Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species are reactive, partly reduced derivatives of molecular oxygen. Important reactive oxygen species in biological systems include superoxide radical anion, hydrogen peroxide, and hydroxyl radical. Peroxynitrite, is another important species in biological systems. A variety of enzymatic and non-enzymatic processes can generate reactive oxygen species in mammalian cells. An extensive body of experimental evidence from studies using animal models supports the view that reactive oxygen species are important in the pathogenesis of ischemia-reperfusion syndromes, sepsis, acute respiratory distress syndrome, and multiple organ dysfunction syndrome. This view is further supported by data from clinical studies that correlate biochemical evidence of reactive oxygen species-mediated stress with the development of acute respiratory distress syndrome or sepsis in patients. Ethyl pyruvate, a simple derivative of pyruvic acid, has been shown to be efficacious in several animal models of critical illness, and warrants further evaluation in this regard.
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PMID:Reactive oxygen species as mediators of organ dysfunction caused by sepsis, acute respiratory distress syndrome, or hemorrhagic shock: potential benefits of resuscitation with Ringer's ethyl pyruvate solution. 1184 84

Sepsis, a potentially fatal clinical syndrome, is mediated by an early (e.g., tumor necrosis factor and IL-1) and late [e.g., high mobility group B-1 (HMGB1)] proinflammatory cytokine response to infection. Specifically targeting early mediators has not been effective clinically, in part because peak mediator activity often has passed before therapy can be initiated. Late-acting downstream effectors, such as HMGB1, that mediate sepsis lethality may be more relevant therapeutic targets. Ethyl pyruvate (EP) recently was identified as an experimental therapeutic that significantly protects against lethal hemorrhagic shock. Here, we report that EP attenuates lethal systemic inflammation caused by either endotoxemia or sepsis even if treatment begins after the early tumor necrosis factor response. Treatment with EP initiated 24 h after cecal puncture significantly increased survival (vehicle survival = 30% vs. EP survival = 88%, P < 0.005). EP treatment significantly reduced circulating levels of HMGB1 in animals with established endotoxemia or sepsis. In macrophage cultures, EP specifically inhibited activation of p38 mitogen-activated protein kinase and NF-kappaB, two signaling pathways that are critical for cytokine release. This report describes a new strategy to pharmacologically inhibit HMGB1 release with a small molecule that is effective at clinically achievable concentrations. EP now warrants further evaluation as an experimental "rescue" therapeutic for sepsis and other potentially fatal systemic inflammatory disorders.
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PMID:Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. 1220 6

Ethyl pyruvate (EP) is a pyruvate derivative, and has recently been reported to prevent lethality in mice with established lethal sepsis and systemic inflammation. In a previous study, we reported that EP has a neuroprotective effect in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO), in which it was found to be effective when injected as late as 12 h after MCAO/reperfusion. In the present study, we show that therapeutic window of pyruvate in this MCAO animal model is limited to 1 h (30 min before and 30 min after MCAO). Moreover, both pyruvate and EP have a neuroprotective effect during oxygen-glucose deprivation (OGD) or H2O2 challenge in primary cortical culture. In contrast, EP suppressed the LPS-induced activation of primary microglia in culture, but pyruvate did not. The suppression of microglia activation was evidenced by a reduction in nitric oxide release and by a proinflammatory factor induction in primary microglia culture, which were accompanied by the repression of nuclear factor-kappaB activation. These results suggest that EP has a strong protective effect and a wide therapeutic window, and that this protective effect of EP is related to its anti-inflammatory action.
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PMID:Anti-inflammatory mechanism is involved in ethyl pyruvate-mediated efficacious neuroprotection in the postischemic brain. 1622 31

Pyruvic acid is an effective scavenger of reactive oxygen species. Ethyl pyruvate has demonstrated anti-inflammatory actions and improved hyperpermeability and bacterial translocation due to endotoxemia and is of benefit in animal models of sepsis and septic shock. Ethyl pyruvate specifically inhibits tumor necrosis factor-alpha production and decreases circulating levels of high-mobility group box-1 and nuclear factor-kappaB signaling pathways by specifically targeting its p65 subunit in animals with established endotoxemia or sepsis and in macrophage cultures. Ethyl pyruvate also decreases cyclo-oxygenase-2, inducible nitric oxide synthase, and interleukin-6 mRNA expression in the liver, ileal mucosa, and colonic mucosa in animal models with hemorrhagic shock. Similar beneficial actions have been seen in endotoxemia. These and other studies suggest that ethyl pyruvate could be of significant benefit in the treatment of patients who are critically ill and have sepsis/septic shock.
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PMID:Is pyruvate an endogenous anti-inflammatory molecule? 1681 17

