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1.
Int Immunopharmacol ; 136: 112395, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38833845

RESUMO

Asthma is a long-term disease that causes airways swelling and inflammation and in turn airway narrowing. AdipoRonis an orally active synthetic small molecule that acts as a selective agonist at theadiponectin receptor 1 and 2. The aim of the current study is to delineate the protective effect and the potential underlying mechanism ofadipoRon inairway inflammationinduced byovalbumin (OVA) in comparison withdexamethasone. Adult maleSwiss Albino micewere sensitized to OVA on days 0 and 7, then challenged with OVA on days 14, 15 and 16. AdipoRon was administered orally for 6 days starting from the 11th day till the 16th and 1 h prior to OVA in the challenge days. Obtained results from asthmatic control group showed a significant decrease in serum adiponectin concentration, an increase in inflammatory cell counts inthe bronchoalveolar lavage fluid(BALF), CD68 protein expression, inflammatory cytokine concentration and oxidative stress as well. Administration of adipoRon enhanced antioxidant mechanisms limiting oxidative stress by significantly increasing reduced glutathione (GSH) pulmonary content, decreasing serum lactate dehydrogenase (LDH) together with malondialdehyde (MDA) significant reduction in lung tissue. In addition, it modulated the levels of serum immunoglobulin E (IgE), pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, nuclear factor kappa B (NF-κB) and the anti-inflammatory one IL-10 improving lung inflammation as revealed by histopathological evaluation. Furthermore, lung tissue expression of nuclear factor erythroid 2-related factor (Nrf2) and 5'AMP-activated protein kinase (AMPK) were significantly increased adipoRon. Notably, results of adipoRon received group were comparable to those of dexamethasone group. In conclusion, our study demonstrates that adipoRon can positively modulate adiponectin expression with activation of AMPK pathway and subsequent improvement in inflammatory and oxidative signaling.


Assuntos
Proteínas Quinases Ativadas por AMP , Asma , Modelos Animais de Doenças , Ovalbumina , Receptores de Adiponectina , Transdução de Sinais , Animais , Asma/tratamento farmacológico , Asma/imunologia , Asma/induzido quimicamente , Asma/metabolismo , Camundongos , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/metabolismo , Ovalbumina/imunologia , Masculino , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Citocinas/metabolismo , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adiponectina , Antiasmáticos/uso terapêutico , Antiasmáticos/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Imunoglobulina E/sangue , Humanos , Dexametasona/uso terapêutico , Dexametasona/farmacologia , Piperidinas
2.
Br J Gen Pract ; 74(suppl 1)2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902064

RESUMO

BACKGROUND: Fractional exhaled nitric oxide (FeNO) as a predictor of inhaled corticosteroid (ICS) response in asthma has been established. However, the same has not been established in chronic obstructive pulmonary disease (COPD). An optimal value of FeNO for prescribing and monitoring ICS response has not been quantified. AIM: To examine the evidence for this association. METHOD: A systematic review was conducted of randomised controlled trials and observational studies examining the association between FeNO level and response to ICS in COPD patients. All studies examining this association were included. Five databases were searched thoroughly. Systematic screening, full-text reviews, and data extraction were carried out based on eligibility criteria. RESULTS: A total of 8690 studies were identified, 342 texts were screened fully, and six studies were included for the final review. One was a randomised controlled trial and the other five were non-randomised interventional trials. One study was conducted in asthma-COPD overlap (ACO patients). After ICS use, three studies found statistically significant correlations between FeNO and lung function improvement (FEV1), and three studies also found significant correlations between FeNO and COPD quality-of-life scores. CONCLUSION: Measurement of FeNO is non-invasive and standardised, with results available at the point of testing. Because of the small sample size and short duration of studies, exacerbation frequencies were not measured. Despite this, the review suggests that FeNO may be a potential biomarker for assessing ICS response in COPD. Further research that stratifies patients by FeNO levels and assesses the impact on acute exacerbations is needed to understand its potential value in routine clinical practice.


