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PLoS One. 2014 Feb 5;9(2):e88168. doi: 10.1371/journal.pone.0088168. eCollection 2014.

Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers.

Author information

  • 1Airway Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
  • 2Department of Physiology and Anatomy, Nihon University School of Pharmacy, Funabashi, Chiba, Japan.
  • 3Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada.

Erratum in

  • PLoS One. 2014;9(5):e97208.

Abstract

BACKGROUND:

Anti-oxidant capacity is crucial defence against environmental or endogenous oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that plays a key defensive role against oxidative and cytotoxic stress and cellular senescence. However, Nrf2 signalling is impaired in several aging-related diseases, such as chronic pulmonary obstructive disease (COPD), cancer, and neurodegenerative diseases. Thus, novel therapeutics that enhance Nrf2 signalling are an attractive approach to treat these diseases.

METHODOLOGY/PRINCIPAL FINDINGS:

Nrf2 was stabilized by SKI-II (2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole), which is a known sphingosine kinase inhibitor, in human bronchial epithelial cell line, BEAS2B, and in primary human bronchial epithelial cells, leading to enhancement of anti-oxidant proteins, such as HO-1, NQO1 and GCLM. The activation of Nrf2 was achieved by the generation of inactive dimerized form of Keap1, a negative regulator of Nrf2 expression, which was independent of sphingosine kinase inhibition. Using mice that were exposed to cigarette smoke, SKI-II induced Nrf2 expression together with HO-1 in their lungs. In addition, SKI-II reduced cigarette smoke mediated oxidative stress, macrophages and neutrophil infiltration and markers of inflammation in mice.

CONCLUSIONS/SIGNIFICANCE:

SKI-II appears to be a novel activator of Nrf2 signalling via the inactivation of Keap1.

PMID:
24505412
[PubMed - indexed for MEDLINE]
PMCID:
PMC3914928
Free PMC Article
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