Aripiprazole increases NAD(P)H–quinone oxidoreductase-1 and heme oxygenase-1 in PC12 cells
Aripiprazole increases NAD(P)H–quinone oxidoreductase-1 and heme oxygenase-1 in PC12 cells
复制标题
阿立哌唑增加 PC12 细胞中的 NAD(P)H–醌氧化还原酶-1 和血红素加氧酶-1
DOI：
10.1007/s00702-014-1350-8
复制
发表时间：
2015
影响因子：
3.3
通讯作者：
A. Ota
中科院分区：
文献类型：
--
作者：
Y. Kaneko;T. Takayanagi;H. Nagasaki;Y. Kodani;A. Nakashima;K. Mori;A. Suzuki;M. Itoh;Kazunao Kondo;T. Nagatsu;M. Ota;A. Ota
我们先前发现阿立哌唑能增加PC12细胞内NADPH和葡萄糖-6-磷酸脱氢酶基因的表达。阿立哌唑可能激活了一种同时解毒活性氧和补充NADPH的系统。Nrf2是氧化还原稳态基因的主要转录调节因子，也激活磷酸戊糖途径，包括NADPH的产生。因此，我们的目的是确定阿立哌唑是否激活PC12细胞中的Nrf2。阿立哌唑增加Nrf2依赖基因(NAD(P)H-QO1，NQO1；HO-1，谷氨酸-半胱氨酸连接酶催化亚基)的mRNA表达及NQO1和HO1的蛋白表达(P<0.05)。为了保持增加的NRF2活性，有必要抑制NRF2的降解；这是通过使NRF2从Keap1或β-TrCP解离来实现的。然而，在阿立哌唑处理的细胞中，连接到Keap1或β-TrCP上的NRF2的相对数量没有受到影响，细胞核中的NRF2减少(P<0.05)。阿立哌唑不影响Ser40位Nrf2的磷酸化，降低乙酰化Nrf2的相对量(p<0.05)。阿立哌唑处理的细胞中NQO1和HO1的增加不能用典型的Nrf2降解途径来解释。需要进一步的实验来确定阿立哌唑诱导这些酶增加的生化机制。
We previously showed that aripiprazole increases intracellular NADPH and glucose-6-phosphate dehydrogenase mRNA in PC12 cells. Aripiprazole presumably activates a system that concurrently detoxifies reactive oxygen species and replenishes NADPH. Nrf2, a master transcriptional regulator of redox homeostasis genes, also activates the pentose phosphate pathway, including NADPH production. Therefore, our aim was to determine whether aripiprazole activates Nrf2 in PC12 cells. Aripiprazole increased mRNA expression of Nrf2-dependent genes (NAD(P)H–quinone oxidoreductase-1, Nqo1; heme oxygenase-1, HO1; and glutamate-cysteine ligase catalytic subunit) and protein expression of Nqo1 and HO1 in these cells (p < 0.05). To maintain increased Nrf2 activity, it is necessary to inhibit Nrf2 degradation; this is done by causing Nrf2 to dissociate from Keap1 or β-TrCP. However, in aripiprazole-treated cells, the relative amount of Nrf2 anchored to Keap1 or β-TrCP was unaffected and Nrf2 in the nuclear fraction decreased (p < 0.05). Aripiprazole did not affect phosphorylation of Nrf2 at Ser40 and decreased the relative amount of acetylated Nrf2 (p < 0.05). The increase in Nqo1 and HO1 in aripiprazole-treated cells cannot be explained by the canonical Nrf2-degrading pathways. Further experiments are needed to determine the biochemical mechanisms underlying the aripiprazole-induced increase in these enzymes.
登录
查看更多内容
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
NRF2：氧化应激中的INRF2（KEAP1）信号传导。
影响因子：
7.4
作者：
Kaspar, James W.;Niture, Suryakant K.;Jaiswal, Anil K.
通讯作者：
Jaiswal, Anil K.
影响因子：
11.2
作者：
Singh A;Boldin-Adamsky S;Thimmulappa RK;Rath SK;Ashush H;Coulter J;Blackford A;Goodman SN;Bunz F;Watson WH;Gabrielson E;Feinstein E;Biswal S
通讯作者：
Biswal S
DOI：
10.1073/pnas.93.25.14960
发表时间：
1996-12-10
影响因子：
11.1
作者：
Venugopal, R;Jaiswal, AK
通讯作者：
Jaiswal, AK
DOI：
10.1073/pnas.91.21.9926
发表时间：
1994-10-11
影响因子：
11.1
作者：
MOI, P;CHAN, K;KAN, YW
通讯作者：
KAN, YW