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

Ethyl pyruvate (EP) is a simple derivative of the endogenous metabolite, pyruvic acid. Treatment with EP has been shown to improve survival and/or ameliorate organ dysfunction in a wide variety of preclinical models of critical illnesses, such as severe sepsis, acute respiratory distress syndrome, acute pancreatitis and stroke. EP was originally regarded as simply a way to administer pyruvate anion, whilst avoiding some of the problems associated with the instability of pyruvate in aqueous solutions. Increasingly, however, it is becoming apparent that certain pyruvate esters, including EP, have pharmacological effects, such as suppression of inflammation, that are quite distinct from those exerted by pyruvate anion. EP has been tested in human volunteers and shown to be safe at clinically relevant doses. It remains to be determined whether EP can be used successfully to treat human diseases.
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PMID:Ethyl pyruvate: a novel anti-inflammatory agent. 1739 Nov 9

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), a simple aliphatic ester of pyruvic acid, has been shown to improve survival and ameliorate organ damage in animal models of sepsis, ischemia/reperfusion injury and hemorrhagic shock. Incubating IL3-dependent mouse hematopoietic progenitor cell 32Dcl3 cells before or after irradiation with 10 mM EP increased resistance to radiation as assessed by clonogenic radiation survival curves, decreased release of mitochondrial cytochrome C into the cytoplasm, and decreased apoptosis. EP inhibited radiation-induced caspase 3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in 32Dcl3 cells in a concentration-dependent fashion. EP was given i.p. to C57BL/6NHsd mice irradiated with 9.75 Gy total-body irradiation (TBI). This treatment significantly improved survival. The survival benefit was apparent irrespective of whether treatment with EP was started 1 h before TBI and continued for 5 consecutive days after TBI or the compound was injected only 1 h before or only for 5 days after TBI. In all of the in vitro and in vivo experiments, ethyl lactate, an inactive analogue of EP, had no detectable radioprotective or mitigating effects. EP may be an effective radioprotector and mitigator of the hematopoietic syndrome induced by TBI.
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PMID:Ethyl pyruvate, a potentially effective mitigator of damage after total-body irradiation. 1797 49

Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to act as an anti-inflammatory molecule in various pathological conditions, which include sepsis or hemorrhagic shock. Recently, we showed that ethyl pyruvate has a neuroprotective effect in the postischemic brain and also in KA-induced pathogenesis in the brain. In this study, we examined whether aspirin augments neuroprotective effect of ethyl pyruvate in transient focal ischemia model by complementing the neuroprotective effects of ethyl pyruvate. Although, most of neuroprotective effect of aspirin has been attributed to the anti-platelet action, aspirin also has direct neuroprotective effects, including NF-kappaB inhibition. Ethyl pyruvate dose-dependently suppressed infarct formation in the postischemic brain, wherein intravenous administration of 5 mg/kg ethyl pyruvate 30 min after the occlusion reduced infarct volume to 34.5 +/- 15.5% (n = 6, P < 0.01) of that of the untreated control. In combination with aspirin (5 mg/kg, i.v.), the neuroprotective effect was enhanced, resulting in 16.0 +/- 5.9% (n = 6, P < 0.01) infarct volume. The time window for synergistic neuroprotection by ethyl pyruvate and aspirin extended to 9 h post-MCAO. The synergistic reduction in infarct volume was accompanied by suppression of the clinical manifestations associated with cerebral ischemia including motor impairment and neurological deficits. Inflammatory processes including microglial activation and proinflammatory cytokine expression were notably suppressed by the combination treatment in the postischemic brain and in primary microglia cultures, wherein ethyl pyruvate and aspirin modulate NF-kappaB signaling differentially. Aspirin interferes with IkappaB phosphorylation and degradation in the cytoplasm, possibly by specifically inhibiting IkappaB kinase-beta, whereas, the effect of ethyl pyruvate seems to occur in the nucleus, where it may interfere with the binding of NF-kappaB to responsive promoter elements in the target genes. Similar enhancement in neuroprotective effect was also observed in primary cortical cultures after NMDA or Zn(2+) treatment or oxygen-glucose deprivation. Together, these results indicate that combination treatment of ethyl pyruvate and aspirin affords synergistic neuroprotection in the postischemic brain with a wide therapeutic window, in part via differential modulation of the NF-kappaB signaling pathway.
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PMID:Combination treatment with ethyl pyruvate and aspirin enhances neuroprotection in the postischemic brain. 1963 61


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