Assuntos
Corticosteroides , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Administração por Inalação , Corticosteroides/uso terapêutico , Corticosteroides/administração & dosagem , Óxido Nítrico/metabolismo , Teste da Fração de Óxido Nítrico Exalado , Resultado do Tratamento , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Volume Expiratório Forçado , Asma/tratamento farmacológico , Asma/metabolismo , Asma/fisiopatologia , Testes Respiratórios
3.
Int J Mol Sci ; 25(11)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38892470

RESUMO

The nanosized vesicles secreted from various cell types into the surrounding extracellular space are called extracellular vesicles (EVs). Although mesenchymal stem cell-derived EVs are known to have immunomodulatory effects in asthmatic mice, the role of identified pulmonary genes in the suppression of allergic airway inflammation remains to be elucidated. Moreover, the major genes responsible for immune regulation in allergic airway diseases have not been well documented. This study aims to evaluate the immunomodulatory effects of secretoglobin family 1C member 1 (SCGB1C1) on asthmatic mouse models. C57BL/6 mice were sensitized to ovalbumin (OVA) using intraperitoneal injection and were intranasally challenged with OVA. To evaluate the effect of SCGB1C1 on allergic airway inflammation, 5 µg/50 µL of SCGB1C1 was administrated intranasally before an OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), the cytokine profiles of BALF and lung-draining lymph nodes (LLN), and the T cell populations in LLNs. The intranasal administration of SCGB1C1 significantly inhibited AHR, the presence of eosinophils in BALF, eosinophilic inflammation, goblet cell hyperplasia in the lung, and serum total and allergen-specific IgE. SCGB1C1 treatment significantly decreased the expression of interleukin (IL)-5 in the BALF and IL-4 in the LLN, but significantly increased the expression of IL-10 and transforming growth factor (TGF)-ß in the BALF. Furthermore, SCGB1C1 treatment notably increased the populations of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in asthmatic mice. The intranasal administration of SCGB1C1 provides a significant reduction in allergic airway inflammation and improvement of lung function through the induction of Treg expansion. Therefore, SCGB1C1 may be the major regulator responsible for suppressing allergic airway inflammation.


Assuntos
Asma , Camundongos Endogâmicos C57BL , Ovalbumina , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Camundongos , Asma/imunologia , Asma/metabolismo , Pulmão/patologia , Pulmão/imunologia , Pulmão/metabolismo , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Feminino , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Eosinófilos/imunologia , Eosinófilos/metabolismo
4.
Nat Commun ; 15(1): 5226, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38890291

RESUMO

IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo female mouse model of asthma. This shows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses.


Assuntos
Asma , Proteínas de Helminto , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Nematospiroides dubius , Animais , Interleucina-33/metabolismo , Interleucina-33/química , Nematospiroides dubius/imunologia , Proteínas de Helminto/metabolismo , Proteínas de Helminto/química , Proteínas de Helminto/imunologia , Camundongos , Feminino , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Asma/imunologia , Asma/metabolismo , Humanos , Transdução de Sinais , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologia , Infecções por Strongylida/metabolismo , Ligação Proteica , Modelos Animais de Doenças , Sítios de Ligação , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
5.
Mol Med ; 30(1): 93, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38898476

RESUMO

BACKGROUND: The epithelial-mesenchymal transition (EMT) of human bronchial epithelial cells (HBECs) is essential for airway remodeling during asthma. Wnt5a has been implicated in various lung diseases, while its role in the EMT of HBECs during asthma is yet to be determined. This study sought to define whether Wnt5a initiated EMT, leading to airway remodeling through the induction of autophagy in HBECs. METHODS: Microarray analysis was used to investigate the expression change of WNT5A in asthma patients. In parallel, EMT models were induced using 16HBE cells by exposing them to house dust mites (HDM) or interleukin-4 (IL-4), and then the expression of Wnt5a was observed. Using in vitro gain- and loss-of-function approaches via Wnt5a mimic peptide FOXY5 and Wnt5a inhibitor BOX5, the alterations in the expression of the epithelial marker E-cadherin and the mesenchymal marker protein were observed. Mechanistically, the Ca2+/CaMKII signaling pathway and autophagy were evaluated. An autophagy inhibitor 3-MA was used to examine Wnt5a in the regulation of autophagy during EMT. Furthermore, we used a CaMKII inhibitor KN-93 to determine whether Wnt5a induced autophagy overactivation and EMT via the Ca2+/CaMKII signaling pathway. RESULTS: Asthma patients exhibited a significant increase in the gene expression of WNT5A compared to the healthy control. Upon HDM and IL-4 treatments, we observed that Wnt5a gene and protein expression levels were significantly increased in 16HBE cells. Interestingly, Wnt5a mimic peptide FOXY5 significantly inhibited E-cadherin and upregulated α-SMA, Collagen I, and autophagy marker proteins (Beclin1 and LC3-II). Rhodamine-phalloidin staining showed that FOXY5 resulted in a rearrangement of the cytoskeleton and an increase in the quantity of stress fibers in 16HBE cells. Importantly, blocking Wnt5a with BOX5 significantly inhibited autophagy and EMT induced by IL-4 in 16HBE cells. Mechanistically, autophagy inhibitor 3-MA and CaMKII inhibitor KN-93 reduced the EMT of 16HBE cells caused by FOXY5, as well as the increase in stress fibers, cell adhesion, and autophagy. CONCLUSION: This study illustrates a new link in the Wnt5a-Ca2+/CaMKII-autophagy axis to triggering airway remodeling. Our findings may provide novel strategies for the treatment of EMT-related diseases.


