Molecules 2014, 19(3), 3327-3344; doi:10.3390/molecules19033327
Article

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

Received: 17 February 2014; in revised form: 4 March 2014 / Accepted: 13 March 2014 / Published: 18 March 2014
(This article belongs to the Section Natural Products)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: apoptosis; glutathione; hepatic stellate cells; oridonin; reactive oxygen species
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MDPI and ACS Style

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.

AMA Style

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(3):3327-3344.

Chicago/Turabian Style

Kuo, Liang-Mou; Kuo, Chan-Yen; Lin, Chen-Yu; Hung, Min-Fa; Shen, Jiann-Jong; Hwang, Tsong-Long. 2014. "Intracellular Glutathione Depletion by Oridonin Leads to Apoptosis in Hepatic Stellate Cells." Molecules 19, no. 3: 3327-3344.

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