Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis

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

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Background Liver fibrosis is a common response to liver injury and, in severe cases, leads to cirrhosis. The hepatic stellate cells (HSCs) become activated after liver injury and play a significant role in fibrogenesis. The activated HSC is characterized by increased proliferation, overexpression of α smooth muscle actin, and excessive production of extracellular matrix (ECM) proteins. Oridonin, a naturally occurring diterpenoid, has been shown to induce apoptosis in liver and gastric cancer cells. However, its effects on the HSC are unknown. Methods We tested the effects of oridonin on the activated human and rat HSC lines LX-2 and HSC-T6, and the human hepatocyte cell line C3A. Transforming growth factor β1 (TGF-β1) was used to stimulate LX-2 cells. Results Oridonin significantly inhibited LX-2 and HSC-T6 proliferation. In contrast, oridonin had no antiproliferative effect on C3A cells at our tested range. Oridonin induced apoptosis and S-phase arrest in LX-2 cells. These findings were associated with an increase in p53, p21, p16, and cleaved Poly (ADP-ribose) Polymerase (PARP), and with a decrease in Cyclin-dependent kinase 4 (Cdk4). Oridonin markedly decreased expression of α smooth muscle actin and ECM protein type I collagen and fibronectin, blocked TGF-β1-induced Smad2/3 phosphorylation and type I collagen expression. Conclusions Oridonin induces apoptosis and cell cycle arrest involving the p53-p21 pathway in HSC and appears to be nontoxic to hepatocytes. In addition, oridonin suppressed endogenous and TGF-β1-induced ECM proteins. Thus, oridonin may act as a novel agent to prevent hepatic fibrosis.

Original languageEnglish (US)
Pages (from-to)55-63
Number of pages9
JournalJournal of Surgical Research
Volume190
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Hepatic Stellate Cells
Cell Proliferation
Extracellular Matrix Proteins
Transforming Growth Factors
Apoptosis
Collagen Type I
Smooth Muscle
Actins
Hepatocytes
Liver
Fibrosis
Cyclin-Dependent Kinase 4
oridonin
Cell Line
Poly(ADP-ribose) Polymerases
Diterpenes
Wounds and Injuries
Liver Neoplasms
Cell Cycle Checkpoints
S Phase

Keywords

  • Apoptosis
  • Liver fibrosis
  • Oridonin
  • Stellate cells

ASJC Scopus subject areas

  • Surgery

Cite this

Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis. / Bohanon, Fredrick J.; Wang, Xiaofu; Ding, Chunyong; Ding, Ye; Radhakrishnan, Geetha; Rastellini, Cristiana; Zhou, Jia; Radhakrishnan, Ravi.

In: Journal of Surgical Research, Vol. 190, No. 1, 2014, p. 55-63.

Research output: Contribution to journalArticle

Bohanon, Fredrick J. ; Wang, Xiaofu ; Ding, Chunyong ; Ding, Ye ; Radhakrishnan, Geetha ; Rastellini, Cristiana ; Zhou, Jia ; Radhakrishnan, Ravi. / Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis. In: Journal of Surgical Research. 2014 ; Vol. 190, No. 1. pp. 55-63.
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abstract = "Background Liver fibrosis is a common response to liver injury and, in severe cases, leads to cirrhosis. The hepatic stellate cells (HSCs) become activated after liver injury and play a significant role in fibrogenesis. The activated HSC is characterized by increased proliferation, overexpression of α smooth muscle actin, and excessive production of extracellular matrix (ECM) proteins. Oridonin, a naturally occurring diterpenoid, has been shown to induce apoptosis in liver and gastric cancer cells. However, its effects on the HSC are unknown. Methods We tested the effects of oridonin on the activated human and rat HSC lines LX-2 and HSC-T6, and the human hepatocyte cell line C3A. Transforming growth factor β1 (TGF-β1) was used to stimulate LX-2 cells. Results Oridonin significantly inhibited LX-2 and HSC-T6 proliferation. In contrast, oridonin had no antiproliferative effect on C3A cells at our tested range. Oridonin induced apoptosis and S-phase arrest in LX-2 cells. These findings were associated with an increase in p53, p21, p16, and cleaved Poly (ADP-ribose) Polymerase (PARP), and with a decrease in Cyclin-dependent kinase 4 (Cdk4). Oridonin markedly decreased expression of α smooth muscle actin and ECM protein type I collagen and fibronectin, blocked TGF-β1-induced Smad2/3 phosphorylation and type I collagen expression. Conclusions Oridonin induces apoptosis and cell cycle arrest involving the p53-p21 pathway in HSC and appears to be nontoxic to hepatocytes. In addition, oridonin suppressed endogenous and TGF-β1-induced ECM proteins. Thus, oridonin may act as a novel agent to prevent hepatic fibrosis.",
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T1 - Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis

AU - Bohanon, Fredrick J.

