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At least 19 recordsLinked to original sources
PubMed2006

Site specific changes of redox metabolism in adipose tissue of obese Zucker rats.

Adipose tissues are differently involved in lipid metabolism and obesity according to their type and location. Increasing reports stress on the impact of redox metabolism on obesity and metabolic syndrome. The aim of this work is to investigate the site-specific redox metabolism in three different adipose tissues and its changes occurring in obesity. We analysed enzymatic and non-enzymatic parameters, and focused on the reduced/oxidized glutathione and coenzyme Q couples. In lean compared with obese non-diabetic Zucker rats, interscapular brown fat seems well protected against oxidative stress and epididymal adipose tissue shows a more reduced glutathione redox state, associated with a higher susceptibility to lipophilic oxidative stress than inguinal adipose tissue. Epididymal adipose tissue redox metabolism significantly differs from inguinal one by its limited redox metabolism adaptation. Our results demonstrate site-specific managements of reactive oxygen species metabolism in obese Zucker rats. These results are not consistent with the classic deciphering of inflammatory situation and produce a new conception of the redox parameters implication in the development of the metabolic syndrome.

Adipose Tissue, Brown↗
PubMed2006

Monocyte differentiation, activation, and mycobacterial killing are linked to transsulfuration-dependent redox metabolism.

Modulation of the ambient redox status by mononuclear phagocytes is central to their role in health and disease. However, little is known about the mechanism of redox regulation during mononuclear phagocyte differentiation and activation, critical cellular steps in innate immunity, and microbial clearance. An important intermediate in GSH-based redox metabolism is homocysteine, which can undergo transmethylation via methionine synthase (MS) or transsulfuration via cystathionine beta-synthase (CBS). The transsulfuration pathway generates cysteine, the limiting reagent in GSH biosynthesis. We now demonstrate that expression of CBS and MS are strongly induced during differentiation of human monocytes and are regulated at the transcriptional and posttranscriptional levels, respectively. The changes in enzyme expression are paralleled by an approximately 150% increase in S-adenosylmethionine (accompanied by a corresponding increase in phospholipid methylation) and a similar increase in GSH. Activation with lipopolysachharide or infection with Mycobacterium smegmatis diminished expression of both enzymes to a significant extent and decreased S-adenosylmethionine concentration by approximately 30% of the control value while GSH and cysteine concentrations increased approximately 100 and 300%, respectively. Blockade of the transsulfuration pathway with propargylglycine suppressed clearance of M. smegmatis by macrophages and inhibited phagolysosomal fusion, whereas N-acetylcysteine promoted phagolysosomal fusion and enhanced mycobacterial clearance 3-fold compared with untreated cells. We posit that regulation of the transsulfuration pathway during monocyte differentiation, activation, and infection can boost host defense against invading pathogens and may represent a heretofore unrecognized antimicrobial therapeutic target.

Blotting, Northern↗
PubMed2004

Genome-wide transcriptional response of a Saccharomyces cerevisiae strain with an altered redox metabolism.

The genome-wide transcriptional response of a Saccharomyces cerevisiae strain deleted in GDH1 that encodes a NADP(+)-dependent glutamate dehydrogenase was compared to a wild-type strain under anaerobic steady-state conditions. The GDH1-deleted strain has a significantly reduced NADPH requirement, and therefore, an altered redox metabolism. Identification of genes with significantly changed expression using a t-test and a Bonferroni correction yielded only 16 transcripts when accepting two false-positives, and 7 of these were Open Reading Frames (ORFs) with unknown function. Among the 16 transcripts the only one with a direct link to redox metabolism was GND1, encoding phosphogluconate dehydrogenase. To extract additional information we analyzed the transcription data for a gene subset consisting of all known genes encoding metabolic enzymes that use NAD(+) or NADP(+). The subset was analyzed for genes with significantly changed expression again with a t-test and correction for multiple testing. This approach was found to enrich the analysis since GND1, ZWF1 and ALD6, encoding the most important enzymes for regeneration of NADPH under anaerobic conditions, were down-regulated together with eight other genes encoding NADP(H)-dependent enzymes. This indicates a possible common redox-dependent regulation of these genes. Furthermore, we showed that it might be necessary to analyze the expression of a subset of genes to extract all available information from global transcription analysis.

Gene Deletion↗
PubMed2004

Parasitic protozoa: thiol-based redox metabolism.

In a thoughtful and stimulating article, Sylke Müller et al. describe the thiol-based redox metabolism of protozoan parasites and believe that the key enzymes involved in this metabolism have potential use as new drug targets. Additional information on this subject is provided here.

