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PubMed1995

Desulfuromonas palmitatis sp. nov., a marine dissimilatory Fe(III) reducer that can oxidize long-chain fatty acids.

Studies on the microorganisms living in hydrocarbon-contaminated sediments in San Diego Bay, California led to the isolation of a novel Fe(III)-reducing microorganism. This organism, designated strain SDBY1, was an obligately anaerobic, non-motile, non-flagellated, gram-negative rod. Strain SDBY1 conserves energy to support growth from the oxidation of acetate, lactate, succinate, fumarate, laurate, palmitate, or stearate. H2 was also oxidized with the reduction of Fe(III), but growth with H2 as the sole electron donor was not observed. In addition to various forms of soluble and insoluble Fe(III), strain SDBY1 also coupled growth to the reduction of fumarate, Mn(IV), or S0. Air-oxidized minus dithionite-reduced difference spectra exhibited peaks at 552.8, 523.6, and 422.8 nm, indicative of c-type cytochrome(s). Strain SDBY1 shares physiological characteristics with organisms in the genera Geobacter, Pelobacter, and Desulfuromonas. Detailed analysis of the 16S rRNA sequence indicated that strain SDBY1 should be placed in the genus Desulfuromonas. The new species name Desulfuromonas palmitatis is proposed. D. palmitatis is only the second marine organism found (after D. acetoxidans) to oxidize multicarbon organic compounds completely to carbon dioxide with Fe(III) as an electron acceptor and provides the first pure culture model for the oxidation of long-chain fatty acids coupled to Fe(III) reduction.

Electron Transport↗
PubMed1996

A new antihypertensive strategy for black patients: low-dose multimechanism therapy.

Hypertension poses serious health risks for blacks because this population presents with earlier onset and more severe forms of the disease than do nonblacks. Although diuretics are the cornerstone of antihypertensive therapy In the black population, investigators have expressed concern about adverse metabolic effects, such as hypokalemia, produced by the high doses of diuretics traditionally prescribed for blacks. Recent evidence suggests that black patients may respond equally well to the new generation of cardioselective beta-blockers and angiotensin-converting enzyme inhibitors, particularly when these agents are used together with a diuretic. A new low-dose multimechanism agent that combines the cardioselective beta-blocker bisoprolol fumarate with hydrochlorothiazide, a benzothiazine diuretic, is now available for first-line therapy for hypertension. Results of two US multicenter trials--including a subset analysis of black patients--indicate that the once-daily agent is highly effective in reducing diastolic and systolic blood pressure throughout a 24-hour period in both black and nonblack patients. The agent is well tolerated in blacks and non-blacks and has a side-effect profile comparable to placebo. Because of its efficacy and safety in black patients, bisoprolol fumarate/-hydrochlorothiazide is an appropriate therapeutic option for first-line therapy of hypertension in the black population.

Black or African American↗
PubMed1997

Identification of His141 in the active site of Bacillus subtilis adenylosuccinate lyase by affinity labeling with 6-(4-bromo-2,3-dioxobutyl)thioadenosine 5'-monophosphate.

