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PubMed2001

Changes in reactive oxygen species (ROS) production in rat brain during global perinatal asphyxia: an ESR study.

A large body of evidence suggests that the production of reactive oxygen species (ROS) can play an important role in ischemic neuronal injury. However any studies has been performed in hypoxic conditions. In the present experiments we studied using electron spin resonance (ESR) techniques the ROS release in neostriatum of newborn rats subjected to acute perinatal asphyxia (PA) followed by various periods of reoxygenation. Pregnant rats' uteri still containing foetuses were taken out and subjected to PA by immersion in a 37 degrees C water bath during the following periods of time: 5, 10, 15, 19 and 20 min. After performing PA, animals were recovered and ROS measured after 0, 5, 15, 30 or 60 min of reoxygenation. Then, pups were sacrificed, their neostriatum removed and homogenised with N-tert.-butyl-alpha-phenylnitrone (PBN) and diethylenetriamine-pentacetic acid (DPTA) in phosphate-buffered saline (PBS) and the formed complexes were extracted with ethyl acetate an analysed using an X-band ESR spectrometer. A significant release of ROS was detected at 19 and 20 min of PA after 5 min of reoxygenation. These data provide strong evidence that ROS could be involved in neuronal damage during PA.

Animals↗

PubMed1996

Postnatal retinal ganglion cells in vitro: protection against reactive oxygen species (ROS)-induced axonal degeneration by cocultured astrocytes.

Reactive oxygen species (ROS) are supposed to be involved in neurodegenerative processes like Parkinson's or Alzheimer's disease. Beside this there are an increasing number of studies indicating an involvement of ROS in traumatic brain injury. We therefore studied the potential role of astrocytes against neurotoxic effects of ROS in cocultures of rat cortical astrocytes with regenerating postnatal retinal ganglion cells (RGC). The sydnonimine SIN-1, which spontaneously decomposes to yield nitric oxide (NO) and superoxide anion radicals, led to axonal degeneration at concentrations between 1 microM and 10 microM. Comparable effects were seen after addition of iron salts (Fe2+/Fe3+), which catalyze the generation of hydroxyl radicals. In contrast, in cocultures of RGC with astrocytes or after addition of free radical scavengers there was no neurotoxic/neurodegenerative effect of ROS as compared with control cultures. Vitamin E (1-10 microM) and vitamin C (10-100 microM) abolished the neurotoxic effect of both SIN-1 or iron ions. Beside this, there was an additional effect concerning the number and the length of neurites growing out from the retinal explant: in cocultures both parameters were greatly enhanced. These results suggest that (i) astrocytes are able to protect retinal ganglion cells against ROS-induced oxidative stress, (ii) astrocytes release soluble neurotrophic factors supporting RGC axonal regeneration, and (iii) free radical production after tissue injury may partly contribute to the failure of axonal regeneration in the adult mammalian central nervous system.

Animals↗

PubMed2000

Increase of reactive oxygen (ROS) and nitrogen (RNS) species generated by phagocyting granulocytes related to age.

In this present paper the age-induced effect on reactive oxidizing species generated by oxygen (ROS) and nitrogen (RNS) was studied using human phagocyting granulocytes. The ROS and RNS were quantified, respectively, in a chemiluminescence assay and by the measurement of nitrite production. The age-induced reactive oxidizing species generation was studied in healthy subjects ranging from 20 to 80 years old, divided into six age groups: group I, 20-29 years old; group II, 30-39 years old; group III, 40-49 years old; group IV, 50-59 years old; group V, 60-69 years old; and group VI, 70-80 years old. Our results demonstrate a parallelism between generation of the ROS and RNS induced by the age. A significant increase of ROS production was observed from 40 years old (age groups III, IV, V and VI while for RNS this increase was observed only from 50 years old (groups IV, V and VI). These data suggest an increase of oxidizing species generation (ROS/RNS) related to age. The increased generation of ROS (40-49 years old) was induced before the increasing of RNS (50-59 years old) and it may have consequences on inflammation and host defences.

Adult↗

PubMed2005

Simultaneous detection of NO and ROS by ESR in biological systems.

