RESUMO
An excessive inflammatory response in terminal airways, alveoli, and the lung interstitium eventually leads to pulmonary hypertension and chronic obstructive pulmonary disease. Proinflammatory cytokine interleukin-17A (IL-17A) has been implicated in the pathogenesis of pulmonary inflammatory diseases. MLN4924, an inhibitor of NEDD8-activating enzyme (NAE), is associated with the treatment of various types of cancers, but its role in the IL-17A-mediated inflammatory response has not been identified. Here, we report that MLN4924 can markedly reduce the expression of proinflammatory cytokines and chemokines such as IL-1ß, IL-6, and CXCL-1 and neutrophilia in a mouse model of IL-17A adenovirus-induced pulmonary inflammation. MLN4924 significantly inhibited IL-17A-induced stabilization of mRNA of proinflammatory cytokines and chemokines in vitro. Mechanistically, MLN4924 significantly blocked the activation of MAPK and NF-κB pathways and interfered with the interaction between ACT1 and tumor necrosis factor receptor-associated factor proteins (TRAFs), thereby inhibiting TRAF6 ubiquitination. Taken together, our data uncover a previously uncharacterized inhibitory effect of MLN4924 on the IL-17A-mediated inflammatory response; this phenomenon may facilitate the development of MLN4924 into an effective small-molecule drug for the treatment of pulmonary inflammatory diseases.
Assuntos
Ciclopentanos/farmacologia , Inibidores Enzimáticos/farmacologia , Hipertensão Pulmonar/prevenção & controle , Pneumonia/prevenção & controle , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Pirimidinas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Linhagem Celular , Quimiocina CXCL1/biossíntese , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/patologia , Interleucina-17/metabolismo , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fator 6 Associado a Receptor de TNF/metabolismo , Ubiquitinação/efeitos dos fármacosRESUMO
Isoalantolactone (IAL) is a sesquiterpene lactone extracted from roots of Inula helenium L and has shown anti-inflammatory effects. In this study we investigated the therapeutic effects of IAL on acute lung injury (ALI) and elucidated the mechanisms underlying its anti-inflammation potential in vitro and in vivo. Treatment with lipopolysaccharide (LPS, 100 ng/mL) drastically stimulated production of inflammatory mediators such as NO, TNF-α, IL-1ß, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2.5, 5, 10, 20 µM). We further revealed that IAL suppressed LPS-induced NF-κB, ERK, and Akt activation. Moreover, the downregulation of non-degradable K63-linked polyubiquitination of TRAF6, an upstream transcription factor of NF-κB, contributed to the anti-inflammatory effects of IAL. ALI was induced in mice by intratracheal injection of LPS (5 mg/kg). Administration of IAL (20 mg/kg, i.p.) significantly suppressed pulmonary pathological changes, neutrophil infiltration, pulmonary permeability, and pro-inflammatory cytokine expression. Our results demonstrate that IAL is a potential therapeutic reagent against inflammation and ALI.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Fator 6 Associado a Receptor de TNF/metabolismo , Ubiquitinação/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Citocinas/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Lipopolissacarídeos , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
A Rh(III)-catalyzed one-pot reaction of N-phenoxyacetamides, ketones, and hydrazines for a facile access to disubstituted and trisubstituted ethylenes is reported. In this method, various ketones are transformed into donor-donor diazo compounds, which engage in insertion with N-phenoxyacetamides, following ß-H elimination under Rh(III) catalysis to generate (E)-polyaryl-substituted olefins. This chemistry features simple starting materials, mild reaction conditions, and good functional group tolerance.
RESUMO
Alternatively activated macrophages (AAMs) are not only associated with asthma but also lead to asthmatic airway inflammation and remodeling. Inhibition of AAMs is an alternative therapeutic strategy for treating asthma. In this study we investigated whether emodin (1,3,8-trihydroxy-6-methylanthraquinone), isolated from the rhizome of Rheum palmatum, alleviated asthmatic airway inflammation and reduced AAM polarization in a murine asthma model. Mice were sensitized with a triple allergen mix containing dust mite, ragweed and aspergillus (DRA). In mice with DRA-induced asthma, asthmatic inflammation was significantly enhanced. Intraperitoneal injection of emodin (20 mg·kg-1·d-1, ip) 1 h prior to DRA challenge on days 12-14 significantly decreased pulmonary eosinophil and lymphocyte infiltration, mucus secretion and serum IgE production, as well as IL-4 and IL-5 production in bronchoalveolar lavage fluid. In response to emodin treatment, activated markers of AAM Ym-1, Fizz-1 and arginase-1 in the lung tissues were remarkably decreased. In mouse bone marrow-derived macrophages (BMDMs) in vitro, emodin (2-50 µmol/L) dose-dependently inhibited IL-4-induced AAM polarization and STAT6 phosphorylation. Collectively, our results suggest that emodin effectively ameliorates asthmatic airway inflammation and AAM polarization, and it may therefore become a potential agent for the treatment of asthma.
Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Emodina/uso terapêutico , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Animais , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Imunoglobulina E/metabolismo , Inflamação/patologia , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Eosinofilia Pulmonar/tratamento farmacológico , Eosinofilia Pulmonar/patologiaRESUMO
Isoalantolactone (IAL), a sesquiterpene lactone, has antiinflammatory activity in lipopolysaccharide (LPS)induced sepsis. However, it remains to be elucidated whether IAL influences asthmatic inflammation. The present study found that IAL inhibited ovalbumin (OVA)induced asthmatic inflammation and attenuated OVAinduced eosinophil infiltration, immunoglobulin E generation and the production of interleukin (IL)4, IL5, CC motif chemokine ligand (CCL)17 and CCL22. In addition, IAL treatment with IL4 reduced the expression of arginase1, Ym1, CCL17 and CCL22 in bone marrowderived macrophages in vitro. Furthermore, IAL inhibited IL4induced STAT6 phosphorylation and the expression of peroxisome proliferatoractivated receptor γ and Krüppellike factor 4. Collectively, the results suggested that IAL attenuated asthmatic inflammation and is a potential therapeutic agent for the treatment of asthma.
Assuntos
Asma/metabolismo , Inflamação/tratamento farmacológico , Fator 4 Semelhante a Kruppel/metabolismo , Macrófagos/metabolismo , Ovalbumina/efeitos adversos , PPAR gama/metabolismo , Fator de Transcrição STAT6/metabolismo , Sesquiterpenos/farmacologia , Animais , Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Quimiocina CCL17/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Imunoglobulina E/metabolismo , Inflamação/metabolismo , Interleucina-4/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Sesquiterpenos/uso terapêuticoRESUMO
Sepsis caused by Gram-negative bacteria is one of major causes for the progression of acute lung injury (ALI) with limited treatment and effective medicines. Tabersonine is an indole alkaloid mainly isolated from Catharanthus roseus, and a potential drug candidate for treatment of cancer and Alzheimer's disease (AD), however, its anti-inflammatory effect has not been revealed. In this study, we reported that tabersonine ameliorated lipopolysaccharides (LPS)-induced ALI in vivo and inhibited LPS-mediated macrophage activation in vitro. By using murine ALI model, we found that tabersonine significantly attenuated LPS-induced pathological injury in the lung. Tabersonine also inhibited LPS-mediated neutrophil infiltration, elevation of MPO activity and the production of TNF-α, IL-6 and IL-1ß. Furthermore, tabersonine inhibited LPS-induced the production of pro-inflammatory mediators such as iNOS, NO and cytokines by suppressing NF-κB and p38 MAPK/MK2 signaling cascades. Tabersonine reduced the K63-linked polyubiquitination of TRAF6. Taken together, these results suggested that tabersonine has anti-inflammatory activities in vitro and in vivo, and is a potential therapeutic candidate for the treatment of ALI/ARDS.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/uso terapêutico , Alcaloides Indólicos/uso terapêutico , Lipopolissacarídeos/toxicidade , Quinolinas/uso terapêutico , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Ubiquitinação/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Relação Dose-Resposta a Droga , Alcaloides Indólicos/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinolinas/farmacologia , Distribuição Aleatória , Fator 6 Associado a Receptor de TNF/metabolismo , Ubiquitinação/fisiologiaRESUMO
Asthma is one of the most common pulmonary diseases that threatens human life because of lack of effective medicines. Protostemonine (PSN), an active alkaloid extracted from the roots of Stemona sesslifolia, has anti-inflammatory effects on acute lung injury and acute liver failure. However, it has not been defined whether PSN alleviates asthmatic inflammation. Here, we reported that PSN inhibits pulmonary eosinophil infiltration, goblet cell hyperplasia, mucus secretion, IgE and Th2 cytokine (IL-4, IL-5, IL-13 and IL-33) production by using DRA (dust mites, ragweed and aspergillus)-induced murine asthma model. Moreover, PSN also attenuated the expression of Arginase-1 (Arg-1), Ym-1 and Fizz-1, markers of AAM (alternatively activated macrophage) polarization, in lung tissues. In addition, PSN attenuated IL-4-induced expression of Arg-1, Ym-1 and Fizz-1 in bone marrow derived macrophages (BMDMs). Treatment with PSN decreased IL-4-induced STAT6 phosphorylation, KLF4 and IRF4 expression in BMDMs. Collectively, our results indicated that PSN ameliorates AAM polarization and asthmatic inflammation and might be a potential agent for treating asthma.
Assuntos
Ambrosia/efeitos adversos , Aspergillus fumigatus , Asma/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Pyroglyphidae , Animais , Asma/induzido quimicamente , Asma/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fator 4 Semelhante a Kruppel , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Distribuição Aleatória , StemonaceaeRESUMO
The title compound, [Co(C11H8O5)(C8H7N3)] n , which is based on (E)-3-[3-(carb-oxy-meth-oxy)phen-yl]acrylic acid (H2L) and 3-(pyridin-4-yl)pyrazole (pp) ligands, has been synthesized under solvothermal conditions. The dihedral angle between pyrazole and pyridine rings in the pp ligands is 23.1â (2)°. In the crystal, helical chains formed by pp and L ligands connected to the CoII atom propagate parallel to the c axis. CoII atoms of adjacent chains are bridged by the acrylic acid groups of L ligands into corrugated polymeric sheets in the ac plane.