Assuntos
Asma , Autofagia , Células Epiteliais , Transição Epitelial-Mesenquimal , Proteína Wnt-5a , Humanos , Proteína Wnt-5a/metabolismo , Proteína Wnt-5a/genética , Asma/metabolismo , Asma/patologia , Asma/genética , Células Epiteliais/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Brônquios/metabolismo , Brônquios/patologia , Masculino , Linhagem Celular , Feminino , Pessoa de Meia-Idade , Transdução de Sinais , Adulto
7.
Int J Mol Sci ; 25(11)2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38891935

RESUMO

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter tissue homeostasis and allow the penetration of allergens and other external agents. Different factors contribute to barrier impairment, such as eosinophilic infiltration and allergen protease action-eosinophilic cationic proteins' effects and allergens' proteolytic activity both contribute significantly to epithelial damage. In the airways, allergen proteases degrade the epithelial junctional proteins, allowing allergen penetration and its uptake by dendritic cells. This increase in allergen-immune system interaction induces the release of alarmins and the activation of type 2 inflammatory pathways, causing or worsening the main symptoms at the skin, bowel, and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic protease-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance, and progression. Moreover, we will explore potential clinical and radiological biomarkers of airway remodeling in allergic asthma patients.


Assuntos
Alérgenos , Asma , Humanos , Asma/metabolismo , Asma/imunologia , Asma/patologia , Alérgenos/imunologia , Animais , Remodelação das Vias Aéreas
8.
Int J Mol Sci ; 25(11)2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38892164

RESUMO

Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. TSLP performs its role by binding to a high-affinity heteromeric complex composed of the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα. In recent years, the important role of proinflammatory cytokines in the etiopathogenesis of various chronic diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic obstructive pulmonary diseases (COPDs), and chronic spontaneous urticaria has been studied. Although alarmins have been found to be mainly implicated in the mechanisms of type 2 inflammation, studies on monoclonal antibodies against TSLP demonstrate partial efficacy even in patients whose inflammation is not definable as T2 and the so-called low T2. Tezepelumab is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. Several clinical trials are evaluating the safety and efficacy of Tezepelumab in various inflammatory disorders. In this review, we will highlight major recent advances in understanding the functional role of TSLP, its involvement in Th2-related diseases, and its suitability as a target for biological therapies.


Assuntos
Anticorpos Monoclonais Humanizados , Citocinas , Linfopoietina do Estroma do Timo , Humanos , Citocinas/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Animais , Receptores de Citocinas/metabolismo , Receptores de Citocinas/antagonistas & inibidores , Terapia de Alvo Molecular , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/metabolismo , Asma/tratamento farmacológico , Asma/metabolismo
9.
Front Immunol ; 15: 1408772, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38863703

RESUMO

Introduction: Macrophage dysfunction is a common feature of inflammatory disorders such as asthma, which is characterized by a strong circadian rhythm. Methods and results: We monitored the protein expression pattern of the molecular circadian clock in human peripheral blood monocytes from healthy, allergic, and asthmatic donors during a whole day. Monocytes cultured of these donors allowed us to examine circadian protein expression in human monocyte-derived macrophages, M1- and M2- polarized macrophages. In monocytes, particularly from allergic asthmatics, the oscillating expression of circadian proteins CLOCK, BMAL, REV ERBs, and RORs was significantly altered. Similar changes in BMAL1 were observed in polarized macrophages from allergic donors and in tissue-resident macrophages from activated precision cut lung slices. We confirmed clock modulating, anti-inflammatory, and lung-protective properties of the inverse ROR agonist SR1001 by reduced secretion of macrophage inflammatory protein and increase in phagocytosis. Using a house dust mite model, we verified the therapeutic effect of SR1001 in vivo. Discussion: Overall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma.