A large body of evidence shows that the generation of nitric oxide (NO) and reactive oxygen species (ROS) and the rate of ROS/NO play an important role in the biological system. We developed a method to simultaneously detect NO free radical and ROS in biological systems using ERS spin trapping technique. The adduct (DETC)2-Fe2+-NO and N-tert- butyl-alpha-phenylnitrone (PBN)-ROS in biological systems can be extracted by organic solvent and then measured on an electron spin resonance (ESR) spectrometer at room temperature because the g = 2.035 of (DETC)2-Fe2+-NO is different from that of PBN-ROS (g = 2.005) and their ESR signals can be separated clearly. Using this method, we measured the production of NO and ROS in plant and animal systems.

Animals↗

PubMed1999

Role of ROS modified human DNA in the pathogenesis and etiology of cancer.

The effect of hydroxyl radical, generated by ultraviolet (UV) irradiation of hydrogen peroxide, on human placental DNA was monitored by UV spectroscopy, melting temperature studies, S1 nuclease digestibility and hydroxyapatite column chromatography. Immunological data indicated that reactive oxygen species (ROS) modified human DNA induced high titer antibodies. In ELISA, serum antibodies from various cancer patients showed a higher recognition of ROS-human DNA as compared to native DNA. Retarded mobility of the immune complex formed between IgG, isolated from cancer sera, and ROS-human DNA provided convincing evidence for antigen-antibody interaction. Oxidative lesions in DNA of cancer patients were probed using anti-ROS-human DNA IgG. DNA from cancer patients were found to inhibit anti-ROS-human DNA IgG activity in the range of 40% to 57%. These binding results indicate the presence of oxidative lesions in the cancer patient's genome.

Antibodies↗

PubMed2006

Modulation of the production of reactive oxygen species (ROS) by cAMP-elevating agents in granulocytes from diabetic patients: an Akt/PKB-dependent phenomenon.

BACKGROUND: Granulocytes from healthy subjects and from patients suffering from diabetes mellitus present differences in reactivity to stimulation with cyclic nucleotide-elevating agents. The production of reactive oxygen species (ROS) is inhibited in cells from non-diabetic subjects following such stimulation, but activated through a PKA-independent signaling pathway in granulocytes from type 1 and type 2 diabetic patients. The aim of the present study was to understand better the changes in signaling mechanisms induced by the disease. METHODS: ROS production in granulocytes from healthy subjects and from type 1 and type 2 diabetic patients was measured using a luminol-dependent chemiluminescence assay. Granulocytes were stimulated by the addition of the cAMP-elevating agent dibutyryl cAMP. In some experiments, granulocytes were pre-treated with an inhibitor of PKA or Akt/PKB prior to cAMP stimulation. RESULTS: Intracellular elevation of cAMP induced a PKA-dependent and Akt/PKB-independent inhibition of ROS production in granulocytes from healthy subjects, but a significant activation in cells from both type 1 and type 2 diabetic patients. Most significantly, activation of ROS generation in cells from diabetic patients was shown to be Akt/PKB-dependent and PKA-independent. CONCLUSIONS: These results suggest that chronic hyperglycaemia could induce metabolic adaptation in cAMP-related signaling mechanisms. Epac (exchange protein directly activated by cAMP) is a novel cAMP receptor besides PKA involved in different signaling pathways. The cAMP-stimulated inverse ROS response in granulocytes from type 1 and type 2 diabetic patients may be due to a change in signaling pathways from cAMP/PKA to cAMP/Epac/Akt/PKB. These preliminary results require further studies in order to evaluate their consequences on innate immunity and pathogenesis of diabetes mellitus.

Adult↗

PubMed1999

Functional consequences of a rod outer segment membrane guanylate cyclase (ROS-GC1) gene mutation linked with Leber's congenital amaurosis.

