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PubMed2002

Prevention of latently expressed CYP2C11, CYP3A2, and growth hormone defects in neonatally monosodium glutamate-treated male rats by the N-methyl-D-aspartate receptor antagonist dizocilpine maleate.

Neonatal administration of monosodium glutamate (MSG) can produce latently expressed defects in drug metabolism and growth hormone secretion as well as stunted growth and obesity. Instead of secreting growth hormone in the masculine episodic profile, plasma hormone levels are generally undetectable in affected adult male rats. Moreover, male-specific isoforms of cytochrome P450 (P450; e.g., CYP2C11 and CYP3A2), whose combined levels comprise the bulk of the total hepatic P450 in adult male rats, are similarly undetectable in these animals. Since "signaling elements" in the masculine episodic growth hormone profile are solely responsible for the elevated characteristic male-like expression levels of CYP2C11 and CYP3A2, suppression of the isoforms in the MSG-treated rats appeared to be caused by the simple absence of the hormone from the circulation. However, the reported failures of restored physiologic masculine growth hormone profiles to correct the P450 defects suggested the occurrence of direct MSG-induced liver damage independent of the well known hypothalamic lesions produced by the amino acid. Concurrent administration of dizocilpine maleate (MK-801), a selective and highly potent noncompetitive N-methyl-D-aspartate receptor antagonist of glutamate, completely prevented the adverse effects of neonatal MSG treatment on P450 expression, growth hormone secretion, and growth parameters, indicating that the amino acid-induced defects are solely a result of neuronal (i.e., hypothalamic) damage produced at the time of MSG exposure. The irreversibility of the P450 damage is described as resulting from secondary defects initially induced by the neuronal lesions.

Animals↗
PubMed2005

A novel neurotrophic agent, T-817MA [1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl}-3-azetidinol maleate], attenuates amyloid-beta-induced neurotoxicity and promotes neurite outgrowth in rat cultured central nervous system neurons.

Progressive neuronal loss in Alzheimer's disease (AD) is considered to be a consequence of the neurotoxic properties of amyloid-beta peptides (A beta). T-817MA (1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl}-3-azetidinol maleate) was screened as a candidate therapeutic agent for the treatment of AD based on its neuroprotective potency against A beta-induced neurotoxicity and its effect of enhancing axonal regeneration in the sciatic nerve axotomy model. The neuroprotective effect of T-817MA against A beta(1-42) or oxidative stress-induced neurotoxicity was assessed using a coculture of rat cortical neurons with glia. T-817MA (0.1 and 1 microM) was strongly protective against A beta(1-42)-induced (10 microM for 48 h) or H2O2-induced (100 microM for 24 h) neuronal death. T-817MA suppressed the decrease of GSH levels induced by H2O2 exposure (30 microM for 4 h) in cortical neuron culture; therefore, T-817MA was likely to alleviate oxidative stress. Besides the neuroprotective effect, T-817MA (0.1 and 1 microM) promoted neurite outgrowth in hippocampal slice cultures and reaggregation culture of rat cortical neurons. T-817MA also increased the growth-associated protein 43 content in the reaggregation culture of cortical neurons. These findings suggest that T-817MA exerts neuroprotective effect and promotes neurite outgrowth in rat primary cultured neurons. Based on these neurotrophic features, T-817MA may have a potential for disease modification and be useful for patients with neurodegenerative diseases, such as AD.

Amyloid beta-Peptides↗
PubMed2002

Enhancement of L-cystine transport activity and its relation to xCT gene induction at the blood-brain barrier by diethyl maleate treatment.

