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Results for “Redox adaptation”

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PubMed2002

Going malignant: the hypoxia-cancer connection in the prostate.

The metabolic organization of both normal and malignant prostate cellular phenotypes involves some unusual and surprising features. In particular, both conditions exhibit ratios of NADH/NAD+ and NADPH/NADP+ characteristic of high oxidative states despite a chronic shortage of O2 in both conditions. In this paper, we observe that, in prostate cancer cells, the oxidizing power of the fatty acid synthesis (FAS) pathway is so large that redox is stabilized more favorably (more oxidized) than in normal prostate cells. This FAS-facilitated redox improvement occurs despite the fact that malignant cells are more O2 limited and therefore express more hypoxia inducible factor 1 (HIF1) and express hypoxia-regulated genes more robustly. This unusual metabolic situation clearly separates direct regulatory effects of redox balance from secondary effects of hypoxia per se. The physiological significance of the FAS pathway is thus the harnessing of its oxidizing power for improving redox balance despite conditions of more extreme hypoxia. Similar hypoxia defense strategies are found in animal species that are unusually tolerant to oxygen lack. Our hypothesis is that the metabolic organization in the "low zinc, low citrate" phenotype reflects an hypoxia-defense adaptation geared toward redox balance, with prostate cancer cells being relatively more oxidized, even if more hypoxic, than normal prostate cells. Recognition and understanding of these redox balancing and hypoxia defense functions may lead to new intervention strategies by developing new intracellular targets for prostate cancer therapy.

Humans↗

PubMed1999

Stimulation of cystine uptake by nitric oxide: regulation of endothelial cell glutathione levels.

Nitric oxide (NO) is known to produce some of its biological activity through modification of cellular thiols. Return of cellular thiols to their basal state requires the activity of the GSH redox cycle, suggesting important interactions between NO signaling and regulation of cellular redox status. Because continuous exposure to NO may lead to adaptive responses in cellular redox systems, we investigated the effects of NO on cellular GSH levels in vascular endothelial cells. Acute exposure (1 h) of cells to >1 mM S-nitroso-N-acetyl-penicillamine (SNAP) led to depletion of GSH. On the other hand, chronic exposure to lower concentrations of SNAP (</=1 mM) led to a progressive increase in cytosolic GSH, reaching fourfold above basal by 16 h. The mechanism may involve an increase in GSH biosynthesis through effects on biosynthetic enzymes or through increased supply of cysteine, the limiting substrate. In this regard, we report that chronic exposure to SNAP led to a concentration-dependent increase in cystine uptake over a time course similar to that seen for elevation of GSH. The effect of SNAP on cystine uptake was inhibitable by either cycloheximide or actinomycin D, suggesting a requirement for both RNA and protein synthesis. Furthermore, uptake was Na+ independent and was blocked by extracellular glutamate. Extracellular glutamate also blocked SNAP-mediated elevation of cytosolic GSH. Finally, in a coculture model, NO produced by cytokine-pretreated RAW 264.7 cells increased both GSH levels and cystine uptake in naive endothelial cells. These findings strongly suggest that NO leads to adaptive induction of the x-c amino acid transport system, increased cystine uptake, and elevation of intracellular GSH levels.

Animals↗

PubMed2001

A new technique for measuring the cell growth and metabolism of endothelial cells seeded on vascular prostheses.