Adenylosuccinate lyase of Bacillus subtilis is inactivated by 25-400 microM 6-(4-bromo-2,3-dioxobutyl)thioadenosine 5'-monophosphate (6-BDB-TAMP) at pH 7.0 and 25 degrees C. The initial inactivation rate constant exhibits nonlinear dependence on the concentration of 6-BDB-TAMP, implying there is reversible formation of enzyme-reagent complex (K(I) = 30 +/- 4 microM) prior to irreversible modification (kmax = 0.139 +/- 0.005 min(-1)). The tetrameric enzyme incorporates about 1 mol of 6-BDB-[32P]TAMP per mol of enzyme subunit concomitant with complete inactivation. Protection against inactivation and incorporation of [32P]reagent is provided by adenylosuccinate or a combination of AMP and fumarate, whereas either AMP or fumarate alone is much less effective. These observations suggest that 6-BDB-TAMP targets the adenylosuccinate-binding site. Hydrolyzed 6-BDB-TAMP is a competitive inhibitor with respect to adenylosuccinate in the catalytic reaction and also decreases the rate of inactivation by 6-BDB-TAMP. These results account for the decrease in the inactivation rate as the reaction of 6-BDB-TAMP with the enzyme proceeds. Purification by chromatography on dihydroxyboryl-agarose and high performance liquid chromatography of the tryptic digest of inactivated enzyme yields a single radioactive peptide, Thr140-Phe150, as determined by gas-phase sequencing. Modified His141 is the reaction product of 6-BDB-TAMP and adenylosuccinate lyase. We conclude that 6-BDB-TAMP functions as a reactive adenylosuccinate analog in modifying His141 in the substrate-binding site of adenylosuccinate lyase, where it may serve as a general base accepting a proton from the succinyl group during catalysis.

Adenosine Monophosphate↗
PubMed1998

[Intravenous iron in the treatment of postoperative anemia in surgery of the spine in infants and adolescents].

PURPOSE OF THE STUDY: Spinal fusion surgery often leeds to massive bleeding responsible for anemia in the postoperative period. The aim of this study was to compare the effect of IV iron III hydroxide sucrose complex (Venofer) versus oral iron fumarate administration in postoperative anemia. The efficacy of both treatments was evaluated by comparing hemoglobin level in the postoperative period. METHODS: Two groups of sixteen patients, scheduled for anterior and/or posterior spinal fusion, were compared. Group 1, historical, was treated by supplementation of 10 mg/kg/day oral iron fumarate. Administration was started when hemoglobin level fell below 9 g/100 ml. Group 2 was treated by intravenous iron sucrose complex using same criteria as in group 1 for starting administration. The dosage of iron was individually adapted according to a target hemoglobin level of 13 g/100 ml and to the actual lowest hemoglobin level measured. The total iron deficit was calculated with the following formula: total iron deficit (mg) = 0.24 x body weight (kg) x (target Hb-actual Hb)(g/l). The patients were supplemented by 3 mg/kg/day until the calculated iron deficit was compensated. RESULTS: Both groups were identical regarding age and lowest hemoglobin level reached in the postoperative period. Hemoglobin increased by 0.25 g/day in group 1, and by 0.36 g/day in group 2. In others words, the beneficial effect of IV iron versus oral iron administration was as high as 45 per cent (p = 0.003). CONCLUSION: Intravenous iron therapy as ferric sucrose complex is a new and more effective form of iron therapy than oral iron therapy to restore postoperative hemoglobin after spinal surgery in children.

Administration, Oral↗
PubMed1964

MECHANISMS IN THE INHIBITION OF MICROORGANISMS BY SORBIC ACID.

York, George K. (University of California, Davis), and Reese H. Vaughn. Mechanisms in the inhibition of microorganisms by sorbic acid. J. Bacteriol. 88:411-417. 1964.-Oxidative assimilation of glucose, acetate, succinate, and fumarate by washed cells of Escherichia coli, Pseudomonas aeruginosa, and Saccharomyces cerevisiae was inhibited by concentrations of sorbic acid ranging from 15 to 105 mg per 100 ml. At higher concentrations, the oxidation of these substrates was inhibited. Oxidative phosphorylation by submicroscopic particles of E. coli was reduced by about 30% by 37 mg per 100 ml of sorbic acid. The sulfhydryl enzymes fumarase, aspartase, and succinic dehydrogenase were inhibited by sorbic acid. The loss of activity of sorbic acid after reacting with cysteine suggested that a thiol addition occurred, which is believed to be the mechanism of action against sulfhydryl enzymes or cofactors.

Acetates↗
PubMed1997

Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells.

