TY - JOUR
T1 - 3′,4′-Didemethylnobiletin induces phase II detoxification gene expression and modulates PI3K/Akt signaling in PC12 cells
AU - Su, Jeng Dian
AU - Yen, Jui Hung
AU - Li, Shiming
AU - Weng, Ching Yi
AU - Lin, Meng Han
AU - Ho, Chi Tang
AU - Wu, Ming Jiuan
N1 - Funding Information:
We are grateful to the Center of Biotechnology Development of Chia-Nan University of Pharmacy and Science for providing flow cytometry service. This study was supported by Grant NSC-99-2320-B-041-005-MY3 from the National Science Council, Taiwan.
PY - 2012/1/1
Y1 - 2012/1/1
N2 - 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 2O 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 2O 2-treated cells, induced heme 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-κB activation, and addition of NF-κB inhibitor, pyrrolidine dithiocarbamate or Bay 11-7082, synergistically enhanced DTF-mediated HO-1 expression, indicating that HO-1 induction is associated with NF-κB suppression. NOB and DTF also activated the ERK, JNK, 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.
AB - 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 2O 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 2O 2-treated cells, induced heme 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-κB activation, and addition of NF-κB inhibitor, pyrrolidine dithiocarbamate or Bay 11-7082, synergistically enhanced DTF-mediated HO-1 expression, indicating that HO-1 induction is associated with NF-κB suppression. NOB and DTF also activated the ERK, JNK, 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.
KW - 3′,4′-Didemethylnobiletin
KW - Free radicals
KW - GCL
KW - HO-1
KW - NF-κB
KW - Nobiletin
KW - PI3K/Akt
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U2 - 10.1016/j.freeradbiomed.2011.10.002
DO - 10.1016/j.freeradbiomed.2011.10.002
M3 - Article
C2 - 22064360
AN - SCOPUS:84655167653
VL - 52
SP - 126
EP - 141
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
IS - 1
ER -