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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Snyder, Nathaniel W. Golin-Bisello, Franca Gao, Yang Blair, Ian A. Freeman, Bruce A. Wendell, Stacy Gelhaus |
| Description | Country affiliation: United States Author Affiliation: Snyder NW ( University of Pennsylvania, Department of Pharmacology and Center of Excellence in Environmental Toxicology, Philadelphia, PA 19104, USA.); Golin-Bisello F ( University of Pittsburgh, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15261, USA.); Gao Y ( University of Pittsburgh, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15261, USA.); Blair IA ( University of Pennsylvania, Department of Pharmacology and Center of Excellence in Environmental Toxicology, Philadelphia, PA 19104, USA.); Freeman BA ( University of Pittsburgh, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15261, USA.); Wendell SG ( University of Pittsburgh, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15261, USA. Electronic address: gstacy@pitt.edu.) |
| Abstract | Bioactive lipids govern cellular homeostasis and pathogenic inflammatory processes. Current dogma holds that bioactive lipids, such as prostaglandins and lipoxins, are inactivated by 15-hydroxyprostaglandin dehydrogenase (15PGDH). In contrast, the present results reveal that catabolic 'inactivation' of hydroxylated polyunsaturated fatty acids (PUFAs) yields electrophilic ,ß-unsaturated ketone derivatives. These endogenously produced species are chemically reactive signaling mediators that induce tissue protective events. Electrophilic fatty acids diversify the proteome through post-translational alkylation of nucleophilic cysteines in key transcriptional regulatory proteins and enzymes that govern cellular metabolic and inflammatory homeostasis. 15PGDH regulates these processes as it is responsible for the formation of numerous electrophilic fatty acids including the arachidonic acid metabolite, 15-oxoeicosatetraenoic acid (15-oxoETE). Herein, the role of 15-oxoETE in regulating signaling responses is reported. In cell cultures, 15-oxoETE activates Nrf2-regulated antioxidant responses (AR) and inhibits NF-κB-mediated pro-inflammatory responses via IKKß inhibition. Inhibition of glutathione S-transferases using ethacrynic acid incrementally increased the signaling capacity of 15-oxoETE by decreasing 15-oxoETE-GSH adduct formation. This work demonstrates that 15PGDH plays a role in the regulation of cell and tissue homeostasis via the production of electrophilic fatty acid signaling mediators. |
| File Format | HTM / HTML |
| ISSN | 00092797 |
| e-ISSN | 18727786 |
| DOI | 10.1016/j.cbi.2014.10.029 |
| Journal | Chemico-Biological Interactions |
| Volume Number | 234 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2015-06-05 |
| Publisher Place | Ireland |
| Access Restriction | Open |
| Subject Keyword | Discipline Biochemistry Discipline Pharmacology Arachidonic Acids Genetics Metabolism Hydroxyprostaglandin Dehydrogenases Inflammation Signal Transduction Alkylation Antioxidants Arachidonic Acid Cell Line Fatty Acids, Unsaturated Glutathione Transferase Hek293 Cells Homeostasis I-kappa B Kinase Nf-e2-related Factor 2 Nf-kappa B Protein Processing, Post-translational Research Support, N.i.h., Extramural |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Toxicology |
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