Most studies on the antipsoriatic mode of action of dimethylfumarate focused on its antiproliferative effects in keratinocytes. Because inflammatory skin diseases are associated with an upregulation of endothelial cell adhesion molecules and because the presence of inflammatory cells in dermis and epidermis is considered an important feature in psoriasis, we tested the effect of DMF on cytokine-induced adhesion molecule expression in HUVEC, using in situ ELISA and Northern blotting. Dimethylfumarate inhibited ICAM-1, VCAM-1, and E-selectin expression and reduced adhesion of U937 cells to stimulated HUVEC. Monoethylfumarate and fumaric acid had no effect. Similar inhibitory effects for DMF on VCAM-1 expression were observed after stimulation of HUVEC with LPS, PMA, IL-4, and IL-1 alpha or in combinations with TNF alpha. These data are in agreement with previously reported effects of DMF on intracellular thiol levels and inhibition of NF-kappa B activation. The inhibitory effect on cytokine-induced endothelial adhesion molecule expression may represent another target of dimethylfumarate in psoriasis.

Blotting, Northern↗
PubMed1991

L-malic acid production using immobilized Saccharomyces cerevisiae.

L-Malate was produced from fumarate by using immobilized Saccharomyces cerevisiae cells entrapped in polyacrylamide. This preparation performed better when pretreated with malonate. Under the experimental conditions described here, succinate was not detected as a by-product of the reaction, as had been reported for other microorganisms.

Acrylic Resins↗
PubMed1993

Role of protein thiols in intrinsic radiation protection of DNA and cells.

Previous data have been consistent with the hypothesis that the thiol depleter dimethyl fumarate (DMF) increases radiation sensitivity of hypoxic mammalian cells by a combination of two actions: depletion of glutathione (GSH) which interferes with the chemical competition between damage fixation and repair and depletion of protein thiol (PSH) which causes inhibition of enzymatic repair processes. However, one cannot rule out the possibility that PSH also acts in the chemical competition to restitute damaged DNA. The studies presented here have addressed this question by studying the effects of ionizing radiation on isolated nuclei which contain very low levels of GSH, but substantial amounts of PSH, compared to intact cells. The results show that DNA damage, measured using the non-denaturing filter elution assay, is increased about 1.6-fold in isolated nuclei irradiated in air, compared to whole cells, and about 4.3-fold in nuclei irradiated in N2. Thus, the OER for DNA damage decreases from about 3 in whole cells to 1 in isolated nuclei. Also, although DMF increases radiation-induced DNA damage in whole cells irradiated in hypoxia about 2-fold, it does not increase DNA damage in isolated nuclei irradiated in hypoxia. These data do not support the idea that PSH can act in the chemical competition reaction to chemically repair radiation-induced DNA radicals. The data are discussed in relation to the effect that various procedures for nuclei isolation can have on radiation sensitivity of DNA and on the OER. We also address the question of whether radiation-induced DNA damage measured by non-denaturing elution correlates with cell killing.

Animals↗
PubMed2006

Acidity constants in methanol/water mixtures of polycarboxylic acids used in drug salt preparations. Potentiometric determination of aqueous pKa values of quetiapine formulated as hemifumarate.

The acidic dissociation constants in a number of methanol/water mixtures of mono and polycarboxylic acids commonly used in the preparation of drug salts were determined. These solvent mixtures are usually used to determine the pKa of drugs of low aqueous solubility. However, when these drugs are prepared in salt form, the acid-base equilibria of both the basic drug and the counter-anion are involved in the potentiometric titration curves. In these instances, the inclusion of the pKa of acids as constant values in the curve fitting provides easy computation of the drug pKa without the need of any previous step to get the free base. As an application example, the aqueous pKa values of the quetiapine formulated as hemifumarate (Seroquel) were estimated by extrapolation from the experimental pKa in several methanol/water mixtures, which were then calculated according to the suitable constants of fumaric acid. The estimated aqueous pKa values of quetiapine are compared with those directly obtained in aqueous solution by potentiometry and by capillary electrophoresis.

Algorithms↗
PubMed2005

Dimethylfumarate for psoriasis: more than a dietary curiosity.

