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The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant.

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posted on 2018-04-05, 15:41 authored by S. M. H Chan, Mark. P Lowe, A Bernard, A. A Miller, T. P Herbert
Inositol-requiring enzyme 1 alpha (IRE1α) is an endoplasmic reticulum (ER)-transmembrane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). Chronic activation of the UPR has been implicated in the pathogenesis of many common diseases including diabetes, cancer, and neurological pathologies such as Huntington's and Alzheimer's disease. 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4µ8C) is widely used as a specific inhibitor of IRE1α ribonuclease activity (IC50of 6.89 µM in cultured cells). However, in this paper, we demonstrate that 4µ8C acts as a potent reactive oxygen species (ROS) scavenger, both in a cell-free assay and in cultured cells, at concentrations lower than that widely used to inhibit IRE1α activity.In vitrowe show that, 4µ8C effectively decreases xanthine/xanthine oxidase catalysed superoxide production with an IC50of 0.2 µM whereas in cultured endothelial and clonal pancreatic β-cells, 4µ8C inhibits angiotensin II-induced ROS production with IC50values of 1.92 and 0.29 µM, respectively. In light of this discovery, conclusions reached using 4µ8C as an inhibitor of IRE1α should be carefully evaluated. However, this unexpected off-target effect of 4µ8C may prove therapeutically advantageous for the treatment of pathologies that are thought to be caused by, or exacerbated by, both oxidative and ER stress such as endothelial dysfunction and/or diabetes.

History

Citation

Biochemical Journal, 2018, 475 (5), pp. 923-929

Author affiliation

/Organisation/COLLEGE OF SCIENCE AND ENGINEERING/Department of Chemistry

Version

  • AM (Accepted Manuscript)

Published in

Biochemical Journal

Publisher

Portland Press

issn

0264-6021

eissn

1470-8728

Copyright date

2018

Available date

2019-03-09

Publisher version

http://www.biochemj.org/content/475/5/923

Notes

The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en

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