Abstract
Hederacoside C (HSC) has attracted much attention as a novel modulator of inflammation, but its anti-inflammatory mechanism remains elusive. In the present study, we investigated how HSC attenuated intestinal inflammation in vivo and in vitro. HSC injection significantly alleviated TNBS-induced colitis by inhibiting pro-inflammatory cytokine production and colonic epithelial cell apoptosis, and partially restored colonic epithelial cell proliferation. The therapeutic effect of HSC injection was comparable to that of oral administration of mesalazine (200 mg·kg−1·d−1, i.g.). In LPS-stimulated human intestinal epithelial Caco-2 cells, pretreatment with HSC (0.1, 1, 10 μM) significantly inhibited activation of MAPK/NF-κB and its downstream signaling pathways. Pretreatment with HSC prevented LPS-induced TLR4 dimerization and MyD88 recruitment in vitro. Quantitative proteomic analysis revealed that HSC injection regulated 18 proteins in the colon samples, mainly clustered in neutrophil degranulation. Among them, S100A9 involved in the degranulation of neutrophils was one of the most significantly down-regulated proteins. HSC suppressed the expression of S100A9 and its downstream genes including TLR4, MAPK, and NF-κB axes in colon. In Caco-2 cells, recombinant S100A9 protein activated the MAPK/NF-κB signaling pathway and induced inflammation, which were ameliorated by pretreatment with HSC. Notably, HSC attenuated neutrophil recruitment and degranulation as well as S100A9 release in vitro and in vivo. In addition, HSC promoted the expression of tight junction proteins and repaired the epithelial barrier via inhibiting S100A9. Our results verify that HSC ameliorates colitis via restoring impaired intestinal barrier through moderating S100A9/MAPK and neutrophil recruitment inactivation, suggesting that HSC is a promising therapeutic candidate for colitis.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 82073912), Suzhou Science and Technology Plan Project (SYS2019032), and a project funded by Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.
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YLL and QMX designed the research. ZXZ, YL, KXW, and DL conducted the experiments. ZXZ, YL, YLZ, and YLL wrote the manuscript. GQX, QMX, YL, YLZ, and YLL revised the manuscript. All authors read and approved the final manuscript.
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Zha, Zx., Lin, Y., Wang, Kx. et al. Hederacoside C ameliorates colitis via restoring impaired intestinal barrier through moderating S100A9/MAPK and neutrophil recruitment inactivation. Acta Pharmacol Sin 44, 105–119 (2023). https://doi.org/10.1038/s41401-022-00933-3
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DOI: https://doi.org/10.1038/s41401-022-00933-3
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