95. Exposure to NO concentrations insufficient to induce apoptosis abolished the ability of eosinophils to respond to Myr, suggesting the involvement of a NO-sensitive cellular target. Myr has potential as a chemically defined research tool, which can be used to generate large numbers of eosinophils, thereby overcoming current limitations in the biochemical and molecular biological study of murine eosinophils, which has so far depended on complex, labor-intensive and long-term culture protocols for in vitro expansion. SUMMARY: Potent enhancing effects of Myr on eosinophil production in bone marrow stimulated by GM-CSF and IL-5 are mediated by the 5-LO pathway.


Assuntos
Cisteína/metabolismo , Diterpenos/farmacologia , Eosinófilos/efeitos dos fármacos , Leucotrienos/metabolismo , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Medula Óssea/efeitos dos fármacos , Células Cultivadas , Dinoprostona/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Interleucina-5/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Doadores de Óxido Nítrico/farmacologia , Receptores de Leucotrienos/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Int J Mol Med ; 43(4): 1830-1838, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816433

RESUMO

Physalis peruviana L. (PP) is well known for its various properties, including its antioxidant property. In our previous study, the protective effects of PP against cigarette smoke­induced airway inflammation were confirmed. The purpose of the present study was to evaluate the anti­inflammatory effect of PP against ovalbumin (OVA)­induced airway inflammation. Treatment with PP inhibited the numbers of eosinophils and the levels of inflammatory cytokines, including interleukin (IL)­4, IL­5 and IL­13, in the bronchoalveolar lavage fluid (BALF) of animal models with OVA­induced allergic asthma. PP also significantly decreased the production of total immunoglobulin E in the serum. Lung sections stained with hematoxylin and eosin revealed that the influx of inflammatory cells was decreased in the lungs of mice treated with PP compared with cells in the OVA group. The increased expression levels of monocyte chemoattractant protein­1 (MCP­1) and T cell marker KEN­5 were also reduced following PP treatment in the lung tissues compared with those in the OVA group. The PAS staining results showed that PP attenuated the overproduction of mucus in the lung. Additionally, western blot analysis revealed that PP significantly downregulated the activation of nuclear factor­κB/p38 mitogen­activated protein kinase/c­Jun N­terminal kinase, and upregulated the expression of heme oxgenase­1 in the lungs. In an in vitro experiment, PP effectively reduced the levels of LPS­stimulated MCP­1 in a concentration­dependent manner. Taken together, these results indicate that PP has considerable potential in the treatment of allergic asthma.


Assuntos
Inflamação/tratamento farmacológico , Pulmão/patologia , NF-kappa B/metabolismo , Physalis/química , Extratos Vegetais/uso terapêutico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Feminino , Heme Oxigenase (Desciclizante)/metabolismo , Imunoglobulina E/sangue , Inflamação/sangue , Inflamação/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Muco/metabolismo , Ovalbumina , Extratos Vegetais/farmacologia , Células RAW 264.7 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Chem Biol Interact ; 305: 48-53, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30922765

RESUMO

The formation of isonicotinyl-nicotinamide adenine dinucleotide (INH-NAD+) by the mycobacterial catalase-peroxidase enzyme, KatG, was known to be the major component of the mode of action of isoniazid (INH), an anti-tuberculosis drug. However, there are other enzymes that may catalyze this reaction. We have previously reported that neutrophil myeloperoxidase (MPO) is capable of metabolizing INH through the formation of INH-NAD+ adduct, which could be attributed to being a possible mode of action of INH. However, eosinophilic infiltration of the lungs is more pronounced and characteristic of granulomas in Mycobacterium tuberculosis-infected patients. Thus, the aim of the present study is to investigate the role of eosinophil peroxidase (EPO), a key eosinophil enzyme, during INH metabolism and the formation of its active metabolite, INH-NAD+ using purified EPO and eosinophils isolated from asthmatic donors. UV-Vis spectroscopy revealed INH oxidation by EPO led to a new product (λmax = 326 nm) in the presence of NAD+. This adduct was confirmed to be INH-NAD+ using LC-MS analysis where the intact adduct was detected (m/z = 769). Furthermore, EPO catalyzed the oxidation of INH and formed several free radical intermediates as assessed by electron paramagnetic resonance (EPR) spin-trapping; a carbon-centred radical, which is considered to be the reactive metabolite that binds with NAD+, was found when superoxide dismutase was included in the reaction. Our findings suggest that eosinophilic EPO may also play a role in the pharmacological activity of INH through the formation of INH-NAD+ adduct, and supports further evidence that human cells and enzymes are capable of producing the active metabolite involved in tuberculosis treatment.