The purpose of the present study was to elucidate the mechanism of enhancement of L-cystine uptake at the blood-brain barrier (BBB). The uptake of [(14)C]L-cystine and [(3)H]L-glutamic acid (L-Glu) was determined using a mouse brain endothelial cell line (MBEC4) as an in vitro BBB model. The mRNA levels of L-cystine/L-Glu exchanger, system x(c)(-), which consists of xCT and 4F2hc, were determined by quantitative real-time reverse transcription-polymerase chain reaction analysis. The [(14)C]L-cystine uptake by MBEC4 cells appeared to be mediated via an Na(+)-independent saturable process. The corresponding Michaelis-Menten constant (K(m)) was 63.7 microM. In the presence of L-Glu, there was competitive inhibition with an inhibition constant (K(i)) of 83.5 microM. [(3)H]L-Glu uptake in the absence of Na(+) was saturable with a K(m) of 48.1 microM, and it exhibited competitive inhibition with a K(i) of 24.9 microM in the presence of L-cystine. The mutual inhibition between L-cystine and L-Glu and the type of inhibition suggest that system x(c)(-) operates in MBEC4 cells. The xCT and 4F2hc mRNAs were expressed in MBEC4 cells and, following diethyl maleate (DEM) treatment, the xCT mRNA level and L-cystine uptake in MBEC4 cells were enhanced in parallel with an increase in DEM concentration (up to 500 microM). Concomitantly, the glutathione concentration in MBEC4 cells was increased. In conclusion, system x(c)(-)-mediated L-cystine uptake takes place in MBEC4 cells. L-Cystine transport via system x(c)(-) at the BBB is likely to be induced under oxidative stress conditions following DEM treatment due to enhanced transcription of the xCT gene.

Algorithms↗
PubMed1989

Increase in endothelial cell glutathione and precursor amino acid uptake by diethyl maleate and hyperoxia.

Diethyl maleate (DEM, 0.025-0.10 mM) increased glutathione (GSH) levels in calf pulmonary artery endothelial cells up to fivefold in 12-24 h of incubation. Parallel increases occurred in the rates of uptake of cystine and glutamate. The DEM-mediated increases in both GSH levels and glutamate-cystine uptake were inhibited by cycloheximide and actinomycin D, indicating a dependency on protein and RNA synthesis. The stimulatory effects of DEM on amino acid uptake and GSH levels were greater than those in endothelial cells exposed to 80% O2 for 24 h. The effect of hyperoxia on cellular transport processes was also less specific than that of DEM. Although the increase in glutamate uptake produced by hyperoxia appeared to be under the regulation of protein synthesis, the relationship with elevated GSH in the presence of hyperoxia was less clear because of elevation of control cellular GSH by cycloheximide or actinomycin D alone. Inhibition of GSH synthesis by buthionine sulfoximine also stimulated cystine and glutamate uptake. We conclude that elevation of endothelial intracellular GSH by both DEM and hyperoxia is associated with and may be produced by enhanced uptake of precursor amino acids; the effect of DEM is more pronounced and more specific than that of hyperoxia.

Amino Acids↗
PubMed1989

Erythrocytes fail to induce glutathione in response to diethyl maleate or hyperoxia.

We have previously found that exposure of pulmonary artery endothelial cells to hyperoxia or low concentrations of diethyl maleate (DEM) results in elevation of both cellular glutathione (GSH) and uptakes of glutamate and cystine. The present study confirms that this elevation occurs for a variety of lung cells (bovine pulmonary artery endothelial and smooth muscle cells and rat lung fibroblast and epithelial-like cells) but not for human, rat, and chicken erythrocytes. In fact, human and rat erythrocyte GSH levels were reduced substantially at DEM concentrations from 0.05 to 0.5 mM, whereas the GSH level of chicken erythrocytes was almost totally eliminated by 0.05 mM DEM. Also, all erythrocytes failed to accumulate measurable amounts of radioactive glutamate or cystine. The findings suggest the presence of different mechanisms for the regulation of cellular GSH in lung cells from those of erythrocytes. They are consistent with a requirement for a cystine-glutamate transporter and transcriptional and translational events for the elevation of cellular GSH in response to hyperoxia or low levels of DEM in the lung cells.

Animals↗
PubMed1990

Depletion of tissue glutathione with diethyl maleate enhances hyperbaric oxygen toxicity.

Rats exposed to hyperbaric hyperoxia experience severe central nervous system and lung toxicity. Exogenous glutathione administration has been shown to protect rats from the effects of hyperbaric hyperoxia. To explore the hypothesis that decreases in tissue glutathione (GSH) could increase the susceptibility of rats to hyperbaric hyperoxia, we administered diethyl maleate (DEM) (a compound that conjugates with GSH and rapidly lowers tissue levels) and measured tissue GSH levels. DEM administration decreased plasma GSH by 86%, liver GSH by 82%, and brain GSH by 45% between 2 and 4 h after injection with values returning to normal by 24 h. We then treated rats with DEM or saline and began exposure at 2 h after treatment to 100% oxygen at 4 ATA. Time-to-convulsion and time-to-death were recorded. Rats that received DEM 2 h before exposure seized earlier and died earlier than controls. Intraperitoneal administration of GSH to DEM-treated rats abolished the enhanced toxicity occurring during a hyperbaric hyperoxic exposure. DEM appears to increase the toxicity of rats exposed to hyperbaric hyperoxia by lowering tissue GSH levels, and replenishment of lung and brain GSH by exogenous administration reverses these effects.

