3 ',4 '-Didemethylnobiletin induces phase II detoxification gene expression and modulates PI3K/Akt signaling in PC12 cells

doi:10.1016/j.freeradbiomed.2011.10.002

Chia Nan University of Pharmacy & Science Institutional Repository > 藥理學院 > 生物科技系(所) > 期刊論文 > Item 310902800/27725

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標題:	3 ',4 '-Didemethylnobiletin induces phase II detoxification gene expression and modulates PI3K/Akt signaling in PC12 cells
作者:	Su, Jeng-Dian Yen, Jui-Hung Li, Shiming Weng, Ching-Yi Lin, Meng-Han Ho, Chi-Tang Wu, Ming-Jiuan
貢獻者:	生物科技系
關鍵字:	Nobiletin 3 ',4 '-Didemethylnobiletin Gcl Ho-1 Nf-Kappa B Pi3K/Akt Free Radicals
日期:	2012
上傳時間:	2014-03-24 15:22:53 (UTC+8)
出版者:	Elsevier Science Inc
摘要:	Oxidative stress is considered a major cause of neurodegenerative disorders. In this work, we investigated the cytoprotective effects and mechanisms of the citrus flavonoid nobiletin (NOB) and its metabolite, 3',4'didemethylnobiletin (3',4'-dihydroxy-5,6,7,8-tetramethoxyflavone; DTF), in PC12 cells. Both NOB and DTF exhibited strong potency in attenuating serum withdrawal- and H(2)O(2)-caused cell death and increased intracellular GSH level via upregulation of both catalytic and modifier subunits of glutamate-cysteine ligase (GCL). However, only DTF suppressed intracellular ROS accumulation in H(2)O(2)-treated cells, induced home oxygenase-1 (HO-1) expression, and enhanced nuclear factor E2-related factor 2 (Nrf2) binding to the ARE. Nevertheless, DTF-mediated HO-1 upregulation was independent of Nrf2 activation because knockdown of Nrf2 expression by siRNA did not affect its expression. DTF suppressed NF-kappa B activation, and addition of NF-kappa B inhibitor, pyrrolidine dithiocarbamate or Bay 11-7082, synergistically enhanced DTF-mediated HO-1 expression, indicating that HO-1 induction is associated with NF-kappa B suppression. NOB and DTF also activated the ERK, JNIK, and Akt pathways in PC12 cells that had undergone serum starvation. Addition of pharmacological kinase inhibitors, U0126, SP600125, and LY294002, caused cytotoxicity and the last significantly attenuated NOB- and DTF-mediated antiapoptotic actions, indicating the involvement of PI3K/Akt signaling in their cytoprotective effects. In conclusion, HO-1 and GCL upregulation and intrinsic ROS-scavenging activity may contribute to DTF-mediated cytoprotection. Furthermore, modulation of PI3K/Akt signaling is involved in channeling the DTF stimulus for cell survival against oxidative insults. 2011 Elsevier Inc. All rights reserved.
關聯:	Free Radical Biology And Medicine, 52(1), 126-141
显示于类别:	[生物科技系(所)] 期刊論文

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