AU - Wang, Xiaofu

AU - Ding, Chunyong

AU - Ding, Ye

AU - Radhakrishnan, Geetha

AU - Rastellini, Cristiana

AU - Zhou, Jia

AU - Radhakrishnan, Ravi

PY - 2014

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N2 - Background Liver fibrosis is a common response to liver injury and, in severe cases, leads to cirrhosis. The hepatic stellate cells (HSCs) become activated after liver injury and play a significant role in fibrogenesis. The activated HSC is characterized by increased proliferation, overexpression of α smooth muscle actin, and excessive production of extracellular matrix (ECM) proteins. Oridonin, a naturally occurring diterpenoid, has been shown to induce apoptosis in liver and gastric cancer cells. However, its effects on the HSC are unknown. Methods We tested the effects of oridonin on the activated human and rat HSC lines LX-2 and HSC-T6, and the human hepatocyte cell line C3A. Transforming growth factor β1 (TGF-β1) was used to stimulate LX-2 cells. Results Oridonin significantly inhibited LX-2 and HSC-T6 proliferation. In contrast, oridonin had no antiproliferative effect on C3A cells at our tested range. Oridonin induced apoptosis and S-phase arrest in LX-2 cells. These findings were associated with an increase in p53, p21, p16, and cleaved Poly (ADP-ribose) Polymerase (PARP), and with a decrease in Cyclin-dependent kinase 4 (Cdk4). Oridonin markedly decreased expression of α smooth muscle actin and ECM protein type I collagen and fibronectin, blocked TGF-β1-induced Smad2/3 phosphorylation and type I collagen expression. Conclusions Oridonin induces apoptosis and cell cycle arrest involving the p53-p21 pathway in HSC and appears to be nontoxic to hepatocytes. In addition, oridonin suppressed endogenous and TGF-β1-induced ECM proteins. Thus, oridonin may act as a novel agent to prevent hepatic fibrosis.

AB - Background Liver fibrosis is a common response to liver injury and, in severe cases, leads to cirrhosis. The hepatic stellate cells (HSCs) become activated after liver injury and play a significant role in fibrogenesis. The activated HSC is characterized by increased proliferation, overexpression of α smooth muscle actin, and excessive production of extracellular matrix (ECM) proteins. Oridonin, a naturally occurring diterpenoid, has been shown to induce apoptosis in liver and gastric cancer cells. However, its effects on the HSC are unknown. Methods We tested the effects of oridonin on the activated human and rat HSC lines LX-2 and HSC-T6, and the human hepatocyte cell line C3A. Transforming growth factor β1 (TGF-β1) was used to stimulate LX-2 cells. Results Oridonin significantly inhibited LX-2 and HSC-T6 proliferation. In contrast, oridonin had no antiproliferative effect on C3A cells at our tested range. Oridonin induced apoptosis and S-phase arrest in LX-2 cells. These findings were associated with an increase in p53, p21, p16, and cleaved Poly (ADP-ribose) Polymerase (PARP), and with a decrease in Cyclin-dependent kinase 4 (Cdk4). Oridonin markedly decreased expression of α smooth muscle actin and ECM protein type I collagen and fibronectin, blocked TGF-β1-induced Smad2/3 phosphorylation and type I collagen expression. Conclusions Oridonin induces apoptosis and cell cycle arrest involving the p53-p21 pathway in HSC and appears to be nontoxic to hepatocytes. In addition, oridonin suppressed endogenous and TGF-β1-induced ECM proteins. Thus, oridonin may act as a novel agent to prevent hepatic fibrosis.

KW - Apoptosis

KW - Liver fibrosis

KW - Oridonin

KW - Stellate cells

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