Assuntos
Asma , Relógios Circadianos , Macrófagos , Monócitos , Humanos , Monócitos/imunologia , Monócitos/metabolismo , Relógios Circadianos/imunologia , Animais , Macrófagos/imunologia , Macrófagos/metabolismo , Asma/imunologia , Asma/metabolismo , Masculino , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Inflamação/imunologia , Feminino , Camundongos , Adulto , Pyroglyphidae/imunologia , Células Cultivadas , Ritmo Circadiano/imunologia
10.
J Cardiothorac Surg ; 19(1): 314, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824534

RESUMO

BACKGROUND: Asthma is a respiratory disease characterized by airway remodeling. We aimed to find out the role and mechanism of lncRNA MEG3 in asthma. METHODS: We established a cellular model of asthma by inducing human airway smooth muscle cells (HASMCs) with PDGF-BB, and detected levels of lncRNA MEG3, miR-143-3p and FGF9 in HASMCs through qRT-PCR. The functions of lncRNA MEG3 or miR-143-3p on HASMCs were explored by cell transfection. The binding sites of miR-143-3p and FGF9 were subsequently analyzed with bioinformatics software, and validated with dual-luciferase reporter assay. MTT, 5-Ethynyl-2'-deoxyuridine (EdU) assay, and Transwell were used to detect the effects of lncRNA MEG3 or miR-143-3p on proliferation and migration of HASMCs. QRT-PCR and western blot assay were used to evaluate the level of proliferation-related marker PCNA in HASMCs. RESULTS: The study found that lncRNA MEG3 negatively correlated with miR-143-3p, and miR-143-3p could directly target with FGF9. Silence of lncRNA MEG3 can suppress migration and proliferation of PDGF-BB-induced HASMCs via increasing miR-143-3p. Further mechanistic studies revealed that miR-143-3p negatively regulated FGF9 expression in HASMCs. MiR-143-3p could inhibit PDGF-BB-induced HASMCs migration and proliferation through downregulating FGF9. CONCLUSION: LncRNA MEG3 silencing could inhibit the migration and proliferation of HASMCs through regulating miR-143-3p/FGF9 signaling axis. These results imply that lncRNA MEG3 plays a protective role against asthma.


Assuntos
Asma , Movimento Celular , Proliferação de Células , Fator 9 de Crescimento de Fibroblastos , MicroRNAs , Miócitos de Músculo Liso , RNA Longo não Codificante , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Proliferação de Células/genética , Asma/genética , Asma/metabolismo , Miócitos de Músculo Liso/metabolismo , Fator 9 de Crescimento de Fibroblastos/genética , Fator 9 de Crescimento de Fibroblastos/metabolismo , Células Cultivadas , Remodelação das Vias Aéreas/fisiologia , Remodelação das Vias Aéreas/genética
11.
Respir Res ; 25(1): 230, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824593

RESUMO

BACKGROUND: Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma. METHODS: The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor. RESULTS: Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-ß1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression. CONCLUSIONS: Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.


Assuntos
Remodelação das Vias Aéreas , Aminoácido Oxirredutases , Asma , Ovalbumina , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Aminoácido Oxirredutases/metabolismo , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/biossíntese , Ovalbumina/toxicidade , Remodelação das Vias Aéreas/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Humanos , Asma/patologia , Asma/metabolismo , Asma/enzimologia , Asma/genética , Transdução de Sinais/fisiologia , Feminino , Camundongos Endogâmicos BALB C , Masculino , Transição Epitelial-Mesenquimal/fisiologia
12.
J Pharm Biomed Anal ; 247: 116265, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38850849

RESUMO

Dingchuan Decoction (DCD) is a traditional Chinese medicine prescription commonly used in the treatment of asthma, but the mechanism of DCD in treating asthma has not yet been determined. In this study, we employed a combination of metabolomics and network pharmacology to investigate the mechanism of DCD in treating asthma. An allergic asthma rat model was induced by ovalbumin (OVA). Metabolomics based on 1H NMR and UHPLC-MS was used to identify differential metabolites and obtain the major metabolic pathways and potential targets. Network pharmacology was utilized to explore potential targets of DCD for asthma treatment. Finally, the results of metabolomics and network pharmacology were integrated to obtain the key targets and metabolic pathways of DCD for the therapy of asthma, and molecular docking was utilized to validate the key targets. A total of 76 important metabolites and 231 potential targets were identified through metabolomics. Using network pharmacology, 184 potential therapeutic targets were obtained. These 184 targets were overlaid with the 231 potential targets obtained through metabolomics and were analyzed in conjunction with metabolic pathways. Ultimately, the key targets were identified as aldehyde dehydrogenase 2 (ALDH2) and amine oxidase copper-containing 3 (AOC3), and the relevant metabolic pathways affected were glycolysis and gluconeogenesis as well as arginine and proline metabolism. Molecular docking showed that the key targets had high affinity with the relevant active ingredients in DCD, which further demonstrated that DCD may exert therapeutic effects by acting on the key targets. The present study demonstrated that DCD can alleviate OVA-induced allergic asthma and that DCD may have a therapeutic effect by regulating intestinal flora and polyamine metabolism through its effects on ALDH2 and AOC3.


