Antifibrosis effect of novel oridonin analog CYD0618 via suppression of the NF-κB pathway

Claire B. Cummins, Xiaofu Wang, Jimin Xu, Byron D. Hughes, Ye Ding, Haiying Chen, Jia Zhou, Ravi S. Radhakrishnan

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: Liver fibrosis is characterized as excessive deposition of the extracellular matrix proteins, primarily by activated hepatic stellate cells (HSCs). NF-κB has been reported as one of the major mediators of HSC activation. Previously, our team reported that oridonin exhibited antihepatic fibrogenetic activity in vitro. In this study, we examined the effects of its novel derivative CYD0618 on HSC viability, apoptosis, and NF-κB signaling. Methods: Cell proliferation of activated human and rat HSC lines LX-2 and HSC-T6 was measured using Alamar Blue Assay. Apoptosis was measured by a Cell Death Detection ELISA kit. Cellular proteins were determined by Western blots and immunofluorescence. Results: CYD0618 significantly inhibited LX-2 and HSC-T6 cell proliferation in a dose-dependent manner. CYD0618 induced cell apoptosis in both cell lines. CYD0618 treatment increased cell cycle inhibitory protein p21, p27, and induced apoptosis marker cleaved poly (ADP-ribose) polymerase, while suppressing the expression of Collagen type 1. CYD0618 blocked lipopolysaccharide (LPS)-induced NF-κB p65 nuclear translocation and DNA binding activity and prevented LPS-induced NF-κB inhibitory protein IκBα phosphorylation and degradation. LPS-stimulated NF-κB downstream target cytokines IL-6 and MCP-1 were attenuated by CYD0618. Endogenous and LPS-stimulated NF-κB p65 S536 phosphorylation was inhibited by CYD0618 treatment. Conclusions: The potent antihepatic fibrogenetic effect of CYD0618 may be mediated via suppression of the NF-κB pathway.

Original languageEnglish (US)
Pages (from-to)283-292
Number of pages10
JournalJournal of Surgical Research
Volume232
DOIs
StatePublished - Dec 1 2018

Keywords

  • Hepatic stellate cells
  • Liver fibrosis
  • NF-κB pathway
  • Oridonin
  • Therapeutics

ASJC Scopus subject areas

  • Surgery

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