Ethyl pyruvate inhibits HMGB1 release in colitis
Kofi
J Leukoc Biol. 2009 Sep;86(3):633-43. Epub 2009 May 19.
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Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis.
Dave SH, Tilstra JS, Matsuoka K, Li F, DeMarco RA, Beer-Stolz D,
Sepulveda AR, Fink MP, Lotze MT, Plevy SE.
Department of Medicine, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania, USA.
Signals from stressed cells and the enteric microbiota activate
macrophages and dendritic cells and mediate intestinal inflammation.
HMGB1 serves as an immunogenic stimuli causing release of inflammatory
cytokines by myeloid cells. Ethyl pyruvate inhibits secretion of HMGB1
and improves survival in models of endotoxemia and hemorrhagic shock. We
reasoned that ethyl pyruvate may be protective in colitis, which
involves similar inflammatory pathways. In IL-10(-/-) mice with
established chronic colitis, ethyl pyruvate administration ameliorated
colitis and reduced intestinal cytokine production. IL-10(-/-) mice
demonstrated increased intestinal HMGB1 expression and decreased
expression of RAGE compared with wild-type mice. Fecal HMGB1 levels were
decreased in ethyl pyruvate-treated mice. Furthermore, ethyl pyruvate
induced HO-1 expression in intestinal tissue. In TNBS-induced colitis,
intrarectal administration of ethyl pyruvate resulted in amelioration of
colitis and reduced intestinal cytokine production. In LPS-activated
murine macrophages, ethyl pyruvate decreased expression of IL-12 p40 and
NO production but did not affect IL-10 levels. Ethyl pyruvate did not
inhibit nuclear translocation of NF-kappaB family members but attenuated
NF-kappaB DNA binding. Additionally, ethyl pyruvate induced HO-1 mRNA
and protein expression and HO-1 promoter activation. Moreover, ethyl
pyruvate prevented nuclear-to-cytoplasmic translocation of HMGB1. In
conclusion, the HMGB1/RAGE pathway has pathophysiologic and diagnostic
significance in experimental colitis. Ethyl pyruvate and other
strategies to inhibit HMGB1 release and function represent promising
interventions in chronic inflammatory diseases.
Publication Types:
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't
PMID: 19454652
NADH inhibits the life-extending gene Sir2 by blocking the actions of
NAD+ on it; during calorie restriction, NADH levels drop as does the
NADH/NAD+ ratio, resulting in longer lifespan through improved
maintenance of oxidative stress; on the other hand increased NADH/NAD+
ratios lead to elevated lactate/pyruvate levels, enhanced nitric oxide
production and higher blood flow [PMID 14704275]
alpha lipoic acid lowers the NADH/NAD+ ratio which is elevated in
diabetes [PMID 9065743]