Animals↗
PubMed1985

Effect of dehydroepiandrosterone on human erythrocytes redox metabolism: inhibition of glucose-6-phosphate dehydrogenase activity in vivo and in vitro.

In order to elucidate the role of G6PD inhibition by DHEA on erythrocyte redox metabolism, we measured: (1) G6PD activity in erythrocytes collected at different times after injection of synthetic ACTH in 13 normal subjects; (2) G6PD activity and GSH levels in erythrocytes incubated in the presence of different DHEA concentrations; (3) DHEA distribution and metabolic clearance in red cells, together with G6PD activity; (4) GSH regeneration after hydroperoxide oxidative stress in red cells preincubated in the presence of DHEA. In vivo DHEA increase elicits a clear-cut inhibition of red cell G6PD activity. Decreasing DHEA goes in step with the recovery of enzyme activity. In vitro G6PD inhibition by DHEA reaches its maximum within 10-15 min (20-25% inhibition at 10(-7) M DHEA concentration) and the recovery time is dose-dependent. More than 2/3 of DHEA is concentrated in the red cell after 5 min incubation. GSH levels change in step with G6PD activity. After oxidative stress by BHP, DHEA-treated cells fail to restore normal GSH concentrations. These results show that DHEA inhibits human erythrocyte G6PD activity at concentrations usually observed after ACTH plasma increase and increases red cell sensitivity to oxidant agents. Moreover, it is possible that the high DHEA concentrations present in target tissues may interfere with metabolic pathways in which NADPH is the cofactor.

Adrenocorticotropic Hormone↗
PubMed1993

Redox metabolism of vitamin C in blood of normal and malaria-infected mice.

As oxidative mechanisms have been suggested to be part of the host immune reaction against malarial parasites, we investigated the redox metabolism of the antioxidant vitamin C in the blood of control and malaria-infected mice. At the peak of infection (day 6) with the malaria parasite P. vinckei, plasma levels of ascorbate (AH-) were 10.8 +/- 0.9 micrograms/ml compared to 5.7 +/- 0.7 micrograms/ml in control mice, though no significant change was observed in the plasma concentration of dehydroascorbate (DHA). The plasma redox ratio of vitamin C, [AH-]:[DHA], was 7.4 in control mice and 18.5 in infected mice on day 6 post-inoculation. The increased AH- level in plasma of P. vinckei-infected mice was not due to differences in stabilities of either AH- or DHA in plasmas from control or P. vinckei-infected mice. DHA added to plasma was lost rapidly. In contrast, when added to whole blood. DHA was rapidly taken up and reduced to AH by blood cells from both normal mice and P. vinckei-infected mice. Most of the intracellular AH- derived from the exogenously added DHA was released into the plasma by blood cells from the infected but not normal mice. The observed release of AH- into the plasma by blood cells from infected mice was not caused by a plasma factor. Depletion of leukocytes from erythrocytes had no effect on the uptake and reduction of DHA by red blood cells, but the subsequent release of intracellular AH- occurred more rapidly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Shigella sonnei phase I and phase II: susceptibility to direct serum lysis and opsonic requirements necessary for stimulation of leukocyte redox metabolism and killing.

The synthesis of the lipopolysaccharide O-specific repeat polymer by Shigella sonnei phase I is a clearly defined bacterial virulence factor necessary for penetrating epithelial cells; S. sonnei phase II does not synthesize this antigen and is uniformly avirulent. The serum opsonic requirements, relative to differences in gross lipopolysaccharide structure, were investigated by quantification and comparison of polymorphonuclear leukocyte (PMNL) metabolism and PMNL-mediated microbicidal action to phase I and phase II organisms, using normal and immune serum. The stimulation of PMNL O2-redox metabolism, as required for oxidative killing, was quantified by a chemiluminescent technique, using luminol as a chemilumigenic substrate. Susceptibility to direct serum or serum PMNL-mediated killing was evaluated by serum and serum-phagocytic killing assays. Stimulation of PMNL metabolism and phagocytic killing of S. sonnei phase I required opsonification by specific phase I antibody plus the classical pathway of complement. S. sonnei phase II was susceptible to direct complement-mediated serum killing. Likewise, opsonification of the phase II microbe, as measured by PMNL-associated chemiluminescence, was effected by complement in the absence of immune antibody. These data demonstrate the importance of the O-specific repeat polymer in protecting the microbe from the microbicidal action of PMNL and the bacteriolytic action of serum.