Animals↗
PubMed2002

Transcriptional and physiological responses of HepG2 cells exposed to diethyl maleate: time course analysis.

Expression levels of 767 genes were measured in HepG2 cells at eight time points (0, 0.5, 1, 6, 12, 16, 20, and 24 h) following exposure to the oxidizing agent, diethyl maleate (DEM). DEM treatment caused an immediate and sustained loss of intracellular GSH, with a concomitant increase in GSSG. From 6-12 h after exposure, there was a substantial increase in the percentage of cells undergoing S phase arrest and apoptosis. Expression profiles of approximately 90% of the genes fell into one of five clusters generated using hierarchical-clustering software, indicating the well-ordered nature of the stress response. The directional movement and timing of induction for many genes matched closely the known physiological role of the proteins they encode. Inhibitors of the cell cycle (CDKN1, CDKN4D, ATM) were induced, whereas cyclins [proliferating cell nuclear antigen (PCNA), cyclin A, cyclin D1, cyclin K] were downregulated during the period from 6--20 h. Likewise, pro-apoptotic genes such as the caspases (CASP9, CASP3, CASP2) and apoptotic protease activating factor (APAF) were induced during the same period. Results of this study indicate that there is a good correlation between time-dependent physiological, biochemical, and gene expression data.

Apoptosis↗
PubMedDate not supplied

Quantitative morphologic changes in nephron structures and urinary enzyme activity pattern in sodium-maleate-induced renal injury.

The morphologic changes in sodium-maleate-induced acute renal injury in the rat were quantified by a stereologic analysis. The major changes were confined to an increase in endocytic vacuoles and a decrease in mitochondrial inner membrane surface area. These results were found to be linked to significantly increased urinary activities of the cytosolic of the cytosolic enzymes fructose-1,6-bisphosphatase (FBP) and lactate dehydrogenase, the lysosomal enzyme N-acetyl-beta-glucosaminidase (NAG) and the NAD-dependent mitochondrial isocitrate dehydrogenase (ICDH). The highest increase was found for NAG, followed by FBP and ICDH.

Animals↗
PubMed1983

Study on the lipid composition of rat bile during choleresis induced by diethyl maleate.

Diethyl maleate (DEM) is known to produce a rapid depletion of hepatic glutathione (GSH) and to induce an immediate short-term choleresis in experimental animals. The aim of our investigation was to ascertain in rats the effect of DEM on biliary lipid composition during the increment in bile flow. Biochemical and morphological studies of liver tissue were conducted in parallel. In bile fistula rats, a doubling of bile flow occurred immediately after intraperitoneal injection of DEM (0.7 ml/kg body weight) returning to the basal level at 45 min. Choleresis diluted the total bile acid concentration, without modifying the secretion. The phospholipid concentration was not affected by DEM, resulting in increased output (p less than 0.02 vs. controls). Both cholesterol concentration and output were significantly decreased during DEM-induced choleresis. These changes were promptly reversible together with the return of bile flow to control values. Biochemical determinations failed to show a DEM-induced modification of enzymatic activities of the microsomal drug biotransformation pathway. Instead, morphological studies revealed alterations of the Golgi apparatus in hepatocytes with marked distension of the cisternae in coincidence with choleresis. The results demonstrate that the bile acid-independent choleresis induced by DEM is accompanied by an alternation in biliary lipid secretion possibly related to an interaction of the drug with the cellular or subcellular membranes of hepatocytes.

Animals↗
PubMedDate not supplied

Cystathionine pathway-dependent cytotoxicities of diethyl maleate and diamide in rat and human hepatoma-derived cell cultures.