Assuntos
Asma , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Metabolômica , Simulação de Acoplamento Molecular , Farmacologia em Rede , Ovalbumina , Ratos Sprague-Dawley , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Metabolômica/métodos , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Farmacologia em Rede/métodos , Masculino , Cromatografia Líquida de Alta Pressão/métodos , Redes e Vias Metabólicas/efeitos dos fármacos , Aldeído-Desidrogenase Mitocondrial/metabolismo , Medicina Tradicional Chinesa/métodos
13.
Cell Death Dis ; 15(6): 400, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849380

RESUMO

Emerging evidence demonstrates that pyroptosis has been implicated in the pathogenesis of asthma. Gasdermin D (GSDMD) is the pyroptosis executioner. The mechanism of GSDMD in asthma remains unclear. The aim of this study was to elucidate the potential role of GSDMD in asthmatic airway inflammation and remodeling. Immunofluorescence staining was conducted on airway epithelial tissues obtained from both asthma patients and healthy controls (HCs) to evaluate the expression level of N-GSDMD. ELISA was used to measure concentrations of cytokines (IL-1ß, IL-18, IL-17A, and IL-10) in serum samples collected from asthma patients and healthy individuals. We demonstrated that N-GSDMD, IL-18, and IL-1ß were significantly increased in samples with mild asthma compared with those from the controls. Then, wild type and Gsdmd-knockout (Gsdmd-/-) mice were used to establish asthma model. We performed histopathological staining, ELISA, and flow cytometry to explore the function of GSDMD in allergic airway inflammation and tissue remodeling in vivo. We observed that the expression of N-GSDMD, IL-18, and IL-1ß was enhanced in OVA-induced asthma mouse model. Gsdmd knockout resulted in attenuated IL-18, and IL-1ß production in both bronchoalveolar lavage fluid (BALF) and lung tissue in asthmatic mice. In addition, Gsdmd-/- mice exhibit a significant reduction in airway inflammation and remodeling, which might be associated with reduced Th17 inflammatory response and M2 polarization of macrophages. Further, we found that GSDMD knockout may improve asthmatic airway inflammation and remodeling through regulating macrophage adhesion, migration, and macrophage M2 polarization by targeting Notch signaling pathway. These findings demonstrate that GSDMD deficiency profoundly alleviates allergic inflammation and tissue remodeling. Therefore, GSDMD may serve as a potential therapeutic target against asthma.


Assuntos
Asma , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos Knockout , Ovalbumina , Proteínas de Ligação a Fosfato , Animais , Asma/genética , Asma/patologia , Asma/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Camundongos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Humanos , Remodelação das Vias Aéreas , Feminino , Inflamação/patologia , Inflamação/metabolismo , Inflamação/genética , Camundongos Endogâmicos C57BL , Masculino , Citocinas/metabolismo , Piroptose , Pulmão/patologia , Pulmão/metabolismo , Gasderminas
14.
Crit Rev Immunol ; 44(6): 87-98, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38848296

RESUMO

In this study, network pharmacology combined with biological experimental verification was utilized to screen the targets of isoforskolin (ISOF) and investigate the potential underlying mechanism of ISOF against asthma. Asthma-related targets were screened from the Genecards and DisGeNET databases. SEA and Super-PRED databases were used to obtain the targets of ISOF. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed to identify enriched regulatory pathways of key targets in ISOF acting on asthma. Then, a protein-protein interaction (PPI) network was constructed via STRING database and hub genes of ISOF against asthma were further screened using molecular docking. Finally, CCK-8, qPCR, and Western blotting were performed to confirm the targets of ISOF in treating asthma. A total of 96 drug potential therapeutic targets from the relevant databases were screened out. KEGG pathway enrichment analysis predicted that the target genes might be involved in the PI3K-Akt pathway. The core targets of ISOF in treating asthma were identified by the PPI network and molecular docking, including MAPK1, mTOR, and NFKB1. Consistently, in vitro experiments showed that ISOF acting on asthma was involved in inflammatory response by reducing the expression of MAPK1, mTOR, and NFKB1. The present study reveals that MAPK1, mTOR, and NFKB1 might be key targets of ISOF in asthma treatment and the anti-asthma effect might be related to the PI3K-AKT signaling pathway.


