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

Molecules

Liang-Mou Kuo¹  Chan-Yen Kuo²  Chen-Yu Lin²  Min-Fa Hung²  Jiann-Jong Shen² 

[1] Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; E-Mail:;Graduate Institute of Natural Products, School of Traditional Chinese Medicine, Collage of Medicine, Chang Gung University, Taoyuan 333, Taiwan; E-Mails:

关键词: apoptosis;    glutathione;    hepatic stellate cells;    oridonin;    reactive oxygen species;   

DOI  :  10.3390/molecules19033327

来源: mdpi

【 摘 要 】

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.

【 授权许可】

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© 2014 by the authors; licensee MDPI, Basel, Switzerland.