Animals↗
PubMed1989

Mathematical modelling of metabolic pathways affected by an enzyme deficiency. Energy and redox metabolism of glucose-6-phosphate-dehydrogenase-deficient erythrocytes.

The effects of various forms of glucose-6-phosphate dehydrogenase deficiency on erythrocyte metabolism have been studied on the basis of a complex mathematical model which comprises the main pathways of this cell: glycolysis, pentose pathway, reactions of the glutathione and adenine nucleotide metabolism. The calculated flux rates through the oxidative pentose pathway with and without methylene blue are in good accord with experimental results. The degree of deficiency as predicted by the model on the basis of calculated upper oxidative load boundaries, as well as of maximal methylene blue stimulation, correlates with the individual clinical manifestation of the metabolic disease. Therefore, the model allows one to judge the degree of metabolic disorder in the presence of glucose-6-phosphate dehydrogenase enzymopathies if the kinetic properties of the defect enzyme are known. Experimentally accessible parameters for an assessment of the oxidative load capacity of cells in vivo are proposed. It is pointed out that the threshold of tolerance as to energetic load is drastically reduced in the case of severe glucose-6-phosphate dehydrogenase deficiency.

Catalysis↗
PubMed2003

Discordance of endothelial nitric oxide synthase in the arterial wall and its circulating products in baboons: interactions with redox metabolism.

BACKGROUND: Although peripheral arteries and circulating factors have been frequently used to assess systemic or central arterial, such as coronary artery, endothelial nitric oxide synthase (eNOS) functions, there is no direct evidence to support that they are related. DESIGN: We explored relationships in eNOS levels among coronary, aortic, carotid and brachial arteries, and interactions with redox metabolisms in 40 necropsied baboons (Papio hamadryas). RESULTS: We found no correlations in eNOS or NOx levels among all four arteries (R: 0.02-0.19, P > 0.05). While eNOS levels were high in both coronary (133.78 +/- 10.9 pg mg-1 protein) and aortic arteries (168.53 +/- 16.32 pg mg-1 protein), they were low in brachial (82.88 +/- 5.5 pg mg-1 protein) and carotid (89.83 +/- 7.15 pg mg-1 protein) arteries. Arterial eNOS were not correlated with plasma NOx either. However, coronary and aortic eNOS were positively correlated with the corresponding arterial total antioxidant status (TAS) (r = 0.638, P= 0.001, and r = 0.615, P= 0.0001). Coronary eNOS was also negatively associated with coronary advanced glycation end products (AGE) (r = -0.454, P= 0.003). Furthermore, there were significant associations in TAS levels between plasma and arterial wall extracts (R: 0.344-0.369, P < 0.05) and among arteries of different anatomic sites (R: 0.637-0.877, P < 0.001). While arterial TAS was negatively correlated with corresponding arterial AGE, TAS in the arterial wall and plasma were positively associated with plasma AGE. CONCLUSIONS: Our study shows that eNOS is differentially expressed in different anatomic sites and is not associated with plasma NOx, suggesting that brachial eNOS may not be used to assess coronary eNOS. The positive or negative associations between eNOS and TAS or AGE, especially in the coronary artery, indicate an important role of eNOS in arterial wall redox balance.

Animals↗
PubMed2004

Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani.

Despite extensive use of antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (Sb(III)) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, Sb(III) decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, Sb(III) inhibits trypanothione reductase in intact cells resulting in accumulation of the disulfide forms of trypanothione and glutathione. These two mechanisms combine to profoundly compromise the thiol redox potential in both amastigote and promastigote stages of the life cycle. Furthermore, we demonstrate that sodium stibogluconate, a pentavalent antimonial used clinically for the treatment for leishmaniasis, induces similar effects on thiol redox metabolism in axenically cultured amastigotes. These observations suggest ways in which current antimony therapies could be improved, overcoming the growing problem of antimony resistance.

Animals↗
PubMed2003

Thiol-based redox metabolism of protozoan parasites.

The review considers redox enzymes of Plasmodium spp., Trypanosomatida, Trichomonas, Entamoeba and Giardia, with special emphasis on their potential use as targets for drug development. Thiol-based redox systems play pivotal roles in the success and survival of these parasitic protozoa. The synthesis of cysteine, the key molecule of any thiol metabolism, has been elucidated in trypanosomatids and anaerobes. In trypanosomatids, trypanothione replaces the more common glutathione system. The enzymes of trypanothione synthesis have recently been identified. The role of trypanothione in the detoxification of reactive oxygen species is reflected in the multiplicity of trypanothione-dependent peroxidases. In Plasmodium falciparum, the crystal structures of glutathione reductase and glutamate dehydrogenase are now available; another drug target, thioredoxin reductase, has been demonstrated to be essential for the malarial parasite.