ROS-GC1 is the original member of the subfamily of membrane guanylate cyclases with two Ca2+ switches, which have been defined as CRM1 and CRM2. These are separately located within the intracellular domain of the cyclase. CRM1 switches on the enzyme at nanomolar concentrations of Ca2+ and is linked with phototransduction; the other stimulates at micromolar Ca2+ concentrations and is predicted to be linked with retinal synaptic activity. Ca2+ acts indirectly via Ca2+-binding proteins, GCAP1 and CD-GCAP. GCAP1 is a modulator of the CRM1 switch, and CD-GCAP turns on the CRM2 switch. A Leber's congenital amaurosis, termed LCA1, involves F514S point mutation in ROS-GC1. The present study shows that the mutation severely damages its intrinsic cyclase activity and inactivates its CRM1 switch but does not affect the CRM2 switch. In addition, on the basis of the established modulatory features of ROS-GC1, it is predicted that, in two other forms of LCA1 involving deletion of nt 460C or 693C, there is a frameshift in ROS-GC1 gene, which results in the nonexpression of the cyclase. For the first time, the findings define the linkage of distinct molecular forms of LCA to ROS-GC1 in precise biochemical terms; they also explain the reasons for the insufficient production of cyclic GMP in photoreceptors to sustain phototransduction, which ultimately leads to the degeneration of the photoreceptors.

Animals↗

PubMed2000

Role of reactive oxygen species (ROS) in apoptosis induction.

Reactive oxygen species (ROS) and mitochondria play an important role in apoptosis induction under both physiologic and pathologic conditions. Interestingly, mitochondria are both source and target of ROS. Cytochrome c release from mitochondria, that triggers caspase activation, appears to be largely mediated by direct or indirect ROS action. On the other hand, ROS have also anti-apoptotic effects. This review focuses on the role of ROS in the regulation of apoptosis, especially in inflammatory cells.

Animals↗

PubMed2004

A ROS repressor-mediated binary regulation system for control of gene expression in transgenic plants.

We describe a novel binary system to control transgene expression in plants. The system is based on the prokaryotic repressor, ROS, from Agrobacterium tumefaciens, optimized for plant codon usage and for nuclear targeting (synROS). The ROS protein bound in vitro to double stranded DNA comprising the ROS operator sequence, as well as to single stranded ROS operator DNA sequences, in an orientation-independent manner. A synROS-GUS fusion protein was localized to the nucleus, whereas wtROS-GUS fusion remained in the cytoplasm. The ability of synROS to repress transgene expression was validated in transgenic Arabidopsis thaliana and Brassica napus. When expressed constitutively under the actin2 promoter, synROS repressed the expression of the reporter gene gusA linked to a modified CaMV35S promoter containing ROS operator sequences in the vicinity of the TATA box and downstream of the transcription initiation signal. Repression ranged from 32 to 87% in A. thaliana, and from 23 to 76% in B. napus. These results are discussed in relation to the potential application of synROS in controlling the expression of transgenes and endogenous genes in plants and other organisms.

Agrobacterium tumefaciens↗

PubMed2004

Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells.

Recent studies have suggested that the expression of interleukin-8 (IL-8) directly correlates with the vascularity of human gastric carcinomas. In this study, the effect of IL-1beta on IL-8 expression in human gastric cancer TMK-1 cells and the underlying signal transduction pathways were investigated. IL-1beta induced the IL-8 expression in a time- and concentration-dependent manner. IL-1beta induced the activation of extracellular signal-regulated kinases-1/2 and P38 mitogen-activated protein kinase (MAPK), but not the activation of c-jun amino-terminal kinse and Akt. Specific inhibitors of MEK-1 (PD980590) and P38 MAPK (SB203580) were found to suppress the IL-8 expression and the IL-8 promoter activity. Expression of vectors encoding a mutated-type MEK-1 and P38 MAPK resulted in decrease in the IL-8 promoter activity. IL-1beta also induced the production of reactive oxygen species (ROS). N-acetyl cysteine (NAC) prevented the IL-1beta-induced ROS production and IL-8 expression. In addition, exogenous H2O2 could induce the IL-8 expression. Deletional and site-directed mutagenesis studies on the IL-8 promoter revealed that activator protein-1 (AP-1) and nuclear factor (NF)-kappaB sites were required for the IL-1beta-induced IL-8 transcription. Electrophoretic mobility shift assay confirmed that IL-1beta increased the DNA-binding activity of AP-1 and NF-kappaB. Inhibitor (PD980590, SB203580) and ROS scavenger (NAC) studies revealed that the upstream signalings for the transcription factors AP-1 and NF-kappaB were MAPK and ROS, respectively. Conditioned media from the TMK-1 cells pretreated with IL-1beta could remarkably stimulate the in vitro growth of HUVEC and this effect was partially abrogated by IL-8-neutralizing antibodies. The above results suggest that MAPK-AP-1 and ROS-NF-kappaB signaling pathways are involved in the IL-1beta-induced IL-8 expression and that these paracrine signaling pathways induce endothelial cell proliferation.

