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PubMed2006

Enhancement of endogenous defenses against ROS by supra-nutritional level of selenium is more safe and effective than antioxidant supplementation in reducing hypertensive target organ damage.

Hypertension-induced target organ damage (TOD), is one of the leading causes of morbidity and mortality. Reactive oxygen species (ROS) play an important role in the pathogenesis and development of hypertension. It has been suggested that hypertension-induced TOD is related to the level of oxidative stress, but is in part independent of the level of blood pressure. Therefore, in addition to anti-hypertensive drug therapy, novel strategies against ROS, will provide additional benefits to patient with hypertension. Vitamin E has long been supplemented as an effective antioxidant. However, the potential hazardous effects of vitamin E supplementation as antioxidant revealed by recent studies make its clinical and routine use prudent. Therefore, novel approaches capable of enhancing endogenous system to defend against ROS are required. Here, we propose that enhancement of intrinsic defenses against ROS by supra-nutritional level of selenium is more safe and effective than antioxidant supplementation in reducing hypertensive target organ damage, owing to its role in activating and constitution of native vital proteins and/or enzymes against oxidative stress, and the fact that scarcity of selenium can not be supplemented by normal food, and potentially extra benefits by supra-normal intake.

Antioxidants↗

PubMed2004

Regulatory role of dADAR in ROS metabolism in Drosophila CNS.

Pre-mRNA adenosine deaminase (ADAR) is involved in many physiological processes by either directly converting adenosine to inosine in certain pre-mRNAs or indirectly regulating expression of certain genes. Mutations of Drosophila ADAR (dADAR) results in neuronal dysfunction and hypersensitivity to oxygen deprivation. Recently, we found that the mutant flies were very resistant to paraquat, a compound that generates free radicals. In order to further characterize the neuronal role of dADAR and understand the basis for the resistance to the oxidative stress, we investigated the effect of dADAR on the expression of genes encoding scavengers of cellular reactive oxygen species (ROS) in both dADAR mutant and overexpression flies. Our data show that the expression of the genes encoding known ROS scavengers [superoxide dismutase (SOD) and catalase] is not regulated by dADAR. However, the transcripts of genes encoding two potential ROS scavengers (dhd and Cyp4g1) were robustly increased in dADAR mutant flies, and conversely both were significantly decreased in dADAR overexpressing flies. Using dhd [encoding a Drosophila homolog of the mammalian protein thioredoxin (Trx)] transgenic flies, we confirmed that the resistance of dADAR mutant flies to paraquat resulted, at least partially, from the up-regulation of dhd gene in dADAR mutant flies. Our data not only confirm the importance of ADAR in maintenance of neuronal function but also reveal its regulatory role in the expression of genes encoding ROS scavengers.

Adenosine Deaminase↗

PubMed2004

Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are induced by TNF and responsible for elimination of ROS.

We recently showed that TNF induces accumulation of reactive oxygen species (ROS) that mediates necrosis in murine embryonic fibroblasts (MEFs) derived from TRAF2- and TRAF5-double deficient (DKO) mice. To elucidate the defects that subsequently cause accumulation of ROS in DKO MEFs, we compared gene expression profiles of wild-type and DKO MEFs before and after TNF stimulation using cDNA microarrays. Interestingly, many antioxidant enzymes are induced by TNF in wild-type MEFs, induction of these genes is impaired in DKO MEFs. Taken that TNF induces accumulation of ROS in DKO, but not wild-type MEFs, upregulation of antioxidant enzyme(s) might play a crucial role in elimination of ROS.

Animals↗

PubMed2004

Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain.