Assuntos
Asma , Simulação de Acoplamento Molecular , Farmacologia em Rede , Mapas de Interação de Proteínas , Asma/tratamento farmacológico , Asma/metabolismo , Humanos , Animais , Camundongos , Transdução de Sinais/efeitos dos fármacos , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
15.
Int J Mol Sci ; 25(11)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38892358

RESUMO

Obese patients with asthma present with aggravated symptoms that are also harder to treat. Here, we used a mouse model of allergic asthma sensitised and challenged to house dust mite (HDM) extracts to determine whether high-fat-diet consumption would exacerbate the key features of allergic airway inflammation. C57BL/6 mice were intranasally sensitised and challenged with HDM extracts over a duration of 3 weeks. The impact of high-fat-diet (HFD) vs. normal diet (ND) chow was studied on HDM-induced lung inflammation and inflammatory cell infiltration as well as cytokine production. HFD-fed mice had greater inflammatory cell infiltration around airways and blood vessels, and an overall more severe degree of inflammation than in the ND-fed mice (semiquantitative blinded evaluation). Quantitative assessment of HDM-associated Th2 responses (numbers of lung CD4+ T cells, eosinophils, serum levels of allergen-specific IgE as well as the expression of Th2 cytokines (Il5 and Il13)) did not show significant changes between the HFD and ND groups. Interestingly, the HFD group exhibited a more pronounced neutrophilic infiltration within their lung tissues and an increase in non-Th2 cytokines (Il17, Tnfa, Tgf-b, Il-1b). These findings provide additional evidence that obesity triggered by a high-fat-diet regimen may exacerbate asthma by involving non-Th2 and neutrophilic pathways.


Assuntos
Asma , Citocinas , Dieta Hiperlipídica , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Obesidade , Células Th2 , Animais , Asma/imunologia , Asma/etiologia , Asma/patologia , Asma/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Camundongos , Dieta Hiperlipídica/efeitos adversos , Células Th2/imunologia , Células Th2/metabolismo , Citocinas/metabolismo , Pyroglyphidae/imunologia , Pulmão/patologia , Pulmão/imunologia , Pulmão/metabolismo , Inflamação/patologia , Inflamação/imunologia , Inflamação/metabolismo , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Feminino , Alérgenos/imunologia
16.
Iran J Allergy Asthma Immunol ; 23(2): 211-219, 2024 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-38822515

RESUMO

Asthma is a chronic respiratory disease that is characterized by airway inflammation, excessive mucus production, and airway remodeling. Prevention and treatment for asthma is an urgent issue in clinical studies. In recent years, N6-methyladenosine methylation (m6A) has emerged as a promising regulatory approach involved in multiple diseases. ALKBH5 (alkB homolog 5) is a demethylase widely studied in disease pathologies. This work aimed to explore the regulatory mechanisms underlying the ALKBH5-regulated asthma. We established an interleukin-13 (IL-13)-stimulated cell model to mimic the in vitro inflammatory environment of asthma. ALKBH5 knockdown in bronchial epithelial cells was performed using siRNAs, and the knockdown efficacy was analyzed by quantitative PCR (qPCR). Cell viability and proliferation were measured by cell counting kit 8 (CCK-8) and colony formation assay. The ferroptosis was assessed by measuring the total iron, Fe2+, lipid reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. The enrichment of N6-methyladenosine methylation (m6A) modification was detected by the MeRIP assay. Knockdown of ALKBH5 significantly elevated the survival and colony formation ability of bronchial epithelial cells in the IL-13 induction model. The levels of total iron, Fe2+, lipid ROS, and MDA were remarkedly elevated, and the SOD level was reduced in IL-13-induced bronchial epithelial cells, and depletion of ALKBH5 reversed these effects. Knockdown of ALKBH5 elevated the enrichment of m6A modification and expression of glutathione peroxidase 4 (GPX4). Knockdown of GPX4 abolished the pro-proliferation and anti-ferroptosis effects of siALKBH5. Knockdown of ALKBH5 improved the proliferation of bronchial epithelial cells and alleviated cell ferroptosis.