Fumaric acid esters (FAEs) have been used for the oral treatment of psoriasis since 1959 and have been registered for this indication in Germany since 1994. Dimethylfumarate (DMF) and its metabolite methylhydrogenfumarate (MHF) are the pharmacologically active compounds, with DMF being the main component of the marketed FAE-mixture. However, the mechanism of action of FAE is yet to be fully understood. It has been shown that DMF inhibits NFkappaB translocation, which leads to (i) the inhibition of pro-inflammatory cytokine production and adhesion molecule expression, (ii) the inhibition of dendritic cell differentiation and, at higher concentrations, (iii) the induction of apoptosis. Recent evidence also shows that these effects are mediated through the interference of the intracellular redox system by DMF. Here, the mode of action of FAE and its clinical use for psoriasis will be discussed.

Apoptosis↗
PubMed2005

Inhibition of vesicular monoamine transporter enhances vulnerability of dopaminergic cells: relevance to Parkinson's disease.

Parkinson's disease is a neurodegenerative disorder associated with progressive loss of dopaminergic cells in the substantia nigra. Oxidative stress has been implicated in the pathogenesis of the disease, and dopamine has been suggested as a contributing factor that generates reactive oxygen species due to its unstable catechol moiety. We have previously shown that tetrahydrobiopterin (BH4), an obligatory cofactor for dopamine synthesis, also contributes to the vulnerability of dopamine-producing cells by generating oxidative stress. This study shows that the presence of dopamine in the cytosol enhances the cell's vulnerability to BH4. Upon exposure to ketanserin, a vesicular monoamine transporter inhibitor, BH4-induced dopaminergic cell death is exacerbated, accompanied by increased lipid peroxidation and protein bound quinone. While intracellular amount of DOPAC is elevated by ketanserin, the monoamine oxidase inhibitor pargyline showed no significant protection. Instead, the thiol agent N-acetylcysteine and quinone reductase inducer dimethyl fumarate abolish BH4/ketanserin-induced cell death, suggesting that quinone production plays an important role. Therefore, it can be concluded that the presence of dopamine in the cytosol seems to contribute to the cells' vulnerability to BH4 and that vesicular monoamine transporter plays a protective role in dopaminergic cells by sequestering dopamine not only from monoamine oxidase but also from BH4-induced oxidative stress.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Role of glutathione in repair of free radical damage in hippocampus in vitro.

Depletion of glutathione (GSH), an intrinsic antioxidant, increases vulnerability to free radical damage in a number of cell systems. This study investigates the role of GSH in limiting electrophysiological damage and/or recovery from free radical exposure in slices of guinea pig hippocampus. Synaptic potentials (PSPs) and population spikes (PSs) were recorded from field CA1. Free radicals were generated from 0.006% peroxide through the Fenton reaction. Analysis of the input-output curves showed that peroxide treatment decreased PSPs and impaired ability of the PSPs to generate PSs as previously reported. Recovery was nearly total within a half hour. Treatment with 5 mM buthionine sulfoximine (BSO) for 2 h depleted hippocampal GSH to 79.2% of control values. The extent of free radical damage was not increased. Recovery, however, was only partial. GSH was further depleted by oxidation with diamide or covalent bonding with dimethyl fumarate (DMF) immediately before and during the peroxide treatment. Neither diamide nor DMF treatment in BSO-incubated tissue enhanced peroxide-induced electrophysiological deficits. Following these treatments, however, tissue showed little recovery from free radical damage. We conclude that glutathione is essential for repair processes in hippocampal neurons exposed to oxidative damage.

Animals↗
PubMed1999

Effect of inducers of DT-diaphorase on the toxicity of 2-methyl- and 2-hydroxy-1,4-naphthoquinone to rats.

