Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The glycolytic intermediate, pyruvate, is capable of scavenging reactive oxygen species (ROS). However, this compound is relatively unstable and hence is not useful as a therapeutic agent. Ethyl pyruvate, a simple derivative of pyruvate, appears to be more stable, and when formulated in a calcium-containing Ringer's-type balanced salt solution (REPS), has been shown to be salutary in rat models of two pathophysiological conditions--mesenteric ischemia/reperfusion and hemorrhagic shock/resuscitation--that are thought to be mediated, at least in part, by ROS. Because ROS also have been implicated in the pathogenesis of lipopolysaccharide (LPS)-induced shock, we carried out a series of experiments to determine if REPS is beneficial in this condition. Anesthetized rats were challenged with intravenous LPS (20 mg/kg). When mean arterial pressure (MAP) decreased to 60 mmHg, 3- to 5-mL boluses of either REPS (n = 10) or Ringer's lactate solution (RLS; n = 10) were infused as needed to prevent MAP from decreasing further. By design, the maximal volume of fluid infused was 7 mL/kg. Resuscitation with REPS as compared with RLS prolonged survival time (498 +/- 48 min vs. 362 +/- 30 min; P = 0.0014). Resuscitation with REPS as compared with RLS also was associated with significantly lower circulating concentrations of nitrite/nitrate and interleukin (IL)-6 and higher plasma levels of IL-10. These data support the view that delayed treatment with REPS modulates the inflammatory response to LPS, and prolongs survival time in a lethal model of endotoxic shock.
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PMID:Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharide-induced shock. 1246 57

Ethyl pyruvate (EP) solution ameliorates ileal mucosal hyperpermeability and decreases the expression of several proinflammatory genes in ileal and/or colonic mucosa when it is used instead of Ringer's lactate solution (RLS) to resuscitate mice from hemorrhagic shock. To test the hypothesis that EP can ameliorate gut barrier dysfunction induced by other forms of inflammation, we incubated Caco-2 monolayers for 24 to 48 h with cytomix (a mixture of interferon-gamma, tumor necrosis factor-alpha, and interleukin-1beta) in the presence or absence of graded concentrations of EP or sodium pyruvate. Cytomix increased the permeability of Caco-2 monolayers to fluorescein isothiocyanate-labeled dextran (FD4; average molecular mass 4 kDa), but this effect was inhibited by adding 0.1 to 10 mM EP (but not similar concentrations of sodium pyruvate) to the culture medium. EP inhibited several other cytomix-induced phenomena, including nuclear factor-kappaB activation, inducible nitric oxide synthase mRNA expression, and nitric oxide production. Cytomix altered the expression and localization of the tight junctional proteins, ZO-1 and occludin, but this effect was prevented by EP. Delayed treatment with EP solution instead of RLS ameliorated ileal mucosal hyperpermeability to FD4 and bacterial translocation to mesenteric lymph nodes in mice challenged with lipopolysaccharide (LPS). These data support the view that EP ameliorates cytokine- and/or LPS-induced derangements in intestinal epithelial barrier function.
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PMID:Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in endotoxemic mice and immunostimulated caco-2 enterocytic monolayers. 1249 Jun 23

Ethyl pyruvate (EP), an effective scavenger of reactive oxygen species, is also an anti-inflammatory agent in a variety of in vivo and in vitro model systems. To gain a better understanding of the molecular basis for the anti-inflammatory effects of EP, we compared the pharmacological properties of EP andN-acetyl-l-cysteine (NAC), a well studied scavenger of reactive oxygen species and a precursor for the endogenous antioxidant glutathione (GSH). The studies were performed using RAW 264.7 murine macrophage-like cells that were stimulated with lipopolysaccharide (LPS). Although EP and NAC both inhibited LPS-induced nitric oxide and interleukin (IL)-6 secretion, the former compound was considerably more potent than the latter. EP markedly inhibited inducible nitric-oxide synthase, IL-6, and IL-10 mRNA induction, whereas the effects of NAC were minimal. EP inhibited LPS-induced nuclear factor-kappaB DNA binding to a much greater extent than did NAC. Both compounds inhibited LPS-induced lipid peroxidation, but the two compounds had qualitatively different effects on cellular levels of GSH. Although NAC increased GSH levels, EP had the opposite effect. The anti-inflammatory effects of EP were partially reversed when RAW 264.7 cells were treated with a cell-permeable GSH analog, glutathione ethyl ester. These data support the view that the anti-inflammatory effects of EP are mediated, at least in part, by the ability of EP to deplete cellular GSH stores. Moreover, the findings presented here suggest that an unusual combination of biochemical effects (inhibition of lipid peroxidation and GSH depletion) might account for the anti-inflammatory effects of EP.
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PMID:Evidence that glutathione depletion is a mechanism responsible for the anti-inflammatory effects of ethyl pyruvate in cultured lipopolysaccharide-stimulated RAW 264.7 cells. 1456 76