Cell Line, Tumor↗

PubMed2006

Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS).

Overexpression of the c-Met/hepatocyte growth factor receptor(HGF-R) proto-oncogene and abnormal generation of intracellular oxygen species (reactive oxygen species (ROS)) have been linked, by independent lines of evidence, to cell transformation and to malignant growth. By comparing two subpopulations of the B16 mouse melanoma (B16-F0 and B16-F10) endowed with different lung metastasis capacities (low and high, respectively) we found that both the expression/phosphorylation of c-Met and the steady-state levels of ROS positively correlated with metastatic growth. shRNA-mediated downregulation of c-Met in F10 cells led to a parallel decrease in the generation of oxygen species and in metastatic capacity, suggesting that oxidants may mediate the pro-metastatic activity of the HGF receptor. c-Met activation by a ligand elicits the formation of oxidant species through the oxidase-coupled small GTPase Rac-1, a relevant downstream target of the HGF-R. Moreover, cell treatment with the catalytic ROS scavengers EUK-134 and EUK-189 attenuates Met signaling to ERKs and inhibits the anchorage-independent growth of F10 cells, consistent with a critical role for oxygen species in HGF signaling and in aggressive cell behavior. Finally, genetic manipulation of the Rac-ROS cascade at different levels demonstrated its crucial role in the pro-metastatic activity of c-Met in vivo. Thus, we have outlined a novel cascade triggered by c-Met and mediated by ROS, linked to metastasis and potentially targetable by new antimetastatic, redox-based therapies.

Animals↗

PubMed2006

[The Nox/Duox family of ROS-generating NADPH oxidases].

Reactive oxygen species (ROS) generated by the NADPH oxidases are conventionally thought to be cytotoxic and mutagenic and at high levels induce an oxidative stress response. The phagocyte NADPH oxidase catalyzes the NADPH-dependent reduction of molecular oxygen to generate superoxide O2-., which can dismute to generate ROS species. Together, these ROS participate in host defence by killing or damaging invading microbes. Flavocytochrome b558 is the catalytic core of the phagocyte NADPH oxidase and consists of a large glycoprotein gp91phox or Nox-2 and a small protein p22phox. The other components of the NADPH oxidase are cytosolic proteins, namely p67phox, p47phox, p40phox and Rac. A defect in any of the genes encoding gp91phox, p22phox, p67phox or p47phox results in chronic granulomatous disease, a genetic disorder characterized by severe and recurrent infections. Evidence is rapidly accumulating that low level of ROS were produced by NADPH oxidase homologs in non-phagocytic cells. To date, six human homologs (Nox-1, Nox-3, Nox-4, Nox-5, Duox-1 and Duox-2) have been recently identified in a variety of non-phagocytic cells. The identification of Nox-1 was quickly followed by the cloning of Nox-3, Nox-4, and Nox-5. In parallel, two very large members of the Nox family were discovered, namely Duox-1 and Duox-2, initially also referred to as thyroid oxidases. The physiological functions of Nox-dependent ROS generation are in progress and still require detailed characterization. Activation mechanisms and tissue distribution of the different members of the Nox family are very different, suggesting distinct physiological functions. Nox family enzymes are likely to be involved in a variety of physiological events including cell proliferation, host defence, differentiation, apoptosis, senescence and activation of growth-related signaling pathways. An increase and a decrease in the function of Nox enzymes can contribute to a wide range of pathological processes.

