Enhanced effects of novel oridonin analog CYD0682 for hepatic fibrosis

Fredrick J. Bohanon, Xiaofu Wang, Brittany M. Graham, Chunyong Ding, Ye Ding, Geetha Radhakrishnan, Cristiana Rastellini, Jia Zhou, Ravi Radhakrishnan

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Background Activated hepatic stellate cells (HSCs) are responsible for excess extracellular matrix (ECM) protein deposition in liver fibrosis. Previously, our group reported that the natural compound oridonin induces apoptosis, inhibits cell proliferation, and downregulates ECM proteins in activated HSC. In this study, the antifibrogenic effects of oridonin derivative CYD0682 on the activated human LX-2 and rat HSC-T6 stellate cell lines were investigated. Methods Cell proliferation was measured by alamarBlue assay. Apoptosis was detected by Cell Death ELISA and staining of Yo-Pro-1 and propidium iodide. Cell cycle was determined by flow cytometry. Immunoblot and immunofluorescence staining were performed for cellular protein expression. Results CYD0682 treatment significantly inhibited LX-2 cell proliferation in a dose- and time-dependent manner with an IC50 value of 0.49 μM for 48 h, ∼10-fold greater potency than oridonin. Similar results were observed in HSC-T6 cells. In contrast, 2.5 μM of CYD0682 treatment had no significant effects on proliferation of the human hepatocyte cell line C3A. CYD0682 treatment induced LX-2 cell apoptosis and S-phase cell cycle arrest and was associated with activation of p53, p21, and cleaved caspase-3. The myofibroblast marker protein α-smooth muscle actin and major ECM proteins type I collagen and fibronectin were markedly suppressed in a time- and dose-dependent fashion by CYD0682. Furthermore, pretreatment with CYD0682 blocked transforming growth factor-β–induced type I collagen and fibronectin production. Conclusions In comparison with oridonin, its novel derivative CYD0682 may act as a more potent antihepatic fibrosis agent.

Original languageEnglish (US)
Pages (from-to)441-449
Number of pages9
JournalJournal of Surgical Research
Volume199
Issue number2
DOIs
StatePublished - Dec 1 2015

Keywords

  • Derivatives
  • Fibrosis
  • Liver
  • Oridonin
  • Stellate cells

ASJC Scopus subject areas

  • Surgery
  • Medicine(all)

Fingerprint Dive into the research topics of 'Enhanced effects of novel oridonin analog CYD0682 for hepatic fibrosis'. Together they form a unique fingerprint.

  • Cite this