Ethyl pyruvate (EP) has been shown to be an effective anti-inflammatory agent. Herein, we sought to test the following hypotheses: 1) the pharmacological effects of EP persist after cells have been exposed to the compound in vitro, even if the cultures are washed to minimize the amount of EP that is retained in the media; 2) the pharmacological effects of EP persist in vivo, even after waiting a prolonged period (i.e., 6 h) after the last dose of the compound; and 3) the in vivo pharmacological effects of EP are distinct from those of the closely related compound, sodium pyruvate. Incubation of Caco-2 human enterocyte-like monolayers with cytomix, a mixture of interleukin-1beta, interferon-gamma, and tumor necrosis factor, increased permeability to the fluorescent macromolecule, FITC-labeled Dextran (mol wt 4,000 Da). Co-incubation of the cells with 5 mM EP ameliorated cytomix-induced hyperpermeability and induction of iNOS mRNA expression. EP was associated with similar pharmacological effects when cells were pre-incubated with the compound for 24 h prior and then washed extensively prior to adding the cytokine cocktail. Injecting C57Bl/6 mice with lipopolysaccharide (LPS) resulted in gut barrier dysfunction and hepatocellular injury. Although equivalent doses of both EP and sodium pyruvate ameliorated these phenomena, EP was more efficacious than pyruvate. Pretreatment with EP ameliorated the deleterious effects of LPS, even when the duration between the last dose of EP and the endotoxic challenge was 6 h. We conclude that EP provides durable protection against some of the deleterious effects of LPS or pro-inflammatory cytokines.
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PMID:Ethyl pyruvate provides durable protection against inflammation-induced intestinal epithelial barrier dysfunction. 1462 76

Ethyl pyruvate has been shown to have anti-inflammatory properties in numerous cell culture and animal studies. In this series of experiments, we tested the hypothesis that ethyl pyruvate inhibits signaling by the pro-inflammatory transcription factor, NF-kappaB. Ethyl pyruvate inhibited luciferase expression in lipopolysaccharide-stimulated murine macrophage-like RAW 264.7 cells transfected with an NF-kappaB-dependent luciferase reporter vector. Ethyl pyruvate also decreased NF-kappaB DNA-binding activity in lipopolysaccharide-stimulated RAW 264.7 cells and decreased lipopolysaccharide-induced expression of an NF-kappaB-dependent gene, inducible nitric oxide synthase. Ethyl pyruvate had no effect on the degradation of IkappaBalpha or IkappaBbeta in lipopolysaccharide-stimulated RAW 264.7 cells, suggesting that ethyl pyruvate acts distally to this step in the activation of NF-kappaB. In a cell-free system, binding of p50 homodimers to an NF-kappaB consensus oligonucleotide sequence was unaffected by ethyl pyruvate over a wide range of concentrations, indicating that ethyl pyruvate probably does not modify or interact with the p50 subunit of NF-kappaB. In contrast, ethyl pyruvate inhibited DNA binding by ectopically overexpressed wild-type p65 homodimers. However, ethyl pyruvate failed to inhibit the DNA-binding activity of homodimers of an overexpressed mutant form of a p65 with substitution of serine for cysteine 38. Taken together, these results suggest that ethyl pyruvate inhibits DNA-binding by covalently modifying p65 at Cys(38). We conclude that some of the beneficial anti-inflammatory effects of ethyl pyruvate may be due to modification of p65, thereby inhibiting signaling via the NF-kappaB pathway.
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PMID:Ethyl pyruvate inhibits nuclear factor-kappaB-dependent signaling by directly targeting p65. 1552 91

Ethyl pyruvate (EP) is a simple aliphatic ester derived from the endogenous metabolite, pyruvic acid. EP has been shown to decrease the expression of various pro-inflammatory mediators, including nitric oxide (NO*), tumor necrosis factor (TNF), cyclooxygenase-2, and interleukin (IL)-6, in a variety of in vitro and in vivo model systems. In an effort to better understand the chemical features that might explain the anti-inflammatory properties of EP, we screened 15 commercially available compounds for cytoprotective or anti-inflammatory effects using two in vitro assay systems: TNF and NO* production by lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage-like cells and changes in the permeability of Caco-2 human enterocyte-like monolayers stimulated with a cocktail of pro-inflammatory cytokines called cytomix (1000U/ml IFN-gamma plus 10ng/ml TNF-alpha plus 1ng/ml IL-1beta). Two compounds, namely diethyl oxaloproprionate (DEOP) and 2-acetamidoacrylate (2AA), demonstrated consistent anti-inflammatory or cytoprotective pharmacological properties in this screening process. Treatment of mice with either of these compounds ameliorated LPS-induced ileal mucosal hyperpermeability to the fluorescent probe, fluorescein isothiocyanate-labeled dextran (average molecular mass 4kDa), and bacterial translocation to mesenteric lymph nodes. Treatment with either of these compounds also improved survival in mice challenged with a lethal dose of LPS. Finally, in a study that compared 2AA to its methyl ester, we showed that methyl-2-acetamidoacrylate is at least 100-fold more potent than the parent carboxylate as an inhibitor of LPS-induced NO* production by RAW 264.7 cells. Collectively, these data are consistent with the view that anti-inflammatory activity is demonstrable for a number of compounds that either incorporate an olefinic linkage conjugated to a carbonyl moiety or are capable of undergoing tautomeric rearrangement to form such a structure. Moreover, our findings suggest that esters with these general characteristics, perhaps because of their greater lipophilicity or electrophilicity, are more potent anti-inflammatory agents than are the parent carboxylates.
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PMID:The ethyl pyruvate analogues, diethyl oxaloproprionate, 2-acetamidoacrylate, and methyl-2-acetamidoacrylate, exhibit anti-inflammatory properties in vivo and/or in vitro. 1622 25

