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    Keywords: SACCHAROMYCES-CEREVISIAE ; NITRIC-OXIDE ; TRANSGENIC MICE ; ESCHERICHIA-COLI ; MAMMALIAN-CELLS ; OXIDATIVE STRESS ; HYDROGEN-PEROXIDE ; POSITIVE SELECTION ; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE G6PD ; DNA GLYCOSYLASES
    Abstract: Mice that harbored the x-ray-induced low efficiency allele of the major X-linked isozyme of glucose-6-phospate dehydrogenase (G6PD), Gpdx(a-m2Neu), and, in addition, harbored the transgenic shuttle vector for the determination of mutagenesis in vivo, pUR288, were employed to further our understanding of the interdependence of general metabolism, oxidative stress control, and somatic mutagenesis. The Gpdx(a-m2Neu) mutation conferred moderate G6PD deficiency in hemizygous males (Gpdx(a-m2Neu/y)) displaying residual enzyme activities of 27% in red blood cells and 13% in brain (compared to wild-type controls, Gpdx(a/y) males). In spite of this mild phenotype, the brains of G6PD-deficient males exhibited a significant distortion of redox control ( approximately 3-fold decrease in the ratio of reduced glutathione to oxidized glutathione), a considerable accumulation of promutagenic etheno DNA adducts ( approximately 13-fold increase in ethenodeoxyadenosine and approximately 5-fold increase in ethenodeoxycytidine), and a substantial elevation of somatic mutation rates ( approximately 3-fold increase in mutant frequencies in lacZ, the target and reporter gene of mutagenesis in the shuttle vector, pUR288). The mutation pattern in the brain was dominated by illegitimate genetic recombinations, a presumed hallmark of oxidative mutagenesis. These findings suggested a critical function for G6PD in limiting oxidative mutagenesis in the mouse brain.
    Type of Publication: Journal article published
    PubMed ID: 11909700
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    Keywords: APOPTOSIS ; CELLS ; tumor ; Germany ; human ; PROTEIN ; TISSUE ; RELEASE ; ACTIVATED MACROPHAGES ; COMPLEX ; NITRIC-OXIDE ; COMPLEXES ; MACROPHAGES ; INDUCED APOPTOSIS ; STRESS ; CELL-LINE ; leukemia ; LINE ; TRANSFORMATION ; OVEREXPRESSION ; COMPLEX-FORMATION ; Bcl-2 ; free radicals ; TRANSFECTION ; CASPASE ACTIVATION ; LEVEL ; nitric oxide ; macrophage ; dinitrosyl iron complexes ; ELECTRON SPIN RESONANCE ; EPR spectroscopy ; FAS-INDUCED APOPTOSIS ; NITROSATIVE STRESS ; NONHEME IRON ; OXIDE-MEDIATED APOPTOSIS ; PC12 CELLS
    Abstract: Cells expressing the cytokine-inducible NO synthase are known to trigger apoptosis in neighboring cells. Paramagnetic dinitrosyl nonheme iron complexes (DNIC) were found in tumor tissue about 40 years ago; however, the role of these NO+-bearing species is not completely understood. In the human Jurkat leukemia cell line, the application of the model complex DNIC-thiosulfate (50-200 mu M) induced apoptosis (defined by phosphatidylserine externalization) in a concentration- and time-dependent manner. In Jurkat cells, the an-caspase inhibitor, zVADfmk