ReferenceID 2190
Ligustilide attenuates airway remodeling in COPD mice by covalently binding to MH2 domain of Smad3 in pulmonary epithelium, disrupting the Smad3-SARA interaction
Phytother Res
Airway remodeling is one of the hallmarks of chronic obstructive pulmonary disease (COPD) and is closely related to the dysregulation of epithelial-mesenchymal transition (EMT). Smad3, an important transcriptional regula
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Record Fields
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- Reference Id
- 2190
- Evidence Id
- 18780
- Core Evidence Id
- 18780
- Source Reference Id
- 4425
- Herb2 Reference Id
- HBREF005222
- Subject Paper Key
- HBIN033198_36216328
- Pubmed Id
- 36216328
- Doi
- 10.1002/ptr.7655
- Paper Title
- Ligustilide attenuates airway remodeling in COPD mice by covalently binding to MH2 domain of Smad3 in pulmonary epithelium, disrupting the Smad3-SARA interaction
- Paper Abstract
- Airway remodeling is one of the hallmarks of chronic obstructive pulmonary disease (COPD) and is closely related to the dysregulation of epithelial-mesenchymal transition (EMT). Smad3, an important transcriptional regulator responsible for transducing TGF-β1 signals, is a promising target for EMT modulation. We found that ligustilide (Lig), a novel Smad3 covalent inhibitor, effectively inhibited airway remodeling in cigarette smoke (CS) combined with lipopolysaccharide (LPS)-induced COPD mice. Oral administration of an alkynyl-modified Lig probe was used to capture and trace target proteins in mouse lung tissue, revealing Smad3 in airway epithelium as a key target of Lig. Protein mass spectrometry and Smad3 mutation analysis via in-gel imaging indicated that the epoxidized metabolite of Lig covalently binds to the MH2 domain of Smad3 at Cys331/337. This irreversible bonding destroys the interaction of Smad3-SARA, prevents Smad3 phosphorylation activation, and subsequently suppresses the nuclear transfer of p-Smad3, the EMT process, and collagen deposition in TGF-β1-stimulated BEAS-2B cells and COPD mice. These findings provide experimental support that Lig attenuates COPD by repressing airway remodeling which is attributed to its suppression on the activation of EMT process in the airway epithelium via targeting Smad3 and inhibiting the recruitment of the Smad3-SARA heterodimer in the TGF-β1/Smad3 pathway.
- Journal
- Phytother Res
- Publish Year
- 2022
- Experiment Subject
- mouse; tgf-β1-stimulated beas-2b cells
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Chronic Obstructive Pulmonary Disease
- Paper Title Cn
- Paper Title En
- Ligustilide attenuates airway remodeling in COPD mice by covalently binding to MH2 domain of Smad3 in pulmonary epithelium, disrupting the Smad3-SARA interaction
- Bilingual Status
- semi_complete