Assuntos
Adenosina , Homólogo AlkB 5 da RNA Desmetilase , Asma , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Asma/genética , Asma/metabolismo , Asma/patologia , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Proliferação de Células/genética , Metilação , Progressão da Doença , Linhagem Celular , Ferroptose/genética , Células Epiteliais/metabolismo , Regulação para Baixo , Brônquios/patologia , Brônquios/metabolismo , Técnicas de Silenciamento de Genes , Sobrevivência Celular/genética
17.
Zhonghua Er Ke Za Zhi ; 62(6): 542-547, 2024 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-38763876

RESUMO

Objective: To observe the expression of Galectin-7 in the serum and sputum of asthmatic children and to explore its significance in asthmatic children. Methods: The study prospectively case-control selected 183 children diagnosed with bronchial asthma at Department Ⅱ of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Beijing Children's Hospital of Capital Medical University. The control group consisted of 41 children with other bronchial diseases and 43 healthy children. Children in the asthma group were divided into acute and non-acute exacerbation groups. Acute exacerbation group was divided as mild acute, moderate acute and severe acute groups; non-acute exacerbation group was divided as mild persistent, moderate persistent and severe persistent groups. Children without acute exacerbation asthma in the asthma group were divided into high and low Galectin-7 groups based on median serum Galectin-7 levels. Serum and sputum were collected, Galectin-7 levels were measured using enzyme-linked immunosorbent assay. The study compared and analyzed the differences in Galectin-7 levels between children with asthma and the control groups using Mann-Whitney U test or the Kruskal-Wallis or the Chi-square test for inter-group comparisons. Results: Among 183 children, 61 cases had acute asthma exacerbation, and 122 cases had persistent asthma without acute exacerbation. The asthma group comprised 110 males and 73 females. The control group consisted of 41 children with other bronchial diseases, including 24 cases of bronchiectasis and 17 cases of obliterans bronchitis. The control group comprised 26 males and 15 females. Forty-three healthy children who underwent physical examination, including 22 males and 21 females. The levels of Galectin-7 in serum were significantly higher in children with an acute asthma exacerbation than that of healthy children (0.1 (0, 0.7) vs. 0 (0, 0.2) µg/L, Z=2.09, P=0.001). Galectin-7 levels in sputum were higher in children with an acute asthma exacerbation than that in children with other bronchial diseases (1.2 (0.1,3.7) vs. 0.4 (0.1, 1.5) µg/L, Z=2.20, P<0.001). Serum Galectin-7 levels were significantly higher in children with persistent asthma compared to children with other bronchial diseases and healthy children (0.6 (0.3, 1.2) vs. 0.1 (0, 0.5) and 0 (0, 0.2) µg/L, Z=-6.12,-7.63, both P<0.001), and the levels were significantly and positively correlated with asthma severity (r=0.77, P<0.001), disease duration (r=0.34, P=0.001), and number of previous attacks (r=0.51, P<0.001). There were 61 children in the high-Galectin-7 group and 61 children in the low-Galectin-7 group. Children with high Galectin-7 had more asthma triggers, a greater proportion with a positive family history, more previous asthma attacks, longer duration of asthma, and higher serum total IgE levels compared to those with low Galectin-7 (χ2=9.30, 22.46, Z=5.06, 3.57, 2.31, all P<0.05). Conclusion: The expression of Galectin-7 is found to be elevated in the serum and sputum of asthmatic children and correlated with asthma conditions.


Assuntos
Asma , Galectinas , Escarro , Humanos , Galectinas/sangue , Galectinas/metabolismo , Asma/metabolismo , Asma/sangue , Asma/diagnóstico , Escarro/metabolismo , Criança , Estudos de Casos e Controles , Estudos Prospectivos , Masculino , Feminino , Adolescente , Biomarcadores/sangue , Pré-Escolar
18.
Int Immunopharmacol ; 135: 112331, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38795597

RESUMO

CCR5 may be involved in the pathogenesis of asthma; however, the underlying mechanisms remain unclear. In comparison with a mild asthma model, subepithelial fibrosis was more severe and CCR5 gene expression in the lungs was significantly higher in our recently developed murine model of steroid-resistant severe asthma. Treatment with the CCR5 antagonist, maraviroc, significantly suppressed the development of subepithelial fibrosis in bronchi, whereas dexamethasone did not. On the other hand, increases in leukocytes related to type 2 inflammation, eosinophils, Th2 cells, and group 2 innate lymphoid cells in the lungs were not affected by the treatment with maraviroc. Increases in neutrophils and total macrophages were also not affected by the CCR5 antagonist. However, increases in transforming growth factor (TGF)-ß-producing interstitial macrophages (IMs) were significantly reduced by maraviroc. The present results confirmed increases in CCR5-expressing IMs in the lungs of the severe asthma model. In conclusion, CCR5 on IMs plays significant roles in the development of subepithelial fibrosis in severe asthma through TGF-ß production in the lungs.