Reactive oxygen species (ROS) are free radicals produced in biological systems that are involved in various degenerative brain diseases. The present study tests the hypothesis that ROS also play an important role in neuropathic pain. In the rat spinal nerve ligation (SNL) model of neuropathic pain, mechanical allodynia develops fully 3 days after nerve ligation and persists for many weeks. Systemic injection of a ROS scavenger, phenyl-N-tert-butylnitrone (PBN), relieves SNL-induced mechanical allodynia in a dose-dependent manner. Repeated injections cause no development of tolerance or no loss of potency. Preemptive treatment with PBN is also effective in preventing full development of neuropathic pain behavior. Systemic injection was mimicked by intrathecal injection with a little less efficacy, while intracerebroventricular administration produced a much smaller effect. These data suggest that PBN exerts its anti-allodynic action mainly by spinal mechanisms. Systemic treatment with other spin-trap reagents, 5,5-dimethylpyrroline-N-oxide and nitrosobenzene, showed similar analgesic effects, suggesting that ROS are critically involved in the development and maintenance of neuropathic pain. Thus this study suggests that systemic administration of non-toxic doses of free radical scavengers could be useful for treatment of neuropathic pain.

Analgesics↗

PubMed2006

Ferric iron increases ROS formation, modulates cell growth and enhances genotoxic damage by 4-hydroxynonenal in human colon tumor cells.

Iron is a relevant risk factor for colorectal cancer due to its genotoxic properties. Here we hypothesised that iron-overload causes other toxic effects, which contribute to carcinogenesis. For this, we investigated formation of reactive oxygen species (ROS), DNA repair, cell growth and glutathione (GSH) in human colon tumor cells (HT29 clone 19A) treated with ferric nitrilotriacetate (Fe-NTA, 0-2000 microM). Intracellular formation of ROS was analysed with the peroxide-labile fluorescent dye carboxy-dichlorodihydrofluorescine-diacetate. DNA repair, reflected as the persistency of DNA damage induced by selected genotoxins, was determined with the Comet assay. Cell growth and GSH were measured by fluorimetrical analysis. Key findings were that ROS formation increased with time (1000 microM Fe-NTA, p < 0.001). DNA damage was largely repaired after 120 min, but was not affected by 10 microM Fe-NTA. In contrast, 10 microM Fe-NTA significantly increased DNA damage induced by 4-hydroxynonenal. Doses of 25 microM Fe-NTA increased cell growth (p < 0.05), whereas high concentrations (2000 microM) resulted in growth arrest (p < 0.05), that was accompanied by increased GSH levels (p < 0.01). In conclusion, high concentrations of Fe-NTA caused cellular effects, which reflect a stress response, and resulted in formation of ROS. Carcinogenic risks from ferric iron could be derived also from lower concentrations, which enhance tumor cell growth and cause progenotoxic effects.

Aldehydes↗

PubMed1999

Regions in vertebrate photoreceptor guanylyl cyclase ROS-GC1 involved in Ca(2+)-dependent regulation by guanylyl cyclase-activating protein GCAP-1.

The membrane bound guanylyl cyclase (GC) photoreceptor membrane GC1 (ROS-GCI) of photoreceptor cells synthesizes cGMP, the intracellular transmitter of vertebrate phototransduction. The activity of ROS-GCI is controlled by small Ca(2+)-binding proteins, named GC-activating proteins (GCAPs). We identified and characterized two short regulatory regions (M445-L456 and L503-1522) in the juxtamembrane domain (JMD) of ROS-GC1 by peptide competition and mutagenesis studies. Both regions are critical for the activation of ROS-GCI by GCAP-1.

Amino Acid Sequence↗

PubMed2002

Relationship between lipophilicity of C6-10 hydrocarbon solvents and their ROS-inducing potency in rat cerebellar granule cells.

We have studied the effects of aliphatic, alicyclic, and aromatic C6-10 solvents on the formation of reactive oxygen species (ROS) in rat cerebellar granule cell cultures. ROS formation was assessed by monitoring oxidation of 2',7'-dichlorofluorescin (DCFH) to the fluorescent compound 2',7'-dichlorofluorescein (DCF). We found that aromatic solvents with C > 7, and aliphatic and alicyclic solvents with C > or = 7 induce ROS formation in rat cerebellar granule cells in vitro. The response increased with increasing solvent concentration. The potency of the compounds within each homologous group seemed to be correlated to their octanol water partition-coefficients. The aromatic solvents were generally less efficient in inducing ROS formation than the aliphatic and the alicyclic compounds.

