Background. Chronic obstructive pulmonary disease (COPD) is a long-term respiratory disorder marked by restricted airflow and persistent respiratory symptoms. According to previous studies, icariin combined with nobiletin (I&N) significantly ameliorates COPD, but the therapeutic mechanisms remain unclear. Purpose. The aim of the study is to investigate the therapeutic mechanisms of I&N against COPD using network pharmacology and experimental validation. Methods. The targets of I&N and related genes of COPD were screened and their intersection was selected. Next, the protein-protein interaction (PPI) networks, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Further, a COPD rat model was established to validate the effect and mechanisms of I&N. Results. 445 potential targets I&N were obtained from SwissTargetPrediction, STITCH 5.0, and PharmMapper databases. 1831 related genes of COPD were obtained from GeneCards, DrugBank, and DisGeNet databases. 189 related genes were screened via matching COPD targets with I&N. 16 highest score targets among 189 targets were obtained according to PPI networks. GO and KEGG pathway enrichment analyses of 16 highest score targets suggested that these key genes of I&N were mostly enriched in the tumor necrosis factor (TNF) pathway, mitogen-activated protein kinase (MAPK) pathway, and phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (AKT) pathway. Therefore, the treatments of I&N for COPD were connected with inflammation-related pathways. In in vivo experiments, the studies indicated that I&N improved the lung function and alleviated the damage of pulmonary histopathology. Moreover, I&N reduced levels of interleukin (IL)-6, IL-1β, and TNF-α in lung tissues of COPD rats and inhibited the activation of the MAPK pathway and PI3K-Akt pathway. Conclusions. Icariin combined with nobiletin has therapeutic effects on COPD by inhibiting inflammation. The potential mechanisms of I&N may relate to the MAPK pathway and PI3K-Akt pathway.
Background: The airway epithelium acts as a physical barrier to protect pulmonary airways against pathogenic microorganisms and toxic substances, such as cigarette smoke (CS), bacteria, and viruses. The disruption of the structural integrity and dysfunction of the airway epithelium is related to the occurrence and progression of chronic obstructive pulmonary disease.Purpose: The aim of this study is to compare the effects of CS, Klebsiella pneumoniae (KP), and their combination on airway epithelial barrier function. Methods:The mice were exposed to CS, KP, and their combination from 1 to 8 weeks. After the cessation of CS and KP at Week 8, we observed the recovery of epithelial barrier function in mice for an additional 16 weeks. To compare the epithelial barrier function among different groups over time, the mice were sacrificed at Weeks 4, 8, 16, and 24 and then the lungs were harvested to detect the pulmonary pathology, inflammatory cytokines, and tight junction proteins. To determine the underlying mechanisms, the BEAS-2B cells were treated with an epidermal growth factor receptor (EGFR) inhibitor (AG1478). Results:The results of this study suggested that the decreased lung function, increased bronchial wall thickness (BWT), elevated inflammatory factors, and reduced tight junction protein levels were observed at Week 8 in CS-induced mice and these changes persisted until Week 16. In the KP group, increased BWT and elevated inflammatory factors were observed only at Week 8, whereas in the CS + KP group, decreased lung function, lung tissue injury, inflammatory cell infiltration, and epithelial
Background. The effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) with 5 ingredients (ginsenoside Rh1, astragaloside, icariin, nobiletin, and paeonol) has been shown to protect against chronic obstructive pulmonary disease (COPD). The present study aimed to observe the effects of ECC-BYF III in a COPD rat model and dissect its potential mechanisms in regulating mucus hypersecretion via the miR-146a-5p/epidermal growth factor receptor (EGFR)/MEK/ERK pathway. Methods. COPD model rats were treated with normal saline, ECC-BYF III, or N-acetylcysteine (NAC). Pulmonary function, lung tissue histology with H & E and AB-PAS staining, expression levels of interleukin (IL)-4, IL-6, IL-1β, MUC5AC, MUC5B, and FOXA2 in lung tissues and the mRNA and proteins involved in the miR-146a-5p/EGFR/MEK/ERK pathway were evaluated. Results. The COPD rats showed a significant decrease in the pulmonary function and serious pathological damage to the lung tissue. ECC-BYF III and NAC significantly improved the ventilation function and small airway pathological damage in the COPD rats. The goblet cells and the expression levels of IL-1β, IL-6, MUC5AC, and MUC5B were increased in the COPD rats and were significantly decreased after ECC-BYF III or NAC intervention. The expression levels of IL-4 and FOXA2 in the COPD rats were markedly decreased and were improved in the ECC-BYF III and NAC groups. ECC-BYF III appeared to have a potent effect in restoring the reduced expression of miR-146a-5p. The increased phosphorylation levels of EGFR, MEK, and ERK1/2 and the protein expression levels of SPDEF in the lungs of COPD rats could be significantly reduced by ECC-BYF III. Conclusions. ECC-BYF III has a significant effect in improving the airway mucus hypersecretion in COPD model rats, as well as a protective effect against limited pulmonary function and injured lung histopathology. The protective effect of ECC-BYF III in reducing airway mucus hypersecretion in COPD may involve the miR-146a-5p/EGFR/MEK/ERK pathway.
Background: To explore the combined efficacy of ECC-BYFIII and exercise rehabilitation (ER) in inhibiting airway mucus hypersecretion in a COPD rat model. Methods: Forty-eight SD rats were divided into control, model, NAC, ECC-BYFIII, ER and ECC-BYFIII+ER groups (n=8). COPD rats were exposed to cigarette smoke and bacteria for eight weeks and administered various treatments over the next eight weeks. Rats were euthanized at week 17 after pulmonary function testing. Pathological examination of lung tissues was performed. IL-6 and IL-10 levels were measured in BALF and protein levels of MUC5AC, MUC5B, AQP-5, EGFR, ERK, JNK, and p38 were measured in lung tissues. Results: Improved pulmonary function and pathological changes were observed in ECC-BYFIII, ECC-BYFIII+ER and NAC groups. ECC-BYFIII and ECC-BYFIII+ER had greater MAN compared to NAC. Lung inflammation and goblet cell generation were reduced and MUC5AC, MUC5B and AQP-5 expression were lower in all treatment groups. ECC-BYFIII has more significant effect on MUC5AC than ER and NAC. ECC-BYFIII+ER had a greater effect on suppressing IL-6 in BALF compared to other treatments. ECC-BYFIII, ER and ECC-BYFIII+ER reduced EGFR, ERK, JNK, and p38 phosphorylated protein levels. ECC-BYFIII+ER had a greater effect on p-JNK and p-p38 than ECC-BYFIII and NAC. Conclusion: ECC-BYFIII, ER and ECC-BYFIII+ER have efficacy in inhibiting airway mucus hypersecretion with improved pulmonary function and pathological changes. ECC-BYFIII had a greater effect in improving MAN and MUC5AC in lung tissue. ECC-BYFIII+ER had a greater effect in alleviating pulmonary pathology and inflammation. These effects may be mediated by inhibition of the EGFR/MAPK pathway.
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