Abstract
Proliferation of hepatic stellate cells (HSCs) plays a key role in the pathogenesis of liver fibrosis. Induction of HSC apoptosis by natural products is considered an effective strategy for treating liver fibrosis. Herein, the apoptotic effects of 7,20-epoxy-ent-kaurane (oridonin), a diterpenoid isolated from Rabdosia rubescens, and its underlying mechanisms were investigated in rat HSC cell line, HSC-T6. We found that oridonin inhibited cell viability of HSC-T6 in a concentration-dependent manner. Oridonin induced a reduction in mitochondrial membrane potential and increases in caspase 3 activation, subG1 phase, and DNA fragmentation. These apoptotic effects of oridonin were completely reversed by thiol antioxidants, N-acetylcysteine (NAC) and glutathione monoethyl ester. Moreover, oridonin increased production of reactive oxygen species (ROS), which was also inhibited by NAC. Significantly, oridonin reduced intracellular glutathione (GSH) level in a concentration- and time-dependent fashion. Additionally, oridonin induced phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). NAC prevented the activation of MAPKs in oridonin-induced cells. However, selective inhibitors of MAPKs failed to alter oridonin-induced cell death. In summary, these results demonstrate that induction of apoptosis in HSC-T6 by oridonin is associated with a decrease in cellular GSH level and increase in ROS production.
Highlights
Liver fibrosis is a common wound-healing response to various forms of chronic stimuli to the liver
Activation of caspase 3 is a fundamental role in the apoptotic responses. These results suggest that oridonin stimulates apoptosis in hepatic stellate cells (HSCs)-T6 through caspase 3-dependent pathway
Collagen, and fibronectin in LX-2 cells, an activated human HSCs. These findings demonstrate that oridonin may have potential to treat liver fibrosis
Summary
Liver fibrosis is a common wound-healing response to various forms of chronic stimuli to the liver. The major cellular process of liver fibrosis is proliferation and activation of hepatic stellate cells (HSCs) [1,2,3]. During the pathogenesis of liver fibrosis, activated HSCs overproduce extracellular matrix proteins and pro-inflammatory growth factors [1,3]. Increasing evidence indicates that decrease in number of activated HSCs by inhibiting proliferation or induction of apoptosis in HSCs can be a useful therapeutic strategy for liver fibrosis [4]. Herbal natural products exhibit potential roles in preventing or treating liver fibrosis [5]. Studying the action mechanisms of potential natural compounds is important in developing better remedial strategies for liver disorders
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