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      Pyruvate: immunonutritional effects on neutrophil intracellular amino or alpha-keto acid profiles and reactive oxygen species production

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          Abstract

          For the first time the immunonutritional role of pyruvate on neutrophils (PMN), free α-keto and amino acid profiles, important reactive oxygen species (ROS) produced [superoxide anion (O 2 ), hydrogen peroxide (H 2O 2)] as well as released myeloperoxidase (MPO) acitivity has been investigated. Exogenous pyruvate significantly increased PMN pyruvate, α-ketoglutarate, asparagine, glutamine, aspartate, glutamate, arginine, citrulline, alanine, glycine and serine in a dose as well as duration of exposure dependent manner. Moreover, increases in O 2 formation, H 2O 2-generation and MPO acitivity in parallel with intracellular pyruvate changes have also been detected. Regarding the interesting findings presented here we believe, that pyruvate fulfils considerably the criteria for a potent immunonutritional molecule in the regulation of the PMN dynamic α-keto and amino acid pools. Moreover it also plays an important role in parallel modulation of the granulocyte-dependent innate immune regulation. Although further research is necessary to clarify pyruvate’s sole therapeutical role in critically ill patients’ immunonutrition, the first scientific successes seem to be very promising.

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          Most cited references102

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          Neutrophils: molecules, functions and pathophysiological aspects.

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            Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis.

            Oxidative stress can be defined as the imbalance between cellular oxidant species production and antioxidant capability. Reactive oxygen species (ROS) are involved in a variety of different cellular processes ranging from apoptosis and necrosis to cell proliferation and carcinogenesis. In fact, molecular events, such as induction of cell proliferation, decreased apoptosis, and oxidative DNA damage have been proposed to be critically involved in carcinogenesis. Carcinogenicity and aging are characterized by a set of complex endpoints, which appear as a series of molecular reactions. ROS can modify many intracellular signaling pathways including protein phosphatases, protein kinases, and transcription factors, suggesting that the majority of the effects of ROS are through their actions on signaling pathways rather than via non-specific damage of macromolecules; however, exact mechanisms by which redox status induces cells to proliferate or to die, and how oxidative stress can lead to processes evoking tumor formation are still under investigation.
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              Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis.

              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.
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                Author and article information

                Contributors
                +31-24-3651548 , +31-24-3614406 , +31-24-3540462 , j.muhling@anes.umcn.nl
                Journal
                Amino Acids
                Amino Acids
                Springer Vienna (Vienna )
                0939-4451
                1438-2199
                14 September 2010
                14 September 2010
                April 2011
                : 40
                : 4
                : 1077-1090
                Affiliations
                [1 ]Clinics of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Giessen and Marburg, Justus-Liebig-University Giessen, Marburg, Federal Republic of Germany
                [2 ]University Department of Anaesthesia, Royal Liverpool University Hospital, Liverpool, UK
                [3 ]Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Giessen and Marburg, Justus-Liebig-University Giessen, Marburg, Federal Republic of Germany
                [4 ]Dr. Ing. Herbert Knauer GmbH, Berlin, Federal Republic of Germany
                [5 ]Department of Anesthesiology, Pain, and Palliative Medicine, Radboud University Medical Center, Huispost 630, route 630, Postbus 9101, 6500 HB Nijmegen, The Netherlands
                Article
                731
                10.1007/s00726-010-0731-z
                3061003
                20839016
                67760896-2146-4706-a401-44f8f97959eb
                © The Author(s) 2010
                History
                : 7 June 2010
                : 23 August 2010
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag 2011

                Genetics
                pyruvate,α-keto acids,immune function,neutrophil,amino acids
                Genetics
                pyruvate, α-keto acids, immune function, neutrophil, amino acids

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