Animals↗
PubMed2001

Cytosolic redox metabolism in aerobic chemostat cultures of Saccharomyces cerevisiae.

Cytosolic redox balance has to be maintained in order to allow an enduring cellular metabolism. In other words, NADH generated in the cytosol has to be re-oxidized back to NAD(+). Aerobically this can be done by respiratory oxidation of cytosolic NADH. However, NADH is unable to cross the mitochondrial inner membrane and mechanisms are required for conveying cytosolic NADH to the mitochondrial electron transport chain. At least two such systems have proved to be functional in S. cerevisiae, the external NADH dehydrogenase (Luttik et al., 1998; Small and McAlister-Henn, 1998) and the G3P shuttle (Larsson et al., 1998). The aim of this investigation was to study the regulation and performance of these two systems in a wild-type strain of S. cerevisiae using aerobic glucose- and nitrogen-limited chemostat cultures. The rate of cytosolic NADH formation was calculated and as expected there was a continuous increase with increasing dilution rate. However, measurements of enzyme activities and respiratory activity on isolated mitochondria revealed a diminishing capacity at elevated dilution rates for both the external NADH dehydrogenase and the G3P shuttle. This suggests that adjustment of in vivo activities of these systems to proper levels is not achieved by changes in amount of protein but rather by, for example, activation/inhibition of existing enzymes. Adenine nucleotides are well-known allosteric regulators and both the external NADH and the G3P shuttle were sensitive to inhibition by ATP. The most severe inhibition was probably on the G3P shuttle, since one of its member proteins, Gpdp, turned out to be exceptionally sensitive to ATP. The external NADH dehydrogenase is suggested as the main system employed for oxidation of cytosolic NADH. The G3P shuttle is proposed to be of some importance at low growth rates and perhaps its real significance is only expressed during starvation conditions.

Adenosine Triphosphate↗
PubMed1995

Three-dimensionally resolved NAD(P)H cellular metabolic redox imaging of the in situ cornea with two-photon excitation laser scanning microscopy.

Three-dimensional maps of cellular metabolic oxidation/reduction states of rabbit cornea in situ were obtained by imaging the fluorescence of the naturally occurring reduced pyridine nucleotides (both reduced nicotinamide-adenine dinucleotide, NADH, and reduced nicotinamide-adenine dinucleotide phosphate, NADPH, denoted here as NAD(P)H). Autofluorescence images with submicrometre lateral resolution were obtained throughout the entire 400 microns thickness of the cornea. Two-photon excitation scanning laser microscopy with near-infrared excitation provided high fluorescence collection efficiency, reduced photodamage, and eliminated ultraviolet chromatic aberration, all of which have previously degraded the visualization of pyridine nucleotide fluorescence. Sharp autofluorescence images of the basal epithelium (40 microns within the cornea) show substantial subcellular detail, providing the ability to monitor autofluorescence intensity changes over time, which reflect changes in oxidative metabolism and cellular dynamics necessary for maintenance of the ocular surface. The autofluorescence was confirmed to be mostly of NAD(P)H origin by cyanide exposure, which increased the fluorescence from all cell types in the cornea by about a factor of two. Autofluorescence images of individual keratocytes in the stroma were observed only after cyanide treatment, while in the predominant extracellular collagen (> 90% of the stromal volume), fluorescence was not distinguished from the background. Observation of keratocyte metabolism demonstrates the sensitivity made available by two-photon microscopy for future redox fluorescence imaging of cellular metabolic states.

Animals↗
PubMed2005

Antiglioma activity of 2,2':6',2"-terpyridineplatinum(II) complexes in a rat model--effects on cellular redox metabolism.