Glutathione (GSH) plays a role in many toxicologically important metabolic processes. It was previously established that L-buthionine S,R-sulphoximine (BSO), a specific inhibitor of (- glutamylcysteine synthetase, reduces the GSH content more efficiently in rat (Fa32) than in human (HEp-G2) hepatoma-derived cells. We therefore investigated whether the cystathionase inhibitor propargylglycine (PPG) could further decrease the BSO-induced GSH depletion in HEp-G2 cells. The influence of the cystathionine precursors N-acetylmethionine, methionine and homocysteine on the cytotoxicity of diethyl maleate (DEM) and diamide [1,1'-azobis(N,N-dimethylformamide)] was also investigated. PPG reduced the GSH content in both cell lines. A further GSH decrease in HEp-G2 was obtained when using a BSO + PPG combination containing relatively high concentrations of PPG. BSO diminished the toxicity of PPG. Homocysteine was the most efficacious of the tested cystathionine precursors in increasing the GSH content and reducing the cytotoxicity of DEM and diamide in Fa32 and HEp-G2 cells.

Alkynes↗
PubMed1997

Magnesium and the N-methyl-D-aspartate receptor antagonist dizocilpine maleate neither increase glucose use nor induce a 72-kilodalton heat shock protein expression in the immature rat brain.

In adult rats N-methyl-D-aspartate receptor (NMDAR) antagonists increase glucose use and induce a 72-kD heat shock protein (HSP72) expression in limbic system areas that later undergo neuronal necrosis, which have limited the clinical development of these drugs. Dizocilpine maleate (MK-801) and magnesium sulfate (MgSO4) reduce hypoxic-ischemic brain injury in immature animals, but the effects on HSP72 expression and glucose use are unknown. Seven-day-old rats received injections of either vehicle (control), 0.5 or 1.0 mg/kg MK-801, or 2 or 4 mmol/kg MgSO4. Glucose utilization was measured with the deoxyglucose method, 30 min, 48 h, and 4 d after injection. HSP72 immunostaining was evaluated 4 or 24 h after injection. Both doses of MK-801 and 4 mmol/kg MgSO4 induced a temporary decrease in glucose use in the posterior cingulate and retrosplenial cortex, the CA1 and CA3 subfields of the hippocampus, the caudoputamen, and the parietal cortex. Doses of 2 mmol/kg MgSO4 did not affect glucose use in any structure. Neuronal HSP72 expression was not found in any drug-treated rats. In conclusion, neither MK-801 nor MgSO4 increased glucose use in the limbic system and did not induce HSP72 expression, suggesting that NMDAR antagonists lack direct neurotoxicity in the immature brain.

Animals↗
PubMed1997

Cytotoxicity of naphthoquinones toward cultured resting murine leukemia L1210 cells in the presence of glutathione, diethyl maleate, or iodoacetamide.

Sixteen naphthoquinones with various substituents were tested for cytotoxicity toward cultured resting leukemia L1210 cells. The cytotoxicity of all the naphthoquinones examined was not affected at all by the treatment in combination with diethyl maleate, a glutathione-specific SH-blocking agent in the cells. Depending on the characteristics of the response to the treatment in combination with iodoacetamide (IAA) and glutathione (GSH), these naphthoquinones were tentatively classified into three groups. The chemicals of Group I, which include naphthoquinones carrying an electron-donating group(s) other than an OH group on the quinone ring moiety, showed synergistic cytotoxicity with IAA and no reduction in cytotoxicity with GSH. Those of Group II, which include naphthoquinones without an electron-donating group on the quinone ring moiety, showed no synergy with IAA but appreciable reductions in cytotoxicity with GSH. Group III includes 2-hydroxylated naphthoquinones, which showed neither synergy with IAA nor cytotoxicity reduction with GSH. Cytotoxicity was discussed in terms of the electron-deficiency of the quinone ring moiety. It is suggested that the cytotoxicity of Group I quinones comes from the active oxygen generation which follows semiquinone formation, whereas that of the other groups of quinones is not likely caused simply by either SH-blocking of biomolecules or active oxygen-related mechanism.

Alkylating Agents↗
PubMed2005

Decreased tissue accumulation of 6-deoxy-6-[18F]fluoro-L-ascorbic acid in glutathione-deficient rats induced by administration of diethyl maleate.

The relationship between in vivo biodistribution of 6-deoxy-6-[18F]fluoro-L-ascorbic acid (18F-DFA) and the content of tissue glutathione (GSH) was investigated in Wistar male rats. Following intravenous administration of 18F-DFA, the accumulation of radioactivity in most tissues, including the adrenal glands, liver and brain, was significantly reduced together with a decrease in the content of GSH by preloading of diethyl maleate (DEM) which depletes cellular GSH. Similar decreased uptake was also observed in the distribution of L-[1-14C]ascorbic acid (14C-AA) after DEM treatment. The possible biological mechanisms, including competition with endogenous AA and ascorbate recycling, that modulate the uptake and accumulation into tissues of 18F-DFA and 14C-AA in GSH-deficient rats are discussed.

