Flavones hydroxylated at 5, 7, 3' and 4' ameliorate skin fibrosis via inhibiting activin receptor-like kinase 5 kinase activity.

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.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Zhang Y,Wang J,Zhou S,Xie Z,Wang C,Gao Y,Zhou J,Zhang X,Li Q

doi

10.1038/s41419-019-1333-7

subject

Has Abstract

pub_date

2019-02-11 00:00:00

pages

124

issue

2

issn

2041-4889

pii

10.1038/s41419-019-1333-7

journal_volume

10

pub_type

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