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5d, a novel analogue of 3-n-butylphthalide, decreases NADPH oxidase activity through the positive regulation of CK2 after ischemia/reperfusion injury.

ABSTRACT: 5d, a novel analogue of the racemic 3-n-butylphthalide (NBP), has been reported for its free radical scavenging activity in vitro and preventive neuroprotection in vivo. Nevertheless, the mechanism by which 5d attenuated ischemia/reperfusion (I/R) injury is still unknown. Our results showed that 5d significantly increased CK2 activity as well as CK2α and 2α' protein levels after I/R injury. Besides, 5d suppressed the translocation of cytosolic p47phox and Rac1 to the membrane, decreased NOX4 expression and ROS generation. Furthermore, 5d blocked the dissociation between CK2α and Rac1 so as to decrease NADPH oxidase activity. Based on these findings, we propose that the neuroprotective effect of 5d is due to an increase of CK2 activity, which blocks I/R-induced dissociation between CK2α and Rac1, decreases NADPH oxidase activity, inhibits ROS production and finally realizes the neuroprotection of I/R. These findings point to that 5d might be considered an attractive candidate for further studies in ischemic stroke.

SUBMITTER: Zhou J

PROVIDER: S-EPMC5129944 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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5d, a novel analogue of 3-n-butylphthalide, decreases NADPH oxidase activity through the positive regulation of CK2 after ischemia/reperfusion injury.

Zhou Jia J Zhang Yi-Hua YH Song Hui-Zhu HZ Ji Hui H Wang Xiao-Li XL Wang Lei L Qian Jun J Ling Jing-Jing JJ Ping Feng-Feng FF

Oncotarget 20160601 26

5d, a novel analogue of the racemic 3-n-butylphthalide (NBP), has been reported for its free radical scavenging activity in vitro and preventive neuroprotection in vivo. Nevertheless, the mechanism by which 5d attenuated ischemia/reperfusion (I/R) injury is still unknown. Our results showed that 5d significantly increased CK2 activity as well as CK2α and 2α' protein levels after I/R injury. Besides, 5d suppressed the translocation of cytosolic p47phox and Rac1 to the membrane, decreased NOX4 exp ...[more]

PMID: 27276705

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Project description:Background & aimsNADPH oxidase 1 (NOX1) has emerged as a prime regulator of intestinal mucosa immunity and homeostasis. Dysregulation of NOX1 may cause inflammatory bowel disease (IBD). It is not clear how NOX1 is regulated in vivo under inflammatory conditions. We studied the role of CK2 in this process.MethodsThe NOX1 organizer subunit, NADPH oxidase organizer 1 (NOXO1), was immunoprecipitated from cytokine-treated colon epithelial cells, and bound proteins were identified by mass spectrometry analysis. Sites on NOXO1 phosphorylated by CK2 were identified by nanoscale liquid chromatography coupled to tandem mass spectrometry. NOX1 activity was determined in colon epithelial cells and colonoids in the presence or absence of CX-4945, a CK2 specific inhibitor. Acute colitis was induced by administration of trinitrobenzenesulfonic acid in mice treated or not with CX-4945. Colon tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and Western blots. CK2 activity, markers of inflammation, and oxidative stress were assessed.ResultsWe identified CK2 as a major partner of NOXO1 in colon epithelial cells under inflammatory conditions. CK2 directly binds NOXO1 at the C-terminus containing the Phox homology domain and phosphorylates NOXO1 on several sites. CX-4945 increased ROS generation by NOX1 in human colon epithelial cells and organoids. Strikingly, CK2 activity was reduced in trinitrobenzenesulfonic acid-induced acute colitis, and CX-4945 exacerbated colitis inflammation as shown by increased levels of CXCL1, ROS generation, lipid peroxidation, and colon damage.ConclusionsThe ubiquitous protein kinase CK2 limits NOX1 activity via NOXO1 binding and phosphorylation in colonic epithelial cells and lessens experimental colitis. Loss of CK2 activity during acute colitis results in excessive ROS production, contributing to the pathogenesis. Strategies to activate CK2 could be an effective novel therapeutic approach in IBD.

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5d, a novel analogue of 3-n-butylphthalide, decreases NADPH oxidase activity through the positive regulation of CK2 after ischemia/reperfusion injury.

Publications

5d, a novel analogue of 3-n-butylphthalide, decreases NADPH oxidase activity through the positive regulation of CK2 after ischemia/reperfusion injury.

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