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Ethyl Pyruvate: A Novel Treatment for Sepsis

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Pyruvic acid is a three-carbon α-ketocarboxylic acid that plays a central role in intermediary metabolism, being the final product of glycolysis and the starting substrate for the tricarboxylic acid cycle. Ethyl pyruvate, which is a simple aliphatic ester derived from pyruvic acid, has been shown to improve survival and ameliorate organ system dysfunction in mice with peritonitis induced by cecal ligation and perforation, even when treatment is started as late as 12-24 hours after the onset of sepsis. In studies using lipopolysaccharidestimulated RAW 264.7 murine macrophage-like cells, ethyl pyruvate inhibits activation of the pro-inflammatory transcription factor, NF-κB, and down-regulates secretion of a number of pro-inflammatory cytokines, such as TNF. In this reductionist in vitro system, ethyl pyruvate also blocks secretion of the late-appearing pro-inflammatory cytokine-like molecule, high mobility group B1 (HMGB1). In murine models of endotoxemia or sepsis, treatment with ethyl pyruvate decreases circulating levels of TNF and HMGB1. While the molecular events responsible for the salutary effects of ethyl pyruvate remain to be elucidated, one mechanism may involve covalent modification of a critical thiol residue in the p65 component of NF-κB. Ethyl pyruvate warrants evaluation as a therapeutic agent for the treatment of sepsis in humans.

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Keywords: LPS; NF-kappaB; acute renal failure; endotoxin; lipopolysaccharide; pyruvic acid; reactive oxygen species; signal transduction

Document Type: Research Article

Affiliations: Department of Critical Care Medicine, University of Pittsburgh Medical School, 616 Scaife Hall, 3550 Terrace Street, Pittsburgh PA 15261.

Publication date: April 1, 2007

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  • Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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