Assuntos
Asma , Antagonistas dos Receptores CCR5 , Macrófagos , Maraviroc , Fibrose Pulmonar , Receptores CCR5 , Fator de Crescimento Transformador beta , Animais , Asma/imunologia , Asma/tratamento farmacológico , Asma/patologia , Asma/metabolismo , Receptores CCR5/metabolismo , Receptores CCR5/genética , Maraviroc/farmacologia , Maraviroc/uso terapêutico , Antagonistas dos Receptores CCR5/farmacologia , Antagonistas dos Receptores CCR5/uso terapêutico , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Camundongos , Pulmão/patologia , Pulmão/imunologia , Pulmão/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Modelos Animais de Doenças , Humanos , Feminino
19.
Biomolecules ; 14(5)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38785919

RESUMO

Asthma has reached epidemic levels, yet progress in developing specific therapies is slow. One of the main reasons for this is the fact that asthma is an umbrella term for various distinct subsets. Due to its high heterogeneity, it is difficult to establish biomarkers for each subset of asthma and to propose endotype-specific treatments. This review focuses on protein glycosylation as a process activated in asthma and ways to utilize it to develop novel biomarkers and treatments. We discuss known and relevant glycoproteins whose functions control disease development. The key role of glycoproteins in processes integral to asthma, such as inflammation, tissue remodeling, and repair, justifies our interest and research in the field of glycobiology. Altering the glycosylation states of proteins contributing to asthma can change the pathological processes that we previously failed to inhibit. Special emphasis is placed on chitotriosidase 1 (CHIT1), an enzyme capable of modifying LacNAc- and LacdiNAc-containing glycans. The expression and activity of CHIT1 are induced in human diseased lungs, and its pathological role has been demonstrated by both genetic and pharmacological approaches. We propose that studying the glycosylation pattern and enzymes involved in glycosylation in asthma can help in patient stratification and in developing personalized treatment.


Assuntos
Asma , Glicoproteínas , Humanos , Asma/metabolismo , Asma/genética , Glicosilação , Glicoproteínas/metabolismo , Glicoproteínas/genética , Hexosaminidases/metabolismo , Hexosaminidases/genética , Biomarcadores/metabolismo , Animais , Polissacarídeos/metabolismo
20.
Biomolecules ; 14(5)2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38785953

RESUMO

Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. Eosinophils contribute to the pathogenesis of airway disease mainly by releasing eosinophil-specific granules, lipid mediators, superoxide anions, and their DNA. Type-2 cytokines such as interleukin (IL)-4 and IL-13 also play roles in the development of bronchial asthma. Among these cytokines, IL-4 is involved in T-cell differentiation, B-cell activation, B-cell differentiation into plasma cells, and the production of immunoglobulin E. Although IL-13 has similar effects to IL-4, IL-13 mainly affects structural cells, such as epithelial cells, smooth muscle cells, and fibroblasts. IL-13 induces the differentiation of goblet cells that produce mucus and induces the airway remodeling, including smooth muscle hypertrophy. IL-4 and IL-13 do not directly activate the effector functions of eosinophils; however, they can induce eosinophilic airway inflammation by upregulating the expression of vascular cell adhesion molecule-1 (for adhesion) and CC chemokine receptor 3 ligands (for migration). Dupilumab, a human anti-IL-4 receptor α monoclonal antibody that inhibits IL-4 and IL-13 signaling, decreases asthma exacerbations and mucus plugs and increases lung function in moderate to severe asthma. In addition, dupilumab is effective for chronic rhinosinusitis with nasal polyps and for atopic dermatitis, and IL-4/IL-13 blocking is expected to suppress allergen sensitization, including transcutaneous sensitization and atopic march.


Assuntos
Asma , Eosinófilos , Interleucina-13 , Interleucina-4 , Humanos , Asma/metabolismo , Asma/patologia , Eosinófilos/metabolismo , Eosinófilos/imunologia , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Animais
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