Animals↗
PubMed1987

Effect of phenothiazines, disodium ethylenediaminetetraacetic acid and diethyl maleate on in vitro rat colonic transport of cefmetazole and inulin.

An in vitro rat colonic sac method developed in this study was found to be suitable for frequent collection of samples and determination of transport of compounds from serosal and mucosal medium, since the volume of both was large. Under no a treatment condition, both cefmetazole and inulin penetrated the intestinal mucosa via the paracellular route, but did so very poorly. Phenothiazines as well as disodium ethylenediaminetetraacetic acid increased the transport of cefmetazole and inulin, probably via the paracellular route, while diethyl maleate increased the transport of only cefmetazole, probably via the intracellular route. The effect of phenothiazines in increasing the clearance rate for both cefmetazole and inulin showed dependency on their initial concentrations in the mucosal medium with maximum action at a concentration of 30 microM for trifluoperazine, 20 microM for perphenazine, 75 microM for profenemine and 50 microM for propericiazine.

Animals↗
PubMed1993

Effects of diethyl maleate on phenyl-hydroquinone-induced cytotoxicity in isolated rat hepatocytes.

1. The effects of diethyl maleate (DEM) on the cytotoxicity of phenyl-hydroquinone (PHQ) and other hydroquinones were studied in freshly isolated rat hepatocytes. 2. Addition of PHQ (0.5 or 0.75 mM) to hepatocytes resulted in dose-dependent cell death accompanied by the abrupt depletion of both GSH and protein thiols and the accumulation of phenyl-benzoquinone (PBQ). 3. Pretreatment with DEM (1.25 mM), which causes an abrupt depletion of cellular GSH in hepatocytes, delayed the onset of PHQ-induced cytotoxicity. The delay correlated with inhibition of PBQ formation. 4. Although the pH of the cell suspension was increased slightly (mean pH 0.18) by incubation under carbogen flow, the addition of DEM to the cell suspension inhibited both the increase in pH and the formation of PBQ from PHQ. 5. In hepatocyte suspensions without DEM, PHQ cytotoxicity was dependent on pH, and toxicity was associated with oxidation of PHQ and accumulation of PBQ. 6. Among other hydroquinones (0.5 mM), tert-butyl-hydroquinone-induced cytotoxicity was decreased by DEM (1.25 mM), but DEM did not affect the cytotoxicity of 2,5-di(tert-butyl)-1,4-benzohydroquinone. 7. PHQ-induced cytotoxicity correlated with the accumulation of PBQ in the cell, and the inhibition of PHQ-induced cytotoxicity by DEM correlated with pH-dependent changes in PBQ formation.

Animals↗
PubMed1997

Pre- and postischemic effects of the NMDA receptor antagonist dizocilpine maleate (MK-801) on collateral cerebral blood flow.

The authors studied the effects of pre- and postischemic administration of dizocilpine maleate (MK-801) on collateral and regional cerebral blood flow (CBF). The ischemic penumbra appears to benefit most from the neuroprotective effects of MK-801. The precise mechanism by which MK-801 provides this neuroprotection remains controversial. Alterations in CBF have been demonstrated with MK-801 administration, but whether the response is an increase or decrease in flow has remained unclear. A left-sided craniectomy was performed in 20 dogs. A branch of the middle cerebral artery (MCA) was cannulated and collateral blood supply-dependent tissue (CDT) was identified using the "shadow flow" technique. Regional CBF was measured using radiolabeled microspheres. Six dogs received MK-801 (1 mg/kg administered intravenously) before they underwent MCA branch occlusion; the remaining 14 dogs received MK-801 after they underwent MCA occlusion. Cerebral blood flow and vascular pressures were measured 30 and 60 minutes after MK-801 administration. In animals that received MK-801 before MCA occlusion, CBF did not change significantly from baseline values before or after occlusion. In contrast, in animals that received MK-801 after MCA occlusion, CBF was significantly reduced in all regions of the brain, including the CDT. Collateral blood supply-dependent tissue showed a 51.7% reduction in flow, whereas normal CBF was reduced by 29.7%. The MK-801 induced cerebral vasoconstriction in both groups. The neuroprotective effects of MK-801 do not appear to be caused by the augmentation of collateral or global cerebral circulation and, in fact, may block the glutamate-mediated vasodilation that occurs during ischemia.