For the improvement of vascular graft patency, an endothelial cell (EC) lining is desirable. It is essential that the EC remains viable after being seeded onto the prosthetic graft. The aim of this study was to adapt an Alamar redox assay (ABRA) as a technique to monitor the viability of ECs seeded on prosthetic grafts. To test the graft types, we seeded human umbilical vein ECs on compliant polyurethane (CPU), expanded polytetrafluoroethylene, and Dacron at a density of 2 x 10(5) cell/cm(2). After 24 h of incubation, ABRA was added, and the absorbance was measured at 4, 8, and 24 h. To assess seeded cell concentrations on grafts, we seeded CPU at densities ranging from 1 x 10(5) to 8 x 10(5) cell/cm(2). The validity of the test was assessed with sodium azide and mitomycin C, known physiological perturbators. ABRA reduction demonstrated that ECs were viable and functional postseeding on the prosthetic grafts. A significant correlation was observed with ABRA reduction and cell concentrations (p < 0.001). The acid phosphatase assay demonstrated enzyme activity in the cells, but they were not maintained under normal physiological conditions. The ABRA bioreduced product was soluble, stable, and noncytotoxic over 24 h. The assay is independent of the geometry or physiochemistry of the graft type. The technique allows the continuous assessment of the metabolism and viability of seeded cells, is simple to perform, and does not destroy the cells or graft materials.

Biocompatible Materials↗

PubMed1992

Interaction of blood flow, diffusive transport and cell metabolism in isovolemic anemia.

1) High blood flow can compensate for half-normal hematocrit, leaving the rate at which O2 is offered to the capillaries unchanged. Nevertheless, intracellular PO2 is lower in anemia, indicating impaired diffusive transport. 2) Anemia increases O2 flux per red cell and decreases functional capillary surface area. These changes increase flux density and the extracellular component of resistance to diffusive O2 transport, in accord with current theory (Federspiel and Popel, 1986; Groebe, 1990; Hellums, 1977). 3) Maintenance of diffusive flux in presence of anemia required a larger delta PO2 between Hb and Mb, and higher intracellular O2 conductance brought about by greater Mb-facilitated diffusion. Both compensations depend on lower PmbO2. 4) PmbO2 and creatine charge fall with increasing VO2 and ATP demand. These responses, as well as adaptive changes in redox help maintain VO2 in the presence of a lower O2 drive on electron transport. 5) Greater engagement of reserves of both transport and metabolism limits the range of aerobic performance in anemia. 6) The match between the transcapillary and mitochondrial O2 fluxes depends on interaction of transport and metabolism as a system.

Anemia↗

PubMed2005

Glutathione in bacteria.

Glutathione metabolism and its role in vital functions of bacterial cells are considered, as well as common features and differences between the functions of glutathione in prokaryotic and eukaryotic cells. Particular attention is given to the recent data for the role of glutathione in bacterial redox-regulation and adaptation to stresses.

Adaptation, Physiological↗

PubMed2002

Protein S-glutathionylation correlates to selective stress gene expression and cytoprotection.

During situations of oxidative stress phenotypic adaptation to altered redox state is achieved by changes in expression of selected genes. The mechanisms regulating this may involve reversible S-glutathionylation of cellular proteins. In this study we compared and contrasted changes in gene expression patterns in human type II lung epithelial A549 cells and human endothelial ECV304 cells in correlation to glutathione oxidation and the formation of glutathione-protein mixed disulphides, after exposure to subtoxic levels of hydrogen peroxide, formed in the medium by addition of glucose oxidase, or the thiol oxidant diamide. Both the number of specific mRNAs and their levels of induction were grossly correlated to the degree of S-glutathionylation of cellular protein. Thus, diamide induced the expression of a variety of protein and DNA chaperones and transcriptional regulators, particularly in ECV304 cells. On the other hand, the peroxide failed to induce many of these species, in association with only minimal disturbances to glutathione homeostasis. The induction of the chaperone responses at the level of mRNA was clearly shown to translate into a more resistant morphological phenotype in response to both heat shock and oxidative stress induced by the DNA-damaging pro-oxidant potassium bromate.

Cell Line↗

PubMedDate not supplied

[Hydrogen metabolism in Anabaena variabilis in the dark].