Assuntos
Peroxidase de Eosinófilo/metabolismo , Eosinófilos/enzimologia , Isoniazida/análogos & derivados , Isoniazida/metabolismo , NAD/análogos & derivados , NAD/metabolismo , Asma/metabolismo , Asma/patologia , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância de Spin Eletrônica , Eosinófilos/química , Eosinófilos/efeitos dos fármacos , Humanos , Isoniazida/sangue , Isoniazida/química , Isoniazida/farmacologia , Espectrometria de Massas , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , NAD/sangue , NAD/química , Oxirredução , Fator de Ativação de Plaquetas/farmacologia , Superóxido Dismutase/metabolismo
19.
Inflamm Res ; 68(5): 387-395, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30874868

RESUMO

OBJECTIVE: AST2017-01 is developed to be used for treatment and prevention of allergic diseases and composed of processed-Cordyceps militaris and processed-Rumex crispus. But, effect of AST2017-01 remains unclear in an allergic rhinitis (AR). So, this study aimed to explore the effects of AST2017-01 in ovalbumin (OVA)-induced AR animal model. METHODS: OVA-induced AR animals were orally administered AST2017-01 and chrysophanol, an active component of AST2017-01 for 10 days. RESULTS: In mice with AR, AST2017-01 and chrysophanol markedly decreased number of rubs, IgE, histamine, thymic stromal lymphopoietin, tumor necrosis factor-α, interleukin (IL)-1ß, IL-4, IL-5, and IL-13 in serum or nasal mucosa tissues. Moreover, activities and protein levels of caspase-1 were markedly diminished by oral administration of AST2017-01 and chrysophanol. Declines of macrophage inflammatory protein-2, intercellular adhesion molecules-1, eosinophil, and mast cells were also noted in nasal mucosa tissues of AST2017-01 and chrysophanol groups. CONCLUSIONS: Taken together, these findings indicate that AST2017-01 has an anti-allergic effect as a therapeutic agent or functional food for treating and preventing AR.


Assuntos
Antialérgicos/uso terapêutico , Cordyceps , Rinite Alérgica/tratamento farmacológico , Rumex , Animais , Antraquinonas/farmacologia , Antraquinonas/uso terapêutico , Antialérgicos/farmacologia , Caspase 1/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos Endogâmicos BALB C , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ovalbumina , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêutico , Rinite Alérgica/imunologia
20.
Int Arch Allergy Immunol ; 179(1): 21-30, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30879003

RESUMO

BACKGROUND: Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need. OBJECTIVE: To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H1-antihistamines. METHODS: We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D2 (PGD2)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content. RESULTS: Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD2-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed. CONCLUSIONS: This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD2-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD2/CRTh2 pathway will be an -effective treatment for CSU.


Assuntos
Acetatos/uso terapêutico , Eosinófilos/efeitos dos fármacos , Indóis/uso terapêutico , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Urticária/tratamento farmacológico , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Administração Oral , Adulto , Idoso , Doença Crônica , Eosinófilos/fisiologia , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prostaglandina D2/farmacologia , Receptores Imunológicos/análise , Receptores de Prostaglandina/análise , Urticária/imunologia
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