The ethyl pyruvate analogues, diethyl oxaloproprionate, 2-acetamidoacrylate, and methyl-2-acetamidoacrylate, exhibit anti-inflammatory properties in vivo and/or in vitro

Sappington, Penny L.; Cruz, Ruy J.; Harada, Tomoyuki; Yang, Runkuan; Han, Yanyan; Englert, Joshua A.; Ajami, Alfred M.; Killeen, Meaghan E.; Delude, Russell L.; Mp, Fink

doi:10.1016/j.bcp.2005.08.015

Cited by 35 publications

(32 citation statements)

References 42 publications

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“…NF-B is known to be activated in many organs in sepsis models and has potent effects on downstream signaling pathways and tissue injury. EP directly inhibits p65 NF-B and thereby attenuates inflammatory responses in vivo (11,38,45). Other EP analogs, including M2AA, also inhibit NF-B activation (38).…”

Section: Discussionmentioning

confidence: 99%

“…NF-B plays a critical role in both inflammation and apoptosis and in organ injury. Moreover, EP and its analogs, including M2AA, can directly inhibit NF-B activation in vitro (38). Therefore, we determined the time course of NF-B activation, active caspase-3-mediated apoptosis, and organ injury in spleen, liver, and kidney examined responses of inflammatory cytokines.…”

Section: B-g and 2)mentioning

confidence: 99%

“…Because of its chemical instability in aqueous solution, EP needs to be prepared immediately before injection in a calcium ion-containing solution (Ringers EP solution) to increase its stability (8) and used shortly after dilution, which limits its usefulness as a therapeutic agent. EP analogs, including methyl-2-acetamidoacrylate (M2AA), also have anti-inflammatory properties and inhibit LPS-induced nitric oxide, TNF-␣, NF-B, and amelioration of the increase of epithelial permeability (38), but with more stable chemical properties.…”

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confidence: 99%

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Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice

Leelahavanichkul

Yasuda²,

Doi³

et al. 2008

American Journal of Physiology-Renal Physiology

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PS, Star RA. Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice. Am J Physiol Renal Physiol 295: F1825-F1835, 2008. First published October 15, 2008 doi:10.1152/ajprenal.90442.2008.-We tested the anti-inflammatory agent methyl-2-acetamidoacrylate (M2AA), an ethyl pyruvate analog, in a cecal ligation-and-puncture (CLP) model of sepsis in CD-1 mice. M2AA administration at the time of CLP improved survival, renal function, kidney histology, liver injury, and splenocyte apoptosis, and lowered cytokine levels (TNF-␣, IL-6, IFN-␥, and IL-10). When M2AA treatment was delayed 6 h (but not 12 h), M2AA still significantly reduced kidney dysfunction, liver injury, splenocyte apoptosis, and cytokine levels. NF-B, a M2AA target, was transiently activated in spleen, peaking at 6 h; kidney and liver NF-B increased steadily with a plateau at 12-24 h. M2AA reduced NF-B activation in spleen at 6 h and in kidney and liver at 24 h. Splenectomy diminished the ability of M2AA to reduce cytokines, especially IL-6, but M2AA still decreased kidney and liver dysfunction, suggesting that splenic NF-B is not central to M2AA action. In contrast, beneficial effects of chloroquine on cytokines and organ damage were neutralized by splenectomy, demonstrating a spleen-specific chloroquine target. Because M2AA and chloroquine act differently, we tested this combination. Survival at 96 h was highest with combination therapy (57%) vs. chloroquine (38%), M2AA (47.6%), or vehicle (5%). The benefit of combination therapy over chloroquine or M2AA alone did not reach statistical significance, indicating potential mechanistic overlap. We conclude that the transient target(s) for M2AA responsible for the narrow 6-h therapeutic window is not splenic NF-B. Identifying this new target and downstream signaling pathways could lengthen the therapeutic window and improve combination therapy with chloroquine. cecal ligation-puncture; spleen; apoptosis; nuclear factor-B; chloroquine THE MORTALITY RATE OF SEPSIS and septic shock remain unacceptably high and have not changed in several decades (9). Approximately 50% of septic patients develop acute kidney injury (AKI) (28, 34). The mortality rate of septic patients with AKI remains as high as 70%, and the development of AKI in septic patients predicts a poor outcome (28). Ethyl pyruvate (EP) is a derivative of an endogenous antioxidant pyruvate (35). EP can scavenge reactive oxygen species and can downregulate proinflammatory cytokines both in vitro and in vivo. EP inhibits high-mobility group box 1 (HMGB1) and decreases the activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-B (NF-B) (35,45,47,51). EP also preserves mucosal histology and permeability after mesenteric ischemia-reperfusion injury (40) and survival and intestinal damage after hemorrhagic shock (42), alcoholic hepatitis (52), and coronary ischemia and reperfusion (50). Previously, our group (2, 33) reported that EP can decrease sepsis-induced AKI and multiple organ failu...

