Journal of ethnopharmacology · 2026
Shema Zhichuan Liquid alleviates airway inflammation in Allergic Asthma by regulating autophagy pathways through DNA methylation.
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Xie Lin, Xie Yanxiao, Chen Yushan, Song Dong, Luo Hongyan, Yuan Qinglin, Li Lingling, Tao Hailan, Jiang Ziyun, Li Leng, Cai Yan, Lian Leshen
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Shema Zhichuan Liquid (SMZCL) is a traditional Chinese medicine formulation used clinically as an adjunct therapy for asthma. Its therapeutic mechanism in allergic asthma (AA), however, remains poorly understood.
AIMS OF THE STUDY: This study aimed to evaluate the efficacy of SMZCL in treating AA and to elucidate its molecular mechanisms, with particular focus on the regulation of autophagy via DNMT1-mediated promoter demethylation of autophagy-related genes.
MATERIALS AND METHODS: The AA mouse model was established by ovalbumin (OVA)/Al(OH)3 sensitization and challenge. Lung histopathological, inflammatory cytokine levels, Th2 cell proportion, methylation status of autophagy-related genes, and the expression of autophagy-associated markers were assessed. Additionally, an in vitro inflammatory model was generated using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages to further investigate the mechanism by which SMZCL modulates autophagy through modulating DNA methylation.
RESULTS: In vivo, SMZCL attenuated airway inflammation in AA mice and reduced the proportion of Th2 cells in BALF. It significantly decreased serum levels of IgE, Th2 cytokines IL-4 and IL-13, and pro-inflammatory cytokines TNF-α and IL-6, while increasing the Th1 cytokine IFN-γ. Mechanistically, SMZCL inhibited DNMT1 mRNA and protein expression, decreased the relative methylation levels of the ATG5 and Beclin-1 promoters, upregulated mRNA and protein levels of ATG5, Beclin-1, and LC3, and downregulated p62 mRNA expression. In vitro, SMZCL treatment reduced pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), suppressed DNMT1 expression, induced demethylation of ATG5 and Beclin-1 promoters, and upregulated their expression. SMZCL restored autophagic flux, as evidenced by elevated absolute levels of LC3-II, enhanced p62 degradation, an upward trend in the LC3-II/I ratio, a concurrent increase in both autophagosome and autolysosome puncta in mCherry-GFP-LC3 dual-fluorescence analysis, and further LC3-II accumulation in the presence of chloroquine. Moreover, SMZCL inhibited the expression of mTOR and phosphorylated mTOR (p-mTOR).
CONCLUSION: SMZCL inhibited DNMT1, leading to demethylation of the ATG5 and Beclin-1 promoters, and concurrently suppressed the mTOR signaling pathway. Through these mechanisms, SMZCL restored autophagic flux, exerted anti-inflammatory effects, and thereby provided protection against AA.
AIMS OF THE STUDY: This study aimed to evaluate the efficacy of SMZCL in treating AA and to elucidate its molecular mechanisms, with particular focus on the regulation of autophagy via DNMT1-mediated promoter demethylation of autophagy-related genes.
MATERIALS AND METHODS: The AA mouse model was established by ovalbumin (OVA)/Al(OH)3 sensitization and challenge. Lung histopathological, inflammatory cytokine levels, Th2 cell proportion, methylation status of autophagy-related genes, and the expression of autophagy-associated markers were assessed. Additionally, an in vitro inflammatory model was generated using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages to further investigate the mechanism by which SMZCL modulates autophagy through modulating DNA methylation.
RESULTS: In vivo, SMZCL attenuated airway inflammation in AA mice and reduced the proportion of Th2 cells in BALF. It significantly decreased serum levels of IgE, Th2 cytokines IL-4 and IL-13, and pro-inflammatory cytokines TNF-α and IL-6, while increasing the Th1 cytokine IFN-γ. Mechanistically, SMZCL inhibited DNMT1 mRNA and protein expression, decreased the relative methylation levels of the ATG5 and Beclin-1 promoters, upregulated mRNA and protein levels of ATG5, Beclin-1, and LC3, and downregulated p62 mRNA expression. In vitro, SMZCL treatment reduced pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), suppressed DNMT1 expression, induced demethylation of ATG5 and Beclin-1 promoters, and upregulated their expression. SMZCL restored autophagic flux, as evidenced by elevated absolute levels of LC3-II, enhanced p62 degradation, an upward trend in the LC3-II/I ratio, a concurrent increase in both autophagosome and autolysosome puncta in mCherry-GFP-LC3 dual-fluorescence analysis, and further LC3-II accumulation in the presence of chloroquine. Moreover, SMZCL inhibited the expression of mTOR and phosphorylated mTOR (p-mTOR).
CONCLUSION: SMZCL inhibited DNMT1, leading to demethylation of the ATG5 and Beclin-1 promoters, and concurrently suppressed the mTOR signaling pathway. Through these mechanisms, SMZCL restored autophagic flux, exerted anti-inflammatory effects, and thereby provided protection against AA.