The mammalian thioredoxin system, comprising the selenoenzyme thioredoxin reductase (TrxR) and the 12-kDa protein thioredoxin (Trx), is implicated in thiol-mediated antioxidant defense and redox regulatory processes including transcriptional control, DNA synthesis, and apoptosis. Cell proliferation supported by the thioredoxin system can be suppressed by TrxR inhibition. In this study, we assessed the effects of the potent hTrxR inhibitors 4-mercaptopyridine (4'-chloro-2,2':6',2"-terpyridine)platinum nitrate (I(23)2N) and 2-mercaptopyridine (4'-chloro-2,2':6',2"-terpyridine)platinum nitrate (I(25)2N) on glioblastoma in a rat model. These compounds show no or little cross-resistance with cisplatin and are thus of great clinical interest. Triple intravenous application of 25-35 mg/kg of the compounds led to a significant decrease of tumor growth as determined by magnetic resonance imaging. Metabolic as well as redox parameters in the blood of the animals were not altered. However, TrxR activity was significantly decreased in the tumor tissue, and redox parameters-including glutathione concentrations, total antioxidant status, and the activities of different antioxidant enzymes-showed tissue-specific variations. As indicated by different apoptotic markers, the antitumor activity of I(23)2N is not mediated by the induction of programmed cell death but rather by hTrxR inhibition and DNA intercalation leading to cell cycle arrest.

Animals↗
PubMed2006

Regulation of redox metabolism in the mouse oocyte and embryo.

Energy homeostasis of the oocyte is a crucial determinant of fertility. Following ovulation, the oocyte is exposed to the unique environment of the Fallopian tube, and this is reflected in a highly specialised biochemistry. The minute amounts of tissue available have made the physiological analysis of oocyte intermediary metabolism almost impossible. We have therefore used confocal imaging of mitochondrial and cytosolic redox state under a range of conditions to explore the oxidative metabolism of intermediary substrates. It has been known for some time that the early mouse embryo metabolises external pyruvate and lactate but not glucose to produce ATP. We now show at the level of single oocytes, that supplied glucose has no effect on the redox potential of the oocyte. Pyruvate is a cytosolic oxidant but a mitochondrial reductant, while lactate is a strong cytosolic reductant via the activity of lactate dehydrogenase. Unexpectedly, lactate-derived pyruvate appears to be diverted from mitochondrial oxidation. Our approach also reveals that the level of reduced glutathione (GSH) in the oocyte is maintained by glutathione reductase, which oxidises intracellular NADPH to reduce oxidised glutathione. Surprisingly, NADPH does not seem to be supplied by the pentose phosphate pathway in the unfertilised oocyte but rather by cytosolic NADP-dependent isocitrate dehydrogenase. Remarkably, we also found that the oxidant action of pyruvate impairs development, demonstrating the fundamental importance of redox state on early development.

Animals↗
PubMed2003

Plasmodium falciparum thioredoxins and glutaredoxins as central players in redox metabolism.

Over the last few years, an increasing number of different functions have been ascribed to small redox-active proteins like thioredoxins (Trx) and glutaredoxins (Grx). These functions include redox regulation of transcription and translation, antioxidant defence, involvement in protein folding and cellular signalling, and reduction of ribonucleotide reductase. In the malarial parasite Plasmodium falciparum, a classical Trx and a typical Grx have been described as well as a number of Trx- and Grx-like proteins including monothiol glutaredoxins. Furthermore, plasmoredoxin, a redox-active protein related to Trx, has been characterized; plasmoredoxin is unique for malarial parasites, therefore having great potential as diagnostic tool. In this minireview, we summarize the current knowledge on members of the thioredoxin superfamily and their function in the malarial parasite P. falciparum.

Amino Acid Sequence↗
PubMed2006

Cofactor engineering in Saccharomyces cerevisiae: Expression of a H2O-forming NADH oxidase and impact on redox metabolism.

The pyridine nucleotides NAD(H) and NADP(H) play major roles in the formation of by-products. To analyse how Saccharomyces cerevisiae (S. cerevisiae) metabolism during growth on glucose might be altered when intracellular NADH pool is decreased, we expressed noxE encoding a water-forming NADH oxidase from Lactococcus lactis (L. lactis) in the S. cerevisiae strain V5. During batch fermentation under controlled microaeration conditions, expression of the NADH oxidase under the control of a yeast promoter lead to large decreases in the intracellular NADH concentration (five-fold) and NADH/NAD+ ratio (six-fold). This increased NADH consumption caused a large redistribution of metabolic fluxes. The ethanol, glycerol, succinate and hydroxyglutarate yields were significantly reduced as a result of the lower NADH availability, whereas the formation of more oxidized metabolites, acetaldehyde, acetate and acetoin was favoured. The biomass yield was low and consumption of glucose, at concentration above 10%, was impaired. The metabolic redistribution in cells expressing the NADH oxidase was a consequence of the maintenance of a redox balance and of the management of acetaldehyde formation, which accumulated at toxic levels early in the process.

Cell Proliferation↗