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Section: Discussionmentioning

confidence: 99%

Section: B-g and 2)mentioning

confidence: 99%

mentioning

confidence: 99%

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Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice

Leelahavanichkul

Yasuda²,

Doi³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…• OH (Dobsak et al, 1999;Sappington et al, 2005). Pyruvate can be transported into or secreted from cells by the specific H + -monocarboxylate co-transporter (Harding et al, 1994) thus, it could act both as an intracellular and an extracellular H 2 O 2 scavenger.…”

Section: Introductionmentioning

confidence: 99%

Protective effect of ethyl pyruvate on msP rat leukocytes damaged by alcohol intake

Fedeli¹,

Falcioni²,

Olek³

et al. 2007

J of Applied Toxicology

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Alcohol consumption for long periods negatively influences physiological functions of many cells, and leads to organ damage. Reactive oxygen and nitrogen species produced by ethanol metabolism cause adverse effects that might be alleviated by simultaneous treatment with various antioxidants. Here, the ability of ethyl pyruvate (EP) to reduce ethanol-induced oxidative stress was evaluated. Chemiluminescence studies show that EP has a higher capacity than pyruvate to scavenge hydrogen peroxide and superoxide anions. In order to evaluate whether EP can exert a protective effect against ethanol, rats were offered 10% ethanol in drinking burettes, containing or not different concentrations of EP (0.3%, 1% and 3%). The comet assay was employed to quantify the alcohol-induced DNA damage in rat lymphocytes. This test is a promising tool for the estimation of DNA damage at the single cell level. A significant protective effect of EP was observed in rat groups treated with this antioxidant, compared with those drinking only ethanol. Since EP has been shown to decrease the expression of numerous pro-inflammatory mediators, the monocyte respiratory burst was evaluated. The activation of monocyte NADPH oxidase by phorbol esters (PMA) showed that superoxide anion production was higher in the ethanol group than in the control group. The presence of EP considerably reduced superoxide anion production. In conclusion, hypotheses on possible mechanisms of action of EP on rat white blood cells are proposed.

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“…Several targets of sepsis mediated injury have been investigated as targets of SA-AKI. Ethyl pyruvate, a potent anti-oxidant and free radical scavenger, leads to more renoprotection in rodent models of SA-AKI (94). Chloroquine, a commonly available anti-inflammatory drug, inhibits toll-like receptor 9 mediated renal damage during SA-AKI (95).…”

Section: Impairment: Oxidative and Inflammatory Injurymentioning

confidence: 99%

Approaches to the Management of Acute Kidney Injury in Children

Basu¹,

Wheeler²

2011

RPBM

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Acute kidney injury (AKI) causes increased morbidity in critically ill children and damage to the kidney, a central mediator of homeostasis in the body, affects survival. The incidence of AKI in pediatrics is significant and despite alarming data, therapeutic interventions have failed to effect a meaningful difference in outcomes. In this review, we will discuss the epidemiology of AKI in pediatrics, treatment strategies attempted to date, experimental therapies targeting molecular patterns associated with AKI, and highlight the needed direction of AKI research and management. Prospective trials in pediatrics are needed to test the validity of diagnostic tools, to identify the point of most efficacious intervention, and to underscore the therapies that can be effective in the different downstream effects of AKI.

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The ethyl pyruvate analogues, diethyl oxaloproprionate, 2-acetamidoacrylate, and methyl-2-acetamidoacrylate, exhibit anti-inflammatory properties in vivo and/or in vitro

Cited by 35 publications

References 42 publications

Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice

Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice

Protective effect of ethyl pyruvate on msP rat leukocytes damaged by alcohol intake

Approaches to the Management of Acute Kidney Injury in Children

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