@article{APS5956,
author = {Ling-ling Xuan and Ji Shi and Chun-suo Yao and Jin-ye Bai and Feng Qu and Jin-lan Zhang and Qi Hou},
title = {Vam3, a resveratrol dimer, inhibits cigarette smoke-induced cell apoptosis in lungs by improving mitochondrial function},
journal = {Acta Pharmacologica Sinica},
volume = {35},
number = {6},
year = {2016},
keywords = {},
abstract = {Ling-ling XUAN1, Ji SHI1, 2, Chun-suo YAO1, Jin-ye BAI1, Feng QU1, Jin-lan ZHANG1, Qi HOU1, *
1State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; 2Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Molecular Nuclear Medicine, Tianjin 300192, China
Aim: To investigate the effects of Vam3 (a resveratrol dimer extracted from Vitis amurensis Rupr) on cigarette smoke (CS)-induced cell apoptosis in lungs in vitro and in vivo and the underlying mechanisms of action.
Methods: Human bronchial epithelial cell line BEAS-2B was exposed to cigarette smoke condensate (CSC, 300 mg/L), and cell apoptosis was determined using flow cytometry and Hoechst staining. Mitochondrial membrane potential was examined with TMRE staining. ROS and ceramide levels were detected with DCFH-DA fluorescence and HPLC-MS/MS, respectively. Cytochrome c release was detected using immunofluorescence. Caspase-9 and neutral sphingomyelinase 2 expression was measured with Western blotting. The breast carcinoma cell line MCF7 stably expressing GFP-tagged Bax was used to elucidate the role of mitochondria in CS-induced apoptosis. For in vivo study, male mice were exposed to CS for 5 min twice a day for 4 weeks. The mice were orally administered Vam3 (50 mg·kg-1·d-1) or resveratrol (30 mg·kg-1·d-1) each day 1 h before the first CS exposure.
Results: Pretreatment of BEAS-2B cells with Vam3 (5 μmol/L) or resveratrol (5 μmol/L) significantly suppressed CSC-induced apoptosis, and prevented CSC-induced Bax level increase in the mitochondria, mitochondrial membrane potential loss, cytochrome c release and caspase-9 activation. Furthermore, pretreatment of BEAS-2B cells with Vam3 or resveratrol significantly suppressed CSC-stimulated intracellular ceramide production, and CSC-induced upregulation of neutral sphingomyelinase 2, the enzyme responsible for ceramide production in bronchial epithelial cells. Similar results were obtained in C6-pyridinium ceramide-induced apoptosis of GFP-Bax-stable MCF7 cells in vitro, and in the lungs of CS-exposed mice that were treated with oral administration of Vam3 or resveratrol.
Conclusion: Vam3 protects bronchial epithelial cells from CS-induced apoptosis in vitro and in vivo by preventing mitochondrial dysfunction.
Keywords: Vam3; resveratrol; lung; bronchial epithelial cell; cigarette smoking; apoptosis; Bax; mitochondria; ceramide; sphingomyelinase
This work was supported by grants from the National Twelfth-Five Year Research Program of China (No 37007 and 37008).
* To whom correspondence should be addressed.
E-mail houq@imm.ac.cn
Received 2013-11-5 Accepted 2014-02-20},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/5956}
}