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2014 ; 190
(1
): 55-63
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Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis
#MMPMID24742622
Bohanon FJ
; Wang X
; Ding C
; Ding Y
; Radhakrishnan GL
; Rastellini C
; Zhou J
; Radhakrishnan RS
J Surg Res
2014[Jul]; 190
(1
): 55-63
PMID24742622
show ga
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 ? 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 ?1
(TGF-?1) 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 ? smooth muscle actin and ECM protein type I collagen and
fibronectin, blocked TGF-?1-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-?1-induced ECM proteins.
Thus, oridonin may act as a novel agent to prevent hepatic fibrosis.