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Flavones hydroxylated at 5, 7, 3′ and 4′ ameliorate skin fibrosis via inhibiting activin receptor-like kinase 5 kinase activity
- Source :
- Cell Death and Disease, Vol 10, Iss 2, Pp 1-13 (2019), Cell Death & Disease
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group, 2019.
-
Abstract
- Skin fibrosis is mainly characterized by excessive collagen deposition. Studies have recently identified a number of flavonoids with variable structures that have the potency of inhibiting collagen synthesis and thus attenuating organ fibrosis. In this study, we found that flavones with 5, 7, 3′, 4′ hydroxy substitution reduced collagen expression most efficiently. Among those flavones, luteolin, quercetin, and myricetin were selected for follow-up. In vivo, the three compounds ameliorated skin fibrosis and reduced collagen deposition. Further analysis showed the compounds had significant inhibition on the proliferation, activation and contractile ability of dermal fibroblasts in vitro and in vivo. More importantly, we revealed that luteolin, quercetin, and myricetin selectively downregulated the phosphorylation of Smad2/3 in TGF-β/Smads signaling via binding to activin receptor-like kinase 5 (ALK5) and impairing its catalytic activity. We also found flavones with 5, 7, 3′, 4′ hydroxy substitution showed stronger affinity with ALK5 compared with other flavonoids. Herein, we identified at least in part the underlying molecular basis as well as the critical structures that contribute to the antifibrotic bioactivity of flavones, which might benefit drug design and modification.
- Subjects :
- 0301 basic medicine
Cancer Research
Immunology
Receptor, Transforming Growth Factor-beta Type I
Smad2 Protein
Molecular Dynamics Simulation
Pharmacology
Hydroxylation
Flavones
Article
Cicatrix
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
0302 clinical medicine
In vivo
Fibrosis
Catalytic Domain
medicine
Animals
Humans
Smad3 Protein
Phosphorylation
Kinase activity
lcsh:QH573-671
Cell Proliferation
Skin
chemistry.chemical_classification
Mice, Inbred BALB C
Binding Sites
Kinase
lcsh:Cytology
Cell Biology
Fibroblasts
medicine.disease
030104 developmental biology
chemistry
030220 oncology & carcinogenesis
Female
Myricetin
Collagen
Quercetin
Luteolin
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 10
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cell Death and Disease
- Accession number :
- edsair.doi.dedup.....ddee0927064b8657c4b289045be168e6