Animals↗

PubMed2003

Cinnamaldehyde induces apoptosis by ROS-mediated mitochondrial permeability transition in human promyelocytic leukemia HL-60 cells.

Cinnamaldehyde is an active compound isolated from the stem bark of Cinnamomum cassia, a traditional oriental medicinal herb, which has been shown to inhibit tumor cell proliferation. In this study, we investigated the effects of cinnamaldehyde on the cytotoxicity, induction of apoptosis and the putative pathways of its actions in human promyelocytic leukemia cells. Using apoptosis analysis, measurement of reactive oxygen species (ROS), and assessment of mitochondrial membrane potentials (DeltaPsim), we show that cinnamaldehyde is a potent inducer of apoptosis and that it transduces the apoptotic signal via ROS generation, thereby inducing mitochondrial permeability transition (MPT) and cytochrome c release to the cytosol. ROS production, mitochondrial alteration, and subsequent apoptotic cell death in cinnamaldehyde-treated cells were blocked by the antioxidant N-acetylcystein. Taken together, our data indicate that cinnamaldehyde induces the ROS-mediated mitochondrial permeability transition and resultant cytochrome c release. This is the first report on the mechanism of the anticancer effect of cinnamaldehyde.

Acrolein↗

PubMed1997

Are the reactive oxygen-derived species (ROS) interactive properties of the many therapeutic drugs from various categories pertinent to their beneficial effects?

Many pathologic states are known to involve the generation of reactive oxygen species, (ROS). It is not known at present to what extent these phenomena are due to ROS formation, or if their formation is a result of the disease. Many therapeutic drugs either scavenge ROS or inhibit their formation. The purpose of this review is to match the drugs used for certain diseases with their anti-ROS actions. This attempted correlation is made to try to give an answer to the title question.

Anesthetics, General↗

PubMed2002

Chromium(III)-induced apoptosis of lymphocytes: death decision by ROS and Src-family tyrosine kinases.

Apoptosis is an active process induced by a variety of physiological and external stimuli, in which elimination of damaged cells are effected through a genetically controlled process. In this study, we have examined the mechanism of chromium(III) [Cr(III)]-induced cytotoxicity with respect to its relationship to oxidative stress. Morphology, flow cytometry, and DNA fragmentation studies show that tris-(1,10-phenanthroline)chromium(III) [Cr(III)-phen], tris-(2,2'-bipyridyl)chromium(III) [Cr(III)-bpy], trans-diaqua[1,2-bis(salicylideneamino)ethanechromium(III)] [Cr(III)-salen], and trans-diaqua[1,3-bis(salicylideneamino)propanechromium(III)] [Cr(III)-salprn] induced apoptosis of lymphocytes. Pentaammineaquachromium(III) [Cr(III)-hpa] does not induce apoptosis. Apoptosis induced by these complexes involves the generation of reactive oxygen species (ROS) as seen by increased fluorescence of dichloroflourescein (DCF) observed through flow cytometry. Pretreatment of lymphocytes with antioxidants completely abrogate apoptosis. Cr(III) treatment also increased the expression and activation of Src-family tyrosine kinases viz. p56lck, p59fyn, and p53/56lyn, as seen by immunoblotting and immune complex kinase assay. PP2, a selective Src-family tyrosine kinase inhibitor, abolishes apoptosis, indicating that Src-family tyrosine kinases are directly involved in eliciting apoptosis. Interestingly, a one-to-one correlation between the expression of Src-family tyrosine kinases and ROS is observed, since antioxidants pretreatment inhibits the expression and the activation of these kinases. These results further indicate that Cr(III)-induced apoptosis is mediated through production of ROS, which in turn activates the Src-family tyrosine kinases. The increased activation of Src-family tyrosine kinases may be a mechanism involved in apoptosis of lymphocytes elicited by various other physiological stimuli that exploit ROS as a second messenger.

Adenosine Triphosphate↗

PubMed2003

Apoptosis of lymphocytes induced by chromium(VI/V) is through ROS-mediated activation of Src-family kinases and caspase-3.