Animals↗

PubMed2002

Thyroid hormone gene targets in ROS 17/2.8 osteoblast-like cells identified by differential display analysis.

Thyroid hormone plays an important role in bone development and metabolism. We used a polymerase chain reaction (PCR)-based mRNA differential display (DD) analysis to obtain a profile of thyroid hormone-responsive genes in osteoblast-like cells (ROS 17/2.8). ROS 17/2.8 cells were treated with 10(-8) M triiodothyronine (T(3)) for 2 and 24 hours. Total RNA was isolated, reverse-transcribed, and amplified using a total of 72 combinations (2 hours) and 240 combinations (24 hours) of 5' and 3' primers. At the 2-hour time point, 1 true-positive novel clone was identified and shown to be the mitochondrial gene, subunit 6 of ATP synthase (ATPase-6). At the 24-hour time point, 3 differentially expressed (DE) mRNAs were confirmed as true-positives including; nonmuscle alkali myosin light chain (NM aMLC), ATPase-6, and one novel clone. T(3)-induction of ATPase-6 mRNA in ROS 17/2.8 cells was seen at 2 and 4 hours, but was maximal at 24 hours (2.1-fold). T(3) induction of ATPase-6 mRNA was increased to fourfold in ROS 17/2.8 cells cultured at a low density. NM aMLC mRNA was modestly upregulated by T(3) in ROS 17/2.8 cells by 1.4-fold, and induction was augmented at low cell density to 1.7-fold. T(3) action on NM aMLC and on the mitochondrial gene ATPase 6, represent novel targets and potential mediators of thyroid hormone action on bone. Cell type, and the extent of cell differentiation, influences T(3) regulation of genes in osteoblast-derived cells.

Adenosine Triphosphatases↗

PubMed2003

Oxidative stress-induced signal transduction pathways in cardiac myocytes: involvement of ROS in heart diseases.

Reactive oxygen species (ROS) are proposed to contribute to the deterioration of cardiac function in patients with heart diseases. It has been reported that ROS are increased in the failing heart and involved in atherosclerosis, myocardial ischemia/reperfusion injury, and heart failure. Antioxidant enzymes are decreased in the decompensated heart, depressing defense mechanisms against oxidative stress. A variety of proteins, including receptors, ionic channels, transporters, and components of signal transduction pathways, are substrates of oxidation by ROS. ROS also function as signal transduction intermediates to induce transcription factor activation, gene expression, cell growth, and apoptosis. Recently, the upstream and downstream molecules of ROS in signal transduction pathways have been the subjects of intense investigation. These molecules include the mitogen-activated protein kinase family, the Rho family of small GTP binding proteins, the Src family of tyrosine kinases, Ras, and cytokines. The modulation of oxidative stress-induced signaling pathways is effective for preventing the progression of heart diseases.

Animals↗

PubMedDate not supplied

Mechanism and characteristics of stimuli-dependent ROS generation in undifferentiated HL-60 cells.

It has been widely believed that undifferentiated human promyelocytic leukemia cells (HL-60) have no ability to generate reactive oxygen species (ROS) responding to stimuli. We report here that undifferentiated HL-60 cells possess NADPH oxidase and that generation of superoxide can be measured using a highly sensitive chemiluminescence dye, L-012. Five subunits of NADPH oxidase, namely, gp91(phox), p22(phox), p67(phox), p47(phox), and Rac 2, were detected in undifferentiated HL-60 cells by immunoblotting analysis. The contents of these NADPH oxidase components in the cells were increased with the differentiation induced by phorbol myristate acetate (PMA), except for p22(phox). Messenger RNAs of these subunits were also detected by the RT-PCR method, and their expressions increased except that of p22(phox) with the differentiation induced by PMA. Kinetic analysis using L-012 revealed that HL-60 cells generated substantial amounts of ROS by various stimulants, including formylmethionyl-leucyl-phenylalanine, PMA, myristic acid, and a Ca2+ ionophore, A23187. Both diphenyleneiodonium (an inhibitor of FAD-dependent oxidase) and apocynin (a specific inhibitor of NADPH oxidase) suppressed this stimuli-dependent ROS generation. Genistein, staurosporine, uric acid, and sodium azide inhibited the ROS generation in undifferentiated HL-60 cells in a similar way to that in undifferentiated neutrophils. These results suggested that the mechanism of ROS generation in undifferentiated HL-60 cells is the same as that in primed neutrophils.