Cells and extracts of the cyanobacterium Anabaena variabilis are capable of hydrogen absorption in the dark in the presence of H-acceptors with various redox potentials. Preliminary adaptation of the cells to anaerobic conditions has no effect on the process. A. variabilis can also evolve hydrogen in the dark. Reduced methylviologen (RMV), formiate, pyruvate, and glucose may be substrates for hydrogen evolution by the cells. The extracts evolve hydrogen in the presence of RMV, benzylviologen, azocarmine, or NAD (P) H + ATP. No adaptation of the cells to anaerobic conditions is required for hydrogen evolution from RMV, and chloramphenicol has no effect on the process. The rate of hydrogen evolution is however higher in the cells adapted to anaerobic conditions. Production of hydrogen from pyruvate by the cells adapted and non-adapted to anaerobic conditions was detected only after their incubation with the substrate during 2--3 hours, and chloramphenicol inhibited the process.

Cell-Free System↗

PubMed2004

Antioxidant and cytoprotective responses to redox stress.

Aerobic cells produce reactive oxygen species as a consequence of normal cellular metabolism, and an array of antioxidant systems are in place to maintain the redox balance. When the redox equilibrium of the cell is upset by pro-oxidant environmental stimuli, adaptive responses to the redox stress take place, which can result in up-regulation of antioxidant proteins and detoxification enzymes. Over the past few years, it has become apparent that members of the CNC (cap 'n' collar)-basic leucine zipper family of transcription factors are principal mediators of defensive responses to redox stress. In mammals, the CNC family members nuclear factor-erythroid 2 p45-related factors 1 and 2 (Nrf1 and Nrf2) have been shown to be involved in the transcriptional up-regulation of cytoprotective genes including those encoding glutamate cysteine ligase, NAD(P)H:quinone oxidoreductase, glutathione S-transferases and aldo-keto reductases. An evolutionarily conserved system exists in Caenorhabditis elegans, and it is possible that Drosophila melanogaster may also utilize CNC transcription factors to induce antioxidant genes in response to pro-oxidant chemicals. The advent of microarray and proteomic technologies has advanced our understanding of the gene batteries regulated by oxidative insult, but has highlighted the complexity of gene regulation by environmental factors. This review focuses on the antioxidant response to environmental stress, and the impact that microarrays and proteomics have made in this field.

Animals↗

PubMed1985

Enzymatic characterization of E.U.E. (embryonal human explants) cells adapted to hypertonic media.

E.U.E. cells (general population) were submitted to biochemical and cytoenzymatic tests to compare the enzymatic profile of E.U.E. cells (controls) with that of E.U.E. adapted to hypertonic medium. The adapted cells are characterized by very high oxoreductase activity (LDH, HBDH, G-6-P DH) and very high alkaline-phosphatase activity. Clones derived from general population were also submitted to biochemical tests to characterize those more strictly related to the enzymatic profile of adapted cells. The profile of clone N. 13 resembles on this respect that of the adapted cells. The high redox activity is a prerequisite supporting energy supply for osmotic work. The increased activity of plasma membrane enzymes of the adapted cells is also demonstrable in cells exposed for short time to salinity.

Adaptation, Physiological↗

PubMed2004

Thioredoxin, a regulator of gene expression.

Cancer cells have high levels of thioredoxin (Trx) and of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Cells from patients with the cancer-prone disease Fanconi anemia (FA) exhibit reduced Trx levels. We found the activity of GAPDH to correlate directly with the endogenous Trx content and mRNA transcripts for GAPDH and TRx reduced in FA cells. The treatment of cells with reduced human Trx stimulated the synthesis of GAPDH mRNA. Similarly, the transfection of cells with an expression plasmid for Trx increased GAPDH mRNA synthesis. Trx treatment of cells and subsequent analysis of the differential gene expression by human cDNA arrays containing about 50 000 different PCR products resulted in more than 300 up- or downregulated genes. Two representative genes, GAPDH and IkappaBalpha/MAD-3, were further investigated to confirm their stimulation by Trx. Trx besides being the major carrier of redox potential of cells is also a regulator of gene expression on the transcriptional level. By regulation via Trx, cells are able to adapt to the prevailing redox conditions. These findings also enlighten the pathophysiology of FA in the respect that the characteristic diminution of Trx that results in the dysregulation of gene expression is a basis for the major symptoms of this disease.