Mechanistic insights into Cr(VI)-induced carcinogenicity and possible implication of Cr(V) species formed by the redox reactions of chromium-bearing species have attracted interest. We have previously demonstrated that when human peripheral blood lymphocytes are exposed to the Cr(V) complexes, viz., sodium bis(2-ethyl-2-hydroxybutyrato)oxochromate(V), Na[Cr(V)O(ehba)(2)] and sodium bis(2-hydroxy-2-methylbutyrato)oxochromate(V), Na[Cr(V)O(hmba)(2)], apoptosis and formation of reactive oxygen species (ROS) are observed. The molecular mechanisms involving cellular signaling pathways leading to apoptosis are addressed in the present study. Treatment of lymphocytes with Na[Cr(V)O(ehba)(2)] and K(2)Cr(2)O(7) leads to the activation of the Src-family protein tyrosine kinases namely, p56(lck), p59(fyn), and p56/53(lyn), which then activates caspase-3, both of which are under the partial influence of ROS. Inhibition of the Src-family tyrosine kinases activity by PP2 and of caspase-3 by Z-DEVD-FMK reverses apoptosis, thereby suggesting their importance. Antioxidants only partially reverse the apoptosis induced by Cr(VI/V), suggesting that pathways other than those induced by ROS cannot be ruled out. Although the complex, Na[Cr(V)O(ehba)(2)] is known to be relatively stable in aqueous solutions, previous studies have shown that the Cr(V) complex, Na[Cr(V)O(ehba)(2)] disproportionates to Cr(VI) and Cr(III) forms at pH 7.4 through complex mechanistic processes. Dynamics studies employing EPR data show that the Cr(V) state in Na[Cr(V)O(ehba)(2)] is relatively more stable in RPMI-1640 medium containing plasma. Formation of ROS during the reaction of redox partners with Na[Cr(V)O(ehba)(2)] is an early event and compares favorably in kinetic terms with the reported rate processes for disproportionation. This investigation presents evidence for the direct implication of Cr(V) in Cr(VI)-induced apoptosis of lymphocytes.

Antioxidants↗

PubMed2004

Sensitization of T cells to apoptosis--a role for ROS?

T cell homeostasis is achieved by balancing the production and proliferation of T cells with their apoptotic cell death. Activation of naïve T cells by antigen in the context of MHC results in the massive expansion of antigen-specific T cells and the production of reactive oxygen species (ROS). Following expansion, the majority of the T cells die via apoptosis, while a small number of them survive and differentiate into memory T cells. This cell fate decision is crucial to our understanding of how autoimmunity is avoided and how immunity is maintained. It has become increasingly clear that ROS can affect this cell fate decision by sensitizing T cells to apoptosis. Interestingly, ROS have effects on both intrinsic and extrinsic apoptosis pathways through modulation of expression of the major molecules in these pathways, Bcl-2 and FasL. In this review, we will focus on the pro-apoptotic effects of ROS and mechanisms by which they regulate the death of T cells.

Animals↗

PubMed2005

Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation.

Amyloid beta (Abeta) is a main component of senile plaques in Alzheimer's disease and induces neuronal cell death. Reactive oxygen species (ROS), nitric oxide and endoplasmic reticulum (ER) stress have been implicated in Abeta-induced neurotoxicity. We have reported that apoptosis signal-regulating kinase 1 (ASK1) is required for ROS- and ER stress-induced JNK activation and apoptosis. Here we show the involvement of ASK1 in Abeta-induced neuronal cell death. Abeta activated ASK1 mainly through production of ROS but not through ER stress in cultured neuronal cells. Importantly, ASK1-/- neurons were defective in Abeta-induced JNK activation and cell death. These results indicate that ROS-mediated ASK1 activation is a key mechanism for Abeta-induced neurotoxicity, which plays a central role in Alzheimer's disease.

Alzheimer Disease↗

PubMed2004

5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation.

