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Butin (7,3′,4′-Trihydroxydihydroflavone) Reduces Oxidative Stress-Induced Cell Death via Inhibition of the Mitochondria-Dependent Apoptotic Pathway
School of Medicine and Applied Radiological Science Research Institute, Jeju National University, Jeju-si 690-756, Korea
Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
Aging Research Center, Korea Institute of Oriental Medicine, Daejeon 305–811, Korea
Department of Neuroscience, College of Medicine, Ewha Womans University, Seoul 110-783, Korea
These authors contributed equally to this study.
* Author to whom correspondence should be addressed.
Received: 7 April 2011; in revised form: 16 May 2011 / Accepted: 31 May 2011 / Published: 10 June 2011
Abstract: Recently, we demonstrated that butin (7,3′,4′-trihydroxydihydroflavone) protected cells against hydrogen peroxide (H2O2)-induced apoptosis by: (1) scavenging reactive oxygen species (ROS), activating antioxidant enzymes such superoxide dismutase and catalase; (2) decreasing oxidative stress-induced 8-hydroxy-2'-deoxyguanosine levels via activation of oxoguanine glycosylase 1, and (3), reducing oxidative stress-induced mitochondrial dysfunction. The objective of this study was to determine the cytoprotective effects of butin on oxidative stress-induced mitochondria-dependent apoptosis, and possible mechanisms involved. Butin significantly reduced H2O2-induced loss of mitochondrial membrane potential as determined by confocal image analysis and flow cytometry, alterations in Bcl-2 family proteins such as decrease in Bcl-2 expression and increase in Bax and phospho Bcl-2 expression, release of cytochrome c from mitochondria into the cytosol and activation of caspases 9 and 3. Furthermore, the anti-apoptotic effect of butin was exerted via inhibition of mitogen-activated protein kinase kinase-4, c-Jun NH2-terminal kinase (JNK) and activator protein-1 cascades induced by H2O2 treatment. Finally, butin exhibited protective effects against H2O2-induced apoptosis, as demonstrated by decreased apoptotic bodies, sub-G1 hypodiploid cells and DNA fragmentation. Taken together, the protective effects of butin against H2O2-induced apoptosis were exerted via blockade of membrane potential depolarization, inhibition of the JNK pathway and mitochondria-involved caspase-dependent apoptotic pathway
Keywords: butin; oxidative stress; mitochondria-dependent apoptotic pathway
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Zhang, R.; Lee, I.K.; Piao, M.J.; Kim, K.C.; Kim, A.D.; Kim, H.S.; Chae, S.; Kim, H.S.; Hyun, J.W. Butin (7,3′,4′-Trihydroxydihydroflavone) Reduces Oxidative Stress-Induced Cell Death via Inhibition of the Mitochondria-Dependent Apoptotic Pathway. Int. J. Mol. Sci. 2011, 12, 3871-3887.
Zhang R, Lee IK, Piao MJ, Kim KC, Kim AD, Kim HS, Chae S, Kim HS, Hyun JW. Butin (7,3′,4′-Trihydroxydihydroflavone) Reduces Oxidative Stress-Induced Cell Death via Inhibition of the Mitochondria-Dependent Apoptotic Pathway. International Journal of Molecular Sciences. 2011; 12(6):3871-3887.
Zhang, Rui; Lee, In Kyung; Piao, Mei Jing; Kim, Ki Cheon; Kim, Areum Daseul; Kim, Hye Sun; Chae, Sungwook; Kim, Hee Sun; Hyun, Jin Won. 2011. "Butin (7,3′,4′-Trihydroxydihydroflavone) Reduces Oxidative Stress-Induced Cell Death via Inhibition of the Mitochondria-Dependent Apoptotic Pathway." Int. J. Mol. Sci. 12, no. 6: 3871-3887.