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1.
Respir Res ; 25(1): 120, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468259

RESUMO

BACKGROUND: Airway basal cells (BC) from patients with chronic obstructive pulmonary disease (COPD) regenerate abnormal airway epithelium and this was associated with reduced expression of several genes involved in epithelial repair. Quercetin reduces airway epithelial remodeling and inflammation in COPD models, therefore we examined whether quercetin promotes normal epithelial regeneration from COPD BC by altering gene expression. METHODS: COPD BC treated with DMSO or 1 µM quercetin for three days were cultured at air/liquid interface (ALI) for up to 4 weeks. BC from healthy donors cultured at ALI were used as controls. Polarization of cells was determined at 8 days of ALI. The cell types and IL-8 expression in differentiated cell cultures were quantified by flow cytometry and ELISA respectively. Microarray analysis was conducted on DMSO or 1 µM quercetin-treated COPD BC for 3 days to identify differentially regulated genes (DEG). Bronchial brushings obtained from COPD patients with similar age and disease status treated with either placebo (4 subjects) or 2000 mg/day quercetin (7 subjects) for 6 months were used to confirm the effects of quercetin on gene expression. RESULTS: Compared to placebo-, quercetin-treated COPD BC showed significantly increased transepithelial resistance, more ciliated cells, fewer goblet cells, and lower IL-8. Quercetin upregulated genes associated with tissue and epithelial development and differentiation in COPD BC. COPD patients treated with quercetin, but not placebo showed increased expression of two developmental genes HOXB2 and ELF3, which were also increased in quercetin-treated COPD BC with FDR < 0.001. Active smokers showed increased mRNA expression of TGF-ß (0.067) and IL-8 (22.0), which was reduced by 3.6 and 4.14 fold respectively after quercetin treatment. CONCLUSIONS: These results indicate that quercetin may improve airway epithelial regeneration by increasing the expression of genes involved in epithelial development/differentiation in COPD. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov on 6-18-2019. The study number is NCT03989271.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Quercetina , Humanos , Quercetina/farmacologia , Quercetina/uso terapêutico , Quercetina/metabolismo , Interleucina-8/metabolismo , Dimetil Sulfóxido/metabolismo , Dimetil Sulfóxido/farmacologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Brônquios/metabolismo , Células Epiteliais/metabolismo , Células Cultivadas , Fatores de Transcrição/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/farmacologia
2.
Res Sq ; 2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37546740

RESUMO

Background: Airway basal cells from patients with chronic obstructive pulmonary disease (COPD) regenerate abnormal airway epithelium and this was associated with reduced expression of several genes involved in epithelial repair. Quercetin reduces goblet cell metaplasia and the expression of pro-inflammatory cytokines in COPD models. This study assessed whether quercetin improves epithelial regeneration from COPD airway basal cells. Methods: COPD airway basal cells were treated with DMSO or 1 µM quercetin for three days. The cells were then cultured at air/liquid interface (ALI) for up to 4 weeks. Basal cells from healthy donors cultured at air/liquid interface were used as controls. Polarization of cells was determined at 8 days of ALI. The cell types and IL-8 expression in differentiated cell cultures were quantified by flow cytometry and ELISA. Microarray analysis was conducted on DMSO or quercetin-treated COPD basal cells to identify differentially regulated genes (DEG) and the enriched biological pathways. Bronchial brushings from COPD patients treated with either placebo or quercetin for 6 months were used to confirm the effects of quercetin on gene expression. Results: Compared to DMSO, quercetin-treated COPD basal cells showed an increase in TER and regenerated the airway epithelium with more ciliated cells, and less goblet cells and IL-8. Comparison of DMSO- and quercetin-treated COPD basal cell transcriptomic profiles indicated that quercetin upregulated genes associated with tissue and epithelial development and differentiation. COPD patients treated with quercetin, but not placebo showed significantly increased expression of two developmental genes HOXB2 and ELF3, which were also increased in quercetin-treated COPD basal cells. Bronchial brushings from active smokers showed significantly increased mRNA expression of TGF-ß and IL-8, and it was reduced after quercetin treatment. Conclusions: These results indicate that quercetin may improve airway epithelial regeneration by increasing the expression of genes involved in epithelial development/differentiation in COPD. Trial registration: This study was registered at ClinicalTrials.gov on 6-18-2019. The study number is NCT03989271.

3.
Trends Cell Mol Biol ; 13: 99-114, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-31156296

RESUMO

Epithelial barrier function studies often attribute alterations in barrier function to induced changes in tight junctional (TJ) complexes. The occurrence of spontaneous and cytokine-induced, focal cell detachment in cell layers of the human gingival epithelial cell line, Gie-3B11, highlights the danger of this assumption without confirmatory experimentation. Gie-3B11 cell layers manifest morphological polarity, TJ complexes and barrier function after confluence but fail to then maintain a stable epithelial barrier. Transepithelial electrical resistance rises to over 100 ohms x cm2 a few days after seeding cell layers at a confluent density, but then spontaneously declines, with simultaneous, inverse changes in transepithelial 14C-D-mannitol diffusion rates. This barrier decline correlates with the appearance of focal cell detachment/hole formation in cell layers. Both barrier compromise (decreased electrical resistance; increased 14C-D-mannitol leak) and hole formation are accelerated and exaggerated by exposing cell layers to proinflammatory cytokines. Both are inhibited by increasing the basal-lateral medium compartment volume, suggesting that cell layers are secreting factor(s) across their basal-lateral surfaces that are causal to hole formation. The molecular mechanism of cell death/detachment here is not as significant as the implications of hole formation for the correct interpretation of barrier function studies. Barrier changes in any epithelial model should be attributed to induced changes in TJ complexes only after thorough investigation.

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