It has previously been shown that rats pre-treated with butylated hydroxyanisole (BHA), a well-known inducer of the enzyme DT-diaphorase, are protected against the toxic effects of 2-methyl-1,4-naphthoquinone but are made more susceptible to the harmful action of 2-hydroxy-1,4-naphthoquinone. In the present experiments, the effects of BHA have been compared with those of other inducers of DT-diaphorase. Rats were dosed with BHA, butylated hydroxytoluene (BHT), ethoxyquin (EQ), dimethyl fumarate (DMF) or disulfiram (DIS) and then challenged with a toxic dose of the naphthoquinones. All the inducers protected against the haemolytic anaemia induced by 2-methyl-1,4-naphthoquinone in rats, with BHA, BHT and EQ being somewhat more effective than DMF and DIS. A similar order of activity was recorded in the relative ability of these substances to increase hepatic activities of DT-diaphorase, consistent with a role for this enzyme in facilitating conjugation and excretion of this naphthoquinone. In contrast, all the compounds increased the haemolytic activity of 2-hydroxy-1,4-naphthoquinone. DMF and DIS were significantly more effective in this regard than BHA, BHT and EQ. DMF and DIS also caused a much greater increase in levels of DT-diaphorase in the intestine, suggesting that 2-hydroxy-1,4-naphthoquinone is activated by this enzyme in the gut. BHA, BHT and EQ had no effect on the nephrotoxicity of 2-hydroxy-1,4-naphthoquinone, but the severity of the renal lesions was decreased in rats pre-treated with DMF and DIS. The results of the present experiments show that modulation of tissue levels of DT-diaphorase may not only alter the severity of naphthoquinone toxicity in vivo, but may also change the relative toxicity of these substances to different target organs.

Animals↗
PubMed1999

Reduction of H2O2-evoked, intracellular calcium increases in the rat N18-RE-105 neuronal cell line by pretreatment with an electrophilic antioxidant inducer.

Pretreatment of the neuronal cell line N18-RE-105 with the antioxidant enzyme inducer dimethyl fumarate (DMF) reduced cell death elicited by H2O2 (50 mM for 1 h) as measured 24 h after H2O2 washout. Oxidants like H2O2 may contribute to cell death by increasing intracellular ionized calcium ([Ca2+]i), suggesting that DMF may in part confer protection by altering H2O2-induced [Ca2+]i signals. To examine this possibility, we measured [Ca2+]i of fura-2-loaded cultures of DMF- and vehicle-pretreated cells during H2O2 superfusion. H2O2 exposure induced a delayed [Ca2+]i increase that was significantly lower in DMF-pretreated cells than controls. Elevation of extracellular cystine also reduced the H2O2 induced [Ca2+]i elevation. Thus, antioxidant upregulation may contribute to protection during oxidative stress by stabilizing [Ca2+]i. However, since oxidative stress may induce cytotoxicity by multiple pathways, [Ca2+]i stabilization may not be the only mechanism responsible for the protective effect of DMF.

Animals↗
PubMed2004

Dietary induction of NQO1 increases the antitumour activity of mitomycin C in human colon tumours in vivo.

The bioreductive antitumour agent, mitomycin C (MMC), requires activation by reductive enzymes like NAD(P)H:quinone oxidoreductase 1 (NQO1). We used a novel approach to increase MMC efficacy by selectively inducing NQO1 in tumour cells in vivo. CD-1 nude mice were implanted with HCT116 cells, and fed control diet or diet containing 0.3% of the NQO1 inducer, dimethyl fumarate (DMF). The mice were then treated with saline, 2.0, 3.5 or 2.0 mg kg(-1) MMC and dicoumarol, an NQO1 inhibitor. The DMF diet increased NQO1 activity by 2.5-fold in the tumours, but had no effect in marrow cells. Mice given control diet/2.0 mg kg(-1) MMC had tumours with the same volume as control mice; however, mice given DMF diet/2.0 mg kg(-1) MMC had significantly smaller tumours. Tumour volumes in mice given DMF/2.0 mg kg(-1) MMC were similar to those in mice given control diet/3.5 mg kg(-1) MMC. Tumour inhibition was partially reversed in mice given DMF/2.0 mg kg(-1) MMC and dicoumarol. DMF diet/2.0 mg kg(-1) MMC treatment did not increase myelosuppression and did not produce any organ toxicity. These results provide strong evidence that dietary inducers of NQO1 can increase the antitumour activity of bioreductive agents like MMC without increasing toxicity.

