Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disease in which impaired mucosal barrier function may increase susceptibility to aspirated oral microbial products. Periodontal disease is associated with COPD development and exacerbation, but the epithelial mechanisms linking periodontal pathogens to pulmonary inflammation remain unclear. Here, we investigated whether a gingipain-active Porphyromonas gingivalis ( P. gingivalis ) extracellular protein/protease fraction (PCS) promotes γδ T-cell-associated inflammation in COPD-like airways. Repeated intratracheal PCS administration to epithelial sodium channel β-subunit (βENaC)-transgenic mice increased γδ T-cell accumulation and pulmonary Ifng , Il17a , Ccl20 , and Ccr6 mRNA expression, without coordinated induction of M2-associated markers. Pulmonary Tslp and Il1 8 mRNA were not significantly altered. Serum CCL20 concentrations increased in both wild-type and βENaC-transgenic mice. In β/γENaC-overexpressing human airway epithelial cells, PCS increased mRNA expression of CCL20 and F2RL1 , encoding protease-activated receptor 2 (PAR-2), and reduced PAR-2 immunoreactivity. PAR-2 agonist stimulation induced CCL20 expression, whereas PAR-2 inhibition suppressed PCS-induced expression. PAR-1 inhibition or lipopolysaccharide neutralization did not significantly suppress this response. Heat treatment of PCS reduced gingipain activities to background levels and attenuated PCS-induced CCL2 0 mRNA expression. These findings support epithelial PAR-2-associated CCL20 induction as a potential link between periodontal bacterial products and γδ T-cell-associated inflammation in COPD-like airways.
Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disease in which impaired mucosal barrier function may increase susceptibility to aspirated oral microbial products. Periodontal disease is associated with COPD development and exacerbation, but the epithelial mechanisms linking periodontal pathogens to pulmonary inflammation remain unclear. Here, we investigated whether a gingipain-active Porphyromonas gingivalis (P. gingivalis) extracellular protein/protease fraction (PCS) promotes γδ T-cell-associated inflammation in COPD-like airways. Repeated intratracheal PCS administration to epithelial sodium channel β-subunit (βENaC)-transgenic mice increased γδ T-cell accumulation and pulmonary Ifng, Il17a, Ccl20, and Ccr6 mRNA expression, without coordinated induction of M2-associated markers. Pulmonary Tslp and Il18 mRNA were not significantly altered. Serum CCL20 concentrations increased in both wild-type and βENaC-transgenic mice. In β/γENaC-overexpressing human airway epithelial cells, PCS increased mRNA expression of CCL20 and F2RL1, encoding protease-activated receptor 2 (PAR-2), and reduced PAR-2 immunoreactivity. PAR-2 agonist stimulation induced CCL20 expression, whereas PAR-2 inhibition suppressed PCS-induced expression. PAR-1 inhibition or lipopolysaccharide neutralization did not significantly suppress this response. Heat treatment of PCS reduced gingipain activities to background levels and attenuated PCS-induced CCL20 mRNA expression. These findings support epithelial PAR-2-associated CCL20 induction as a potential link between periodontal bacterial products and γδ T-cell-associated inflammation in COPD-like airways.
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex pathogenic mechanisms, and the efficacy of single-target interventions remains limited. γ-Oryzanol (Orz) and α-lipoic acid (ALA) exert neuroprotective effects individually, yet their combined effects and molecular mechanisms in ALS remain unclear. Aim: To investigate the therapeutic effects and mechanisms of combined Orz and ALA treatment in ALS. Methods: Network pharmacology was used to identify potential targets shared by the compounds and ALS. Core targets and pathways were identified through protein-protein interaction (PPI) network analysis, molecular docking, and functional enrichment analysis, followed by experimental validation in hSOD1 G93A cell and transgenic mouse models. Results: Six core targets (EGFR, AKT1, HSP90AA1, BCL2, SRC, HSP90AB1) were identified. In hSOD1 G93A cells, combined treatment modulated mRNA expression and protein phosphorylation of the core targets and attenuated cellular injury. In hSOD1 G93A transgenic mice, the combination delayed disease progression, prolonged survival, improved motor function, and reduced motor neuron loss. This combination alleviated inflammation and apoptosis by activating the AKT/GSK3β pathway. Conclusion: Combined Orz and ALA treatment modulates core targets, activates the AKT/GSK3β pathway, and suppresses inflammation and apoptosis. This combination represents a promising therapeutic strategy for ALS.
Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex pathogenic mechanisms, and the efficacy of single-target interventions remains limited. γ-Oryzanol (Orz) and α-lipoic acid (ALA) exert neuroprotective effects individually, yet their combined effects and molecular mechanisms in ALS remain unclear. Aim To investigate the therapeutic effects and mechanisms of combined Orz and ALA treatment in ALS. Methods Network pharmacology was used to identify potential targets shared by the compounds and ALS. Core targets and pathways were identified through protein-protein interaction (PPI) network analysis, molecular docking, and functional enrichment analysis, followed by experimental validation in hSOD1G93A cell and transgenic mouse models. Results Six core targets (EGFR, AKT1, HSP90AA1, BCL2, SRC, HSP90AB1) were identified. In hSOD1G93A cells, combined treatment modulated mRNA expression and protein phosphorylation of the core targets and attenuated cellular injury. In hSOD1G93A transgenic mice, the combination delayed disease progression, prolonged survival, improved motor function, and reduced motor neuron loss. This combination alleviated inflammation and apoptosis by activating the AKT/GSK3β pathway. Conclusion Combined Orz and ALA treatment modulates core targets, activates the AKT/GSK3β pathway, and suppresses inflammation and apoptosis. This combination represents a promising therapeutic strategy for ALS.
