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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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.

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Most cited references 28

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One-thousand-and-one substrates of protein kinase CK2?

Flavio Meggio, Lorenzo Pinna, Frank Rozsa (2003)

CK2 (formerly termed "casein kinase 2") is a ubiquitous, highly pleiotropic and constitutively active Ser/Thr protein kinase whose implication in neoplasia, cell survival, and virus infection is supported by an increasing number of arguments. Here an updated inventory of 307 CK2 protein substrates is presented. More than one-third of these are implicated in gene expression and protein synthesis as being either transcriptional factors (60) or effectors of DNA/RNA structure (50) or translational elements. Also numerous are signaling proteins and proteins of viral origin or essential to virus life cycle. In comparison, only a minority of CK2 targets (a dozen or so) are classical metabolic enzymes. An analysis of 308 sites phosphorylated by CK2 highlights the paramount relevance of negatively charged side chains that are (by far) predominant over any other residues at positions n+3 (the most crucial one), n+1, and n+2. Based on this signature, it is predictable that proteins phosphorylated by CK2 are much more numerous than those identified to date, and it is possible that CK2 alone contributes to the generation of the eukaryotic phosphoproteome more so than any other individual protein kinase. The possibility that CK2 phosphosites play some global role, e.g., by destabilizing alpha helices, counteracting caspase cleavage, and generating adhesive motifs, will be discussed.

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Protein kinase CK2: a challenge to canons.

Lorenzo Pinna (2002)

CK2 is an extremely conserved pleiotropic protein kinase with a growing list of more than 300 substrates, the majority of which are proteins implicated in signal transduction, gene expression and other nuclear functions. The CK2 phosphoacceptor sites are specified by multiple acidic residues, with the one at position +3 relative to the target residue being of crucial relevance. The CK2 holoenzyme is composed of two catalytic subunits (alphaalpha, alpha'alpha' or alphaalpha'), which are essential for cell viability, and a dimer of two non-catalytic beta subunits, whose precise function is still poorly understood. Although the beta subunits deeply affect many properties of CK2, both the isolated catalytic subunits and the holoenzyme are constitutively active, which is probably responsible for the oncogenic potential of CK2. Given the structure of the holoenzyme, the beta subunits could undergo reversible dissociation under physiological conditions and play a role as anchoring elements and/or as a docking platform for protein substrates and effectors. These unusual features are likely to be instrumental in the involvement of CK2 in a number of key biological functions, notably RNA synthesis, Wnt signaling, ubiquitination and cell survival.

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Traumatic Brain Injury and NADPH Oxidase: A Deep Relationship

Cristina Angeloni, Cecilia Prata, Francesco Vieceli Dalla Sega … (2015)

Traumatic brain injury (TBI) represents one of the major causes of mortality and disability in the world. TBI is characterized by primary damage resulting from the mechanical forces applied to the head as a direct result of the trauma and by the subsequent secondary injury due to a complex cascade of biochemical events that eventually lead to neuronal cell death. Oxidative stress plays a pivotal role in the genesis of the delayed harmful effects contributing to permanent damage. NADPH oxidases (Nox), ubiquitary membrane multisubunit enzymes whose unique function is the production of reactive oxygen species (ROS), have been shown to be a major source of ROS in the brain and to be involved in several neurological diseases. Emerging evidence demonstrates that Nox is upregulated after TBI, suggesting Nox critical role in the onset and development of this pathology. In this review, we summarize the current evidence about the role of Nox enzymes in the pathophysiology of TBI.

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Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 28 June 2016

Publication date (Electronic): 12 May 2016

Volume: 7

Issue: 26

Pages: 39444-39457

Affiliations

¹ School of Pharmaceutical Science, Jiangnan University, Wuxi, P.R. China

² State Key Laboratory of Natural Medicines, Center of Drug discovery, China Pharmaceutical University, Nanjing, P.R. China

³ Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, P.R. China

Author notes

Correspondence to: Jing-jing Ling, lingjingjing77@ 123456163.com

Feng-feng Ping, pfftile@ 123456163.com

Article

Publisher ID: 8548

DOI: 10.18632/oncotarget.8548

PMC ID: 5129944

PubMed ID: 27276705

SO-VID: edea87cf-9de5-45b0-a94e-b9c7474d3212

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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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Karger: Oncology

Most cited references 28

One-thousand-and-one substrates of protein kinase CK2?

Protein kinase CK2: a challenge to canons.

Traumatic Brain Injury and NADPH Oxidase: A Deep Relationship

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