Animals↗
PubMed1965

THE RESPIRATION OF ISOLATED RAT-HEPATIC CELLS IN SUSPENSION.

1. Rat-hepatic cells in suspension have been shown to have an endogenous respiration of 5.6+/-0.17 when suspended in 0.1 m-sucrose and 0.02 m-tris-hydrochloric acid buffer. The respiration in 0.25 m-sucrose and 0.02 m-tris-hydrochloric acid buffer is 30-40% less. 2. Potassium chloride (0.05 m) is slightly inhibitory and calcium chloride (0.0025 m) highly inhibitory to endogenous respiration of the hepatic cells in suspension. The cells do not respire in Krebs-Ringer phosphate buffer. 3. The respiration of the hepatic cells in suspension is stimulated by pyruvate, citrate, isocitrate, oxoglutarate, succinate, fumarate, malate and glutamate; there is no significant stimulation (or inhibition) by glucose, fructose, acetate and butyrate. In almost all the cases where stimulation was observed, it was found that the higher the endogenous respiration the lower is the stimulation.

Acetates↗
PubMed1965

ACCELERATION OF RENAL GLUCONEOGENESIS BY KETONE BODIES AND FATTY ACIDS.

1. Acetoacetate or short-chain fatty acids (acetate, butyrate, propionate, n-hexanoate, n-octanoate) accelerate the rate of glucose formation from lactate, fumarate and other precursors in slices of kidney cortex (rat, rabbit, sheep). The cause of this acceleration has been investigated. 2. There are two different mechanisms of acceleration. At low concentrations of glucogenic precursors the acceleration is mainly due to a ;sparing' action. The substances which accelerate are oxidizable and serve as fuel of respiration in place of the glucogenic precursor. This is indicated by the fact that the ratio lactate used/glucose formed falls in the presence of the accelerators and approaches the value 2. 3. At high concentrations of lactate the acceleration appears to be mainly due to the activation of pyruvate carboxylase by acetyl-coenzyme A. The evidence in support of this is summarized. The results indicate that the activation of pyruvate carboxylase by acyl-coenzyme A discovered by Utter & Keech (1963) in purified enzyme preparations also occurs in crude tissue homogenates and can play a part in the control of oxaloacetate synthesis and gluconeogenesis.

Acetates↗
PubMed1965

METABOLISM OF PROPIONATE BY SHEEP LIVER. INTERRELATIONS OF PROPIONATE AND GLUTAMATE IN AGED MITOCHONDRIA.

1. Low concentrations of l-glutamate were slowly and quantitatively converted into aspartate by aged sheep-liver mitochondria with the loss of C-1 of the glutamate. 2. When propionate was present in addition the rate of conversion of glutamate into aspartate was increased slightly, and the presence of glutamate caused a marked stimulation in the rate at which propionate was metabolized. 3. The stimulatory effect of ;sparker' amounts of l-glutamate on propionate metabolism was matched by the effects of alpha-oxoglutarate, pyruvate, citrate and isocitrate, but not by succinate, fumarate, malate or oxaloacetate. Succinate was stimulatory at higher concentrations, whereas oxaloacetate was inhibitory. 4. When propionate was incubated with l-[1-(14)C]glutamate in the presence of a large excess of unlabelled carbon dioxide, some labelling of dicarboxylic acids and aspartate occurred, but this was much less than would have been expected from an obligatory transcarboxylation from C-1 of alpha-oxoglutarate to propionyl-CoA. 5. Possible mechanisms of these effects are discussed.

Acyl Coenzyme A↗