Sepsis is characterized by a concurrent activation of inflammation and coagulation. Recently, recombinant human activated protein C was shown to decrease mortality in patients with severe sepsis presumably due to a combined anti-inflammatory and anticoagulant effect. These promising findings led to a search for other products that influence both the inflammatory and the procoagulant response to severe infection. Ethyl pyruvate (EP) was recently identified as an experimental anti-inflammatory agent during endotoxemia and sepsis. The aim of the present study was to investigate whether EP influences coagulation besides its anti-inflammatory effects. For this we investigated the effects of EP on the expression and function of tissue factor (TF), the principal initiator of coagulation activation in sepsis, in human monocytic (THP-1) cell cultures. EP dose-dependently inhibited the production of tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta by lipopolysaccharide (LPS)-stimulated THP-1 cells at mRNA and protein level, thereby confirming its anti-inflammatory properties in this in-vitro system. In addition, EP dose-dependently attenuated the increases in TF mRNA levels, TF-protein-surface expression and cell-surface-associated TF activity in LPS-stimulated THP-1 cells. These results demonstrate for the first time that EP is a compound with combined anti-inflammatory and anticoagulant effects.
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PMID:Ethyl pyruvate exerts combined anti-inflammatory and anticoagulant effects on human monocytic cells. 1713 74

Ethyl pyruvate (EP), a simple aliphatic ester derived from pyruvic acid, improves survival and ameliorates organ system dysfunction in mice with peritonitis induced by caecal ligation and perforation, even when treatment is started as late as 12-24 hours after the onset of sepsis. In studies using lipopolysaccharide-stimulated RAW 264.7 murine macrophage like cells, EP inhibits activation of the pro-inflammatory transcription factor, NF-kappaB, and down regulates secretion of a number of pro-inflammatory cytokines, such as tumour necrosis factor (TNF). In this reductionist in vitro system, EP also blocks secretion of the late-appearing pro inflammatory cytokine-like molecule, high mobility group box 1 (HMGB1). In murine models of endotoxaemia or sepsis, treatment with EP decreases circulating levels of TNF and HMGB1. While the molecular events responsible for the salutary effects of EP remain to be elucidated, one mechanism may involve covalent modification of a critical thiol residue in the p65 component of NF-kappaB. EP warrants evaluation as a therapeutic agent for the treatment of sepsis in humans.
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PMID:Ethyl pyruvate: a novel treatment for sepsis. 1738 Jul 93

Pyruvic acid is a three-carbon alpha-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 lipopolysaccharide-stimulated RAW 264.7 murine macrophage-like cells, ethyl pyruvate inhibits activation of the pro-inflammatory transcription factor, NF-kappaB, 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-kappaB. Ethyl pyruvate warrants evaluation as a therapeutic agent for the treatment of sepsis in humans.
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PMID:Ethyl pyruvate: a novel treatment for sepsis. 1743 Jan 22

Ethyl pyruvate (EP) is a stable pyruvate derivative that has been shown to exert anti-inflammatory effects in various models of systemic inflammation including endotoxemia. We here sought to determine the local effects of EP, after intrapulmonary delivery, in models of lung inflammation induced by instillation via the airways of either lipopolysaccharide (LPS, a constituent of the gram-negative bacterial cell wall) or lipoteichoic acid (LTA, a component of the gram-positive bacterial cell wall). For this, we first established that EP dose dependently reduced the responsiveness of mouse MH-S alveolar macrophages and mouse MLE-15 and MLE-12 respiratory epithelial cells to stimulation with LPS or LTA in vitro. We then showed that intranasal administration of EP dose dependently inhibited tumor necrosis factor alpha release in bronchoalveolar lavage fluid of mice challenged with either LPS or LTA via the airways. Moreover, EP reduced the recruitment of neutrophils into the bronchoalveolar space after either LPS or LTA administration. These data suggest that intrapulmonary delivery of EP diminishes lung inflammation induced by LPS or LTA, at least in part by targeting alveolar macrophages and respiratory epithelial cells.
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PMID:Intrapulmonary delivery of ethyl pyruvate attenuates lipopolysaccharide- and lipoteichoic acid-induced lung inflammation in vivo. 1757 42


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