Animals↗
PubMed1995

Influence of diethyl maleate and cysteine on tissue glutathione and growth in broiler chickens.

The objectives of this study were to determine the effects of diethyl maleate (DEM) and l-cysteine (L-Cys) on tissue glutathione (GSH) and growth in male broiler chickens. In Experiment 1, broilers were treated with DEM (0, 1.5, 3, 6, or 12.0 mmol/kg BW, i.p.). After 1 h, maximum GSH depletions were to 9, 24, 20, 19, and 35% of control (0 mmol DEM/kg) for liver, lung, kidney, heart, and brain, respectively. In Experiment 2, time-course changes following 1.5 mmol DEM/kg (i.p.) were determined; time-controls received an equal amount of corn oil (CO, .25 mL/kg BW). Levels of GSH in all tissues were low at 1 and 2 h after DEM in comparison to time-control values. Tissue GSH concentrations returned to values that were not different from controls by 5 h in liver and kidney, by 12 h in heart, and by 24 h in brain and lung. In Experiment 3, the effects of feeding a control diet (0% L-Cys) or one supplemented with 1% L-Cys from 3 to 7 wk of age with weekly i.p. injections (at 3,4,5, and 6 wk of age) of DEM (1.5 mmol/kg BW) or CO (.25 mL/kg BW) on growth rate and tissue GSH were determined. There were no differences in BW among treatment groups between 3 and 6 wk of age. Although there were no differences in 7-wk BW between controls (0% L-Cys/CO) and birds treated with DEM fed either diet, the 1% L-Cys/CO group was heavier (P < .05) than either the 0% or 1% L-Cys/DEM groups, and heavier (P = .066) than controls at 7 wk of age. At 5 wk of age, 1% L-Cys raised GSH concentrations in liver, kidney, lung, and duodenum, but had no effect on heart GSH in birds treated with either CO or DEM. Control hepatic GSH concentrations were higher at 7 than at 5 wk of age. With the exception of duodenal GSH in CO birds, 1% L-Cys had no effect on tissue GSH concentrations in 7-wk-old birds. The results of this study provide an initial characterization of GSH metabolism in commercial male broilers and indicate that DEM produced dose- and time-dependent changes in GSH similar to reported changes in mammals. Results of this study also indicate that increased tissue GSH may be beneficial for growth.

Analysis of Variance↗
PubMed1999

Delayed treatment with diethyl maleate prevents E-selectin expression in human endothelial cells.

BACKGROUND: Polymorphonuclear leukocyte (PMN) infiltration is a significant contributor to tissue damage in many disease states and is known to occur through an orderly set of events. The endothelial cell adhesion molecule E-selectin is involved in the initial rolling of PMNs on the endothelium at sites of inflammation. We have previously shown that the glutathione depleting agent diethyl maleate (DEM) attenuates lung injury in a rodent model of intratracheal LPS stimulation. We hypothesized that DEM might attenuate E-selectin in LPS-treated human umbilical vein endothelial cells as a mechanism underlying this effect. Further, we investigated the role of delayed treatment with DEM on E-selectin expression. METHODS: Human umbilical vein endothelial cells were treated with DEM (100 to 400 mumol/L) before or after LPS stimulation (1 microgram/mL). Surface expression of E-selectin was examined using a cellular enzyme-linked immunosorbent assay. E-selectin mRNA transcripts were detected by Northern blot analysis. Nuclear factor-kappa B (NF-kappa B) activity was detected with gel shift assays. RESULTS: DEM significantly inhibited LPS-induced E-selectin surface expression and mRNA levels in a dose-dependent fashion, with complete inhibition at 250 mumol/L, without affecting cell viability. This inhibitory effect was seen even if DEM was added up to 60 minutes after LPS. DEM inhibited NF-kappa B nuclear translocation in a manner that mirrored protein and mRNA levels. CONCLUSIONS: Delayed treatment with DEM attenuates NF-kappa B nuclear translocation and E-selectin expression in human umbilical vein endothelial cells up to 60 minutes after the onset of LPS stimulation. Thus, DEM may represent an effective intervention for PMN-mediated organ injury even when given after an inflammatory insult.

Cells, Cultured↗