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Intracellular Glutathione Depletion by Oridonin Leads to Apoptosis in Hepatic Stellate Cells

1
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
2
Department of General Surgery, Chang Gung Memorial Hospital at Chia-Yi 613, Taiwan
3
Graduate Institute of Natural Products, School of Traditional Chinese Medicine, Collage of Medicine, Chang Gung University, Taoyuan 333, Taiwan
4
Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan 333, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2014, 19(3), 3327-3344; https://doi.org/10.3390/molecules19033327
Received: 17 February 2014 / Revised: 4 March 2014 / Accepted: 13 March 2014 / Published: 18 March 2014
(This article belongs to the Section Natural Products Chemistry)
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. View Full-Text
Keywords: apoptosis; glutathione; hepatic stellate cells; oridonin; reactive oxygen species apoptosis; glutathione; hepatic stellate cells; oridonin; reactive oxygen species
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Kuo, L.-M.; Kuo, C.-Y.; Lin, C.-Y.; Hung, M.-F.; Shen, J.-J.; Hwang, T.-L. Intracellular Glutathione Depletion by Oridonin Leads to Apoptosis in Hepatic Stellate Cells. Molecules 2014, 19, 3327-3344.

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