Identification of Checkpoint Kinase 1 as the Therapeutic Target of Hyperoside in Alleviating Airway Inflammatory and Autophagy of Pediatric Asthma.

Abstract

INTRODUCTION: Pediatric asthma is a respiratory disease and autophagy plays a critical role in its progression. Hyperoside (Hyp) is a flavonoid glycoside with anti-inflammatory property. The aim of present study was to examine the role of Hyp in pediatric asthma and reveal its underlying mechanism. METHODS: Ovalbumin-challenged neonatal mice and IL-13-stimulated BEAS-2B cells were utilized as in vivo and in vitro asthma models. Network pharmacology was used to investigate the target of Hyp in pediatric asthma. RESULTS: Hyp treatment alleviated airway inflammation, airway remodeling, and the infiltration of inflammatory cells in the airway of asthmatic mice. Hyp inhibited autophagy by decreasing Beclin-1, Atg5, and LC3II/I level. Network pharmacology identified checkpoint kinase 1 (CHEK1) was the potential target of Hyp. Decreased expression of p-CHEK1 and CHEK1 upon Hyp treatment was confirmed both in vivo and in vitro, accompanied with the inhibition of the downstream p53/DRAM1 axis. Further rescue experiment confirmed that CHEK1 overexpression reversed the inhibitory effects of Hyp on inflammation and autophagy. As expected, CHEK1 overexpression upregulated p53 and DRAM1 expression in BEAS-2B cells with Hyp treatment. CONCLUSION: Our results demonstrated that Hyp alleviated pediatric asthma, and might exert its effect by regulating CHEK1/p53/DRAM1 axis mediated autophagy.