Acetophenones↗

PubMed2007

Ca2+ storage capacity of rat brain mitochondria declines during the postnatal development without change in ROS production capacity.

Ca2+ overload of mitochondria and oxidants are considered as crucial factors inducing the opening of the permeability transition pore (PTP) in mitochondria. The interdependence between permeability transition (PT), calcium retention capacity (CRC), and reactive oxygen species (ROS) generation was studied in mitochondria from immature and mature rat brain. Brain mitochondria isolated from 1-day- and 1-week-old rats are much more resistant to Ca2+-triggered PT in phosphate-containing incubation medium than mitochondria from adult brain, since the CRC decreases with development. CRC of mitochondria from 1-week-old rat brain was higher than for adult rat brain (450 +/- 112 vs. 175 +/- 35 nmol Ca2+ per mg of protein). In contrast, for ROS generation there was no age difference. In immature and mature mitochondria, basal, respiratory chain-inhibited or glutathione-depleted ROS generations were similar. In addition, the extent of the Ca2+ load was without effect on the basal ROS generation before mitochondria underwent PT. In summary, ROS generation does not crucially affect the ability of immature mitochondria to buffer high levels of extramitochondrial Ca2+ without undergoing PT. However, we hypothesize that the high resistance of immature mitochondria is related to the low content of some PTP complex constituents, such as creatine kinase.

Animals↗

PubMed1998

Susceptibility of natural killer (NK) cells to reactive oxygen species (ROS) and their restoration by the mimics of superoxide dismutase (SOD).

Natural killer (NK) cells are susceptible to reactive oxygen species (ROS), and lose the activity by the effects of ROS. Cancer bearing hosts usually suffer from oxidative stress (OS), and the NK-activity decreases to a significantly lower level than normal controls. Superoxide dismutase (SOD)-mimicking substances, such as protein-bound polysaccharide of Coriolus versicolor (Fr) QUEL (PSK) and iron-chelating chlorine e6-Na (FeCNa), can restore the NK-activity of cancer bearing hosts, when collaborating with catalase. Incorporation of 3H-thymidine by ROS-treated NK-cells is not affected, indicating that these cells are still active in the nucleic acid metabolism. Intraperitoneal administration of anti-Asialo GM1 antibody extinguished the NK-activity. NK-cells affected by ROS lost the adherence to target cancer cells in both in vitro and in vivo. ROS may change the surface charge of NK-cells to anionic, resulting in an inability of adhesion to target cancer cells which usually show the negative surface charge.

Animals↗

PubMed1999

Increased ROS levels contribute to elevated transcription factor and MAP kinase activities in malignantly progressed mouse keratinocyte cell lines.

There is evidence that reactive oxygen species (ROS) are important mediators of tumor promotion and progression. The molecular mechanisms involved in ROS-mediated signaling, however, are unclear at present. Using ionizing radiation and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as model physical and chemical carcinogens, we have malignantly progressed 308 cells, a papilloma-producing mouse keratinocyte cell line, and investigated the molecular alterations in the progressed phenotypes. In this study, we demonstrate that both MNNG and radiation-progressed malignant variants showed elevated ROS levels that contributed to their proliferative capacity in vitro as well as in vivo. We found increased Erk-1/2 and p38 MAP kinase activities to be important components of ROS-mediated signaling. The pro-oxidant state also contributed to constitutive elevation of AP-1, NFkappaB and cAMP response element transactivation in the malignant phenotype. Our data provide evidence for a functional role of elevated ROS levels in tumor progression and implicate Erk-1/2 and p38 MAP kinase activation in the malignant progression of mouse keratinocytes.

Animals↗