Blotting, Northern↗

PubMed2000

Free radicals and antioxidants in the year 2000. A historical look to the future.

In the late 1950's free radicals and antioxidants were almost unheard of in the clinical and biological sciences but chemists had known about them for years in the context of radiation, polymer and combustion technology. Daniel Gilbert, Rebeca Gerschman and their colleagues related the toxic effects of elevated oxygen levels on aerobes to those of ionizing radiation, and proposed that oxygen toxicity is due to free radical formation, in a pioneering paper in 1956. Biochemistry owes much of its early expansion to the development and application of chromatographic and electrophoretic techniques, especially as applied to the study of proteins. Thus, superoxide dismutase (SOD) enzymes (MnSOD, CuZnSOD, FeSOD) were quickly identified. By the 1980's Molecular Biology had evolved from within biochemistry and microbiology to become a dominant new discipline, with DNA sequencing, recombinant DNA technology, cloning, and the development of PCR representing milestones in its advance. As a biological tool to explore reaction mechanisms, SOD was a unique and valuable asset. Its ability to inhibit radical reactions leading to oxidative damage in vitro often turned out to be due to its ability to prevent reduction of iron ions by superoxide. Nitric oxide (NO.) provided the next clue as to how SOD might be playing a critical biological role. Although NO. is sluggish in its reactions with most biomolecules it is astoundingly reactive with free radicals, including superoxide. Overall, this high reactivity of NO. with radicals may be beneficial in vivo, e.g. by scavenging peroxyl radicals and inhibiting lipid peroxidation. If reactive oxygen species are intimately involved with the redox regulation of cell functions, as seems likely from current evidence, it may be easier to understand why attempts to change antioxidant balance in aging experiments have failed. The cell will adapt to maintain its redox balance. Indeed, transgenic animals over-expressing antioxidants show some abnormalities of function. There must therefore be a highly complex interrelationship between dietary, constitutive, and inducible antioxidants with the body, under genetic control. The challenge for the new century is to be able to understand these relationships, and how to manipulate them to our advantage to prevent and treat disease.

Animals↗

PubMed2005

Strategies to maintain redox homeostasis during photosynthesis under changing conditions.

Plants perform photosynthesis and assimilatory processes in a continuously changing environment. Energy production in the various cell compartments and energy consumption in endergonic processes have to be well adjusted to the varying conditions. In addition, dissipatory pathways are required to avoid any detrimental effects caused by over-reduction. A large number of short-term and long-term mechanisms interact with each other in a flexible way, depending on intensity and the type of impact. Therefore, all levels of regulation are involved, starting from energy absorption and electron flow events through to post-transcriptional control. The simultaneous presence of strong oxidants and strong reductants during oxygenic photosynthesis is the basis for regulation. However, redox-dependent control also interacts with other signal transduction pathways in order to adapt metabolic processes and redox-control to the developmental state. Examples are given here for short-term and long-term control following changes of light intensity and photoperiod, focusing on the dynamic nature of the plant regulatory systems. An integrating network of all these mechanisms exists at all levels of control. Cellular homeostasis will be maintained as long as the mechanisms for acclimation are present in sufficiently high capacities. If an impact is too rapid, and acclimation on the level of gene expression cannot occur, cellular damage and cell death are initiated.

Adaptation, Physiological↗

PubMed2005

Chloroplasts as source and target of cellular redox regulation: a discussion on chloroplast redox signals in the context of plant physiology.