5-Lipoxygenase (5LO) is involved in the production of leukotrienes and reactive oxygen species (ROS) from arachidonic acid. Its strong activation has been associated with several diseases like cancer and neurodegeneration. Here we show that 5LO activity increases during senescence-like growth arrest induced by oncogenic ras or culture history in both human and mouse embryo fibroblasts. Overexpression of 5LO promotes senescence-like growth arrest via a p53/p21-dependent pathway, and this occurs independently of telomerase activity. 5LO stabilizes p53 through phosphorylation at Ser15 and increases expression of the p53-transcriptional target p21. This is achieved by regulating ROS production. Indeed, ROS are increased in 5LO-arrested cells. Antioxidants and a low oxygen environment prevent 5LO-induced growth arrest. Finally, 5LO inhibition reduces the growth arrest induced by oncogenic ras or culture history and these effects are neutralized by the addition of exogenous ROS. These data link the 5LO pathway to oxidative crises of primary fibroblast and suggest that the ability of 5LO to induce senescence-like growth arrest may be important in the pathogenesis of 5LO-associated disorders.

Animals↗

PubMed2006

Dietary calcium regulates ROS production in aP2-agouti transgenic mice on high-fat/high-sucrose diets.

OBJECTIVE: We have previously demonstrated that 1alpha, 25(OH)2D3 promotes adipocyte reactive oxygen species (ROS) production. We have now evaluated whether decreasing 1alpha, 25(OH)2D3 levels by increasing dietary calcium will decrease oxidative stress in vivo. METHODS: We fed low-calcium (0.4% Ca) and high-calcium (1.2% Ca from CaCO3) obesity-promoting (high sucrose/high fat) diets to aP2-agouti transgenic mice and assessed regulation of ROS production in adipose tissue and skeletal muscle. RESULTS: Mice on the high-calcium diet gained 50% of the body weight (P=0.04) and fat (P<0.001) as mice on the low-calcium diet (0.4% Ca). The high-calcium diet significantly reduced adipose intracellular ROS production by 64 and 18% (P<0.001) and inhibited adipose tissue nicotinamide adenine dinucleotide phosphate oxidase expression by 49% (P=0.012) and 63% (P=0.05) in visceral and subcutaneous adipose tissue, respectively. Adipocyte intracellular calcium ([Ca2+]i) levels were suppressed in mice on the high-calcium diet by 73-80% (P<0.001). The high-calcium diet also induced 367 and 191% increases in adipose mitochondrial uncoupling protein 2 (UCP2) expression (P<0.001) in visceral and subcutaneous adipose tissue, respectively. The pattern of UCP3 expression and indices of ROS production in skeletal muscle were consistent with those in adipose tissue. The high-calcium diet also suppressed 11beta-hydroxysteroid dehydrogenase (11beta-HSD) expression in visceral adipose tissue by 39% (P=0.034). 11beta-HSD expression was markedly higher in visceral vs subcutaneous adipose tissue in mice on the low-calcium diet (P=0.034), whereas no difference was observed between the fat depots in mice on the high-calcium diet. CONCLUSION: These data support a potential role for dietary calcium in the regulation of obesity-induced oxidative stress.

Adipocytes↗

PubMed2000

[Efficiency of conventional glass wool and SpermFertil columns with respect to ROS-reduction, leukocyte reduction, and CASA-generated sperm counts in semen].

OBJECTIVE: Glass wool filtration has proved to be useful to separate motile from defective spermatozoa and leukocytes in semen from patients with oligozoospermia and azoospermia. With regard to that, we set out to investigate the efficiency of two widely used filter systems. MATERIAL AND METHODS: Semen from 10 patients attending the Dept. of Andrology, FSU Jena, were investigated with home-made coarse glass wool filters and SpermFertil columns regarding elimination of reactive oxygen species (ROS) and enrichment of semen with motile and progressive spermatozoa. RESULTS: Filtration with home-made glass wool columns did not affect the percentage of motile spermatozoa but increased that of progressive spermatozoa. The whole cell count was decreased by a third. Leukocytes were reduced by half and ROS by more than half. SpermFertil columns increased the percentage of both motile and progressive spermatozoa and the whole cell count was decreased severely. Leukocytes were eliminated almost completely, as were ROS. CONCLUSIONS: Our results show the higher potential of SpermFertil columns to enrich semen specimens with motile and progressive spermatozoa and to almost completely eliminate leukocytes and ROS in comparison to home-made glass wool columns. However, SpermFertil columns reduce the whole cell count to about 10% of the original cell count.

Adult↗

PubMed1997

Mutations of Ros differentially effecting signal transduction pathways leading to cell growth versus transformation.

The signaling functions of the oncogenic protein-tyrosine kinase v-Ros were studied by systematically mutating the tyrosine residues in its cytoplasmic domain. The carboxyl mutation of Tyr-564 produces the most pronounced inhibitory effect on v-Ros autophosphorylation and interaction with phospholipase Cgamma. A cluster of 3 tyrosine residues, Tyr-414, Tyr-418, and Tyr-419, within the PTK domain of v-Ros plays an important role in modulating its kinase activity. The mutant F419 and the mutant DI, deleting 6-amino acids near the catalytic loop, retain wild type protein tyrosine kinase and mitogenic activities, but have dramatically reduced oncogenicity. Both mutant proteins are able to phosphorylate or activate components in the Ras/microtubule-associated protein kinase signaling pathway. However, F419 mutant protein is unable to phosphorylate insulin receptor substrate 1 (IRS-1) or promote association of IRS-1 with phosphatidylinositol 3-kinase. This tyrosine residue in the context of the NDYY motif may define a novel recognition site for IRS-1. Both F419 and DI mutants display impaired ability to induce tyrosine phosphorylation of a series of cytoskeletal and cell-cell interacting proteins. Thus the F419 and DI mutations define v-Ros sequences important for cytoskeleton signaling, the impairment of which correlates with the reduced cell transforming ability.

Animals↗

PubMed2003

Matrix-independent activation of phosphatidylinositol 3-kinase, Stat3, and cyclin A-associated Cdk2 Is essential for anchorage-independent growth of v-Ros-transformed chicken embryo fibroblasts.

The question remains open whether the signaling pathways shown to be important for growth and transformation in adherent cultures proceed similarly and play similar roles for cells grown under anchorage-independent conditions. Chicken embryo fibroblasts (CEF) infected with the avian sarcoma virus UR2, encoding the oncogenic receptor protein-tyrosine kinase (RPTK) v-Ros, or with two of its transformation-impaired mutants were grown in nonadherent conditions in methylcellulose (MC)-containing medium, and the signaling functions essential for Ros-induced anchorage-independent growth were analyzed. We found that the overall tyrosine phosphorylation of cellular proteins in CEF transformed by v-Ros or by two oncogenic nonreceptor protein-tyrosine kinases (PTKs), v-Src and v-Yes, was dramatically reduced in nonadherent conditions compared with that in adherent conditions, indicating that cell adhesion to the extracellular matrix plays an important role in efficient substrate phosphorylation by these constitutively activated PTKs. The UR2 transformation-defective mutants were differentially impaired compared with UR2 in the activation of phosphatidylinositol 3-kinase (PI 3-kinase) and Stat3 in nonadherent conditions. Consistently, the constitutively activated mutants of PI 3-kinase and Stat3 rescued the ability of the UR2 mutants to promote anchorage-independent growth. Conversely, dominant negative mutants of PI 3-kinase and Stat3 inhibited UR2-induced anchorage-independent growth. UR2-infected CEF grown in nonadherent conditions displayed faster cell cycle progression than the control or the UR2 mutant-infected cells, and this appeared to correlate with a PI 3-kinase-dependent increase in cyclin A-associated Cdk2 activity. Treatment of UR2-infected cells with Cdk2 inhibitors led to the loss of the anchorage-independent growth-promoting activity of UR2. In conclusion, we have adopted an experimental system enabling us to study the signaling pathways in cells grown under anchorage-independent conditions and have identified matrix-independent activation of PI 3-kinase and Stat3 signaling functions, as well as the PI 3-kinase-dependent increase of cyclin A-associated Cdk2 kinase activity, to be critical for the Ros-PTK-induced anchorage-independent growth.

Animals↗