Hesperetin, a
flavonoid from citrus fruits, possess various pharmacological properties, including anti-inflammatory, anti-oxidative, anti-
tumor potentials. However, the role and its mechanism in
ulcerative colitis (UC) remains unclear. This study aimed to investigate the protective effects and mechanisms of
hesperetin on
dextran sodium sulfate (DSS) -induced
colitis. Our results showed that
hesperetin significantly relieved the symptoms of DSS -induced
colitis and increased the expressions of zonula occludens-1 (ZO-1),
occludin and mucin2 (MUC-2) as well as the decrease of
tumor necrosis factor-α (TNF-α),
interleukin (IL)-1β,
IL-18,
HMGB1 and
IL-6. Of note, results from immunohistochemistry (IHC) and western blotting indicated that
hesperetin inhibited the expressions of receptor-interacting
protein kinase 3 (RIPK3) and mixed lineage
kinase domain-like (MLKL), the two key
proteins of necroptosis pathway, and inactivated RIPK3/MLKL necroptosis signalling. Meanwhile, in the cell-coculture system between Caco-2 and RAW264.7 cells,
hesperetin treatment significantly ameliorated the decrease of trans epithelial electric resistance (TEER) value while
HS-173 (necroptosis inducer) could obviously influence the effect of
hesperetin. In addition,
hesperetin attenuated the LPS-induced increasing in 4-kDa
fluorescein isothiocyanate-dextran (FD4) permeability while
HS-173 could weaken the protective effect of
hesperetin. Meanwhile,
HS-173 reduced the changes in the expressions of phosphorylated RIPK3, phosphorylated MLKL, ZO-1,
occludin and MUC-2 as well as TNF-α, IL-1β. These findings demonstrated
hesperetin ameliorated DSS-induced
colitis by maintaining the epithelial barrier via blocking the intestinal epithelial necroptosis.