During the evolution of plants, chloroplasts have lost the exclusive genetic control over redox regulation and antioxidant gene expression. Together with many other genes, all genes encoding antioxidant enzymes and enzymes involved in the biosynthesis of low molecular weight antioxidants were transferred to the nucleus. On the other hand, photosynthesis bears a high risk for photo-oxidative damage. Concomitantly, an intricate network for mutual regulation by anthero- and retrograde signals has emerged to co-ordinate the activities of the different genetic and metabolic compartments. A major focus of recent research in chloroplast regulation addressed the mechanisms of redox sensing and signal transmission, the identification of regulatory targets, and the understanding of adaptation mechanisms. In addition to redox signals communicated through signalling cascades also used in pathogen and wounding responses, specific chloroplast signals control nuclear gene expression. Signalling pathways are triggered by the redox state of the plastoquinone pool, the thioredoxin system, and the acceptor availability at photosystem I, in addition to control by oxolipins, tetrapyrroles, carbohydrates, and abscisic acid. The signalling function is discussed in the context of regulatory circuitries that control the expression of antioxidant enzymes and redox modulators, demonstrating the principal role of chloroplasts as the source and target of redox regulation.

Cell Nucleus↗

PubMed2006

In situ redox flexibility of FeII-III Oxyhydroxycarbonate green rust and fougerite.

Bacterial activity is commonly thought to be directly responsible for denitrification in soils and groundwater. However, nitrate reduction in low organic sediments occurs abiotically by FeII ions within the fougerite mineral (IMA 2003-057), giving the bluish-green color of gleysols. Fougerite, the mineral counterpart of FeII-III oxyhydroxycarbonate, FeII6(1-x)FeIII6xO12H2(7-3x)CO3, provides a unique in situ redox flexibility, which can adapt x = {[FeIII]/[Fetotal]} between 1/3 and 2/3 as shown using Mössbauer spectroscopy. Chemical potential and Eh-pH diagrams for this system were determined from electrode potential monitored during deprotonation of hydroxycarbonate FeII4FeIII2(OH)12CO3 to assess the possibility of reducing pollutants in the field. Bioreduction of ferric oxyhydroxides in anoxic groundwater yields dissolved FeII, whereas HCO3- anions produced from organic matter are incorporated into fougerite layered double oxyhydroxide structure. Thus, fougerite is the solid-state redox mediator acting as electron shuttle that helps bacterial activity for reducing nitrate by coupling dissimilatory FeIII reduction and oxidation of FeII with reduction of NO3-. It is proposed that this system could be used in the remediation of soils and nitrified waters.

Bicarbonates↗

PubMedDate not supplied

The effect of chronic ethanol consumption on enzyme activities of the energy-supplying metabolism and the alcohol-aldehyde oxidizing system in rat hearts.

We investigated in rat hearts if chronic alcohol consumption causes an enzymatic adaption of the energy-supplying metabolism and/or of the alcohol-aldehyde metabolizing system. 16 rats were pair-fed with a liquid diet for 10 weeks. Ethanol was added to this diet to amount for 35% of calories in eight rats and was isocalorically replaced by saccharose in the control group. Selected enzyme activities of the glycolysis, the glycogenolysis, the beta-oxidation of fatty acids, the citric acid cycle and the alcohol-aldehyde oxidizing system were determined in the supernatants of the homogenized hearts. The intracellular redox state was assessed by measurement of the myocardial nicotinamide coenzymes. Enzyme activities of the alcohol-aldehyde metabolizing system did not alter after chronic alcohol intake. As we found that the capacity to oxidize acetaldehyde was much higher than the ability to oxidize ethanol we must question the role of acetaldehyde in inducing alcoholic cardiomyopathy. Chronic ethanol treatment significantly increased the activity of glyceraldehyde-3-phosphate dehydrogenase and decreased the activity of glycogen phosphorylase. The impairment of the hydroxyacylCoA dehydrogenase was not significant. The other measured enzyme activities did not alter, nor the intracellular redox state. The enzymatic adaption indicates an impaired glycogenolysis, an increased glycolysis, and probably a diminished beta-oxidation of fatty acids. We expect that the measurement of the responding enzyme activities in human endomyocardial biopsies should be a good tool to further classify cardiomyopathies according to biochemical criteria.

Alcoholism↗

PubMed2004

PDILT, a divergent testis-specific protein disulfide isomerase with a non-classical SXXC motif that engages in disulfide-dependent interactions in the endoplasmic reticulum.

Protein disulfide isomerase (PDI) is the archetypal enzyme involved in the formation and reshuffling of disulfide bonds in the endoplasmic reticulum (ER). PDI achieves its redox function through two highly conserved thioredoxin domains, and PDI can also operate as an ER chaperone. The substrate specificities and the exact functions of most other PDI family proteins remain important unsolved questions in biology. Here, we characterize a new and striking member of the PDI family, which we have named protein disulfide isomerase-like protein of the testis (PDILT). PDILT is the first eukaryotic SXXC protein to be characterized in the ER. Our experiments have unveiled a novel, glycosylated PDI-like protein whose tissue-specific expression and unusual motifs have implications for the evolution, catalytic function, and substrate selection of thioredoxin family proteins. We show that PDILT is an ER resident glycoprotein that liaises with partner proteins in disulfide-dependent complexes within the testis. PDILT interacts with the oxidoreductase Ero1alpha, demonstrating that the N-terminal cysteine of the CXXC sequence is not required for binding of PDI family proteins to ER oxidoreductases. The expression of PDILT, in addition to PDI in the testis, suggests that PDILT performs a specialized chaperone function in testicular cells. PDILT is an unusual PDI relative that highlights the adaptability of chaperone and redox function in enzymes of the endoplasmic reticulum.

Amino Acid Motifs↗

PubMed2005

Quantitative and kinetic study of oxidative stress regulons using green fluorescent protein.

Potentially damaging reactive oxygen species (ROS) are involved in a number of pathways ranging from signal transduction to apoptosis. Cells have adapted this alteration in redox status into a complex regulatory mechanism. ROS are specifically able to induce the expression of a multitude of genes. We constructed and characterized "oxidative stress probes" consisting of promoter fusions of several ROS-induced genes and the green fluorescent protein (GFP) reporter gene. Specifically, the sodA, fumC, zwf, acnA, acrAB, and soxS genes from the SoxRS regulon and the katG and ahpC genes from OxyR regulon, which respond to the superoxide anion and hydrogen peroxide, were studied. Our results revealed not only different levels of background transcription, but different induction levels both in terms of timing and strength. These systematic studies were performed under a uniform parallel platform and have provided insight into the complicated gene regulation of the oxidative stress regulons.

Ampicillin↗

PubMed2026

Crosstalk between cysteine and lysine modifications: Integrating redox and metabolic regulation.

Protein post-translational modifications (PTMs) on amino acid residues enable dynamic cellular responses to changes in metabolic and redox state. Cysteine and lysine are among the most extensively modified amino acid residues, with both undergoing a diversity of acylation and oxidative modifications. Indeed, proximal (<10 Å) cysteine and lysine residues may form integration nodes for crosstalk between metabolism and redox homeostasis pathways. This review highlights the interaction of proximal Cys-Lys residues, including influence on residue pKa by local electrostatics, cysteine-to-lysine transfer of PTM moieties, and covalent crosslinking. We discuss candidate Cys-Lys regulatory pairs in proteins involved in redox regulation, proteostasis, metabolic adaptation and inflammation. We further utilize computational modeling to identify proximity between cysteine and lysine residues in proteins known to be regulated by acylation and oxidative PTMs, and to demonstrate changes in these distances and local electrostatic potential due to lysine acetylation. Finally, we review how mass spectrometry-based proteomics and machine-learning PTM predictive tools can enable the identification, validation, and interpretation of proximal Cys-Lys interactions that regulate cellular responses to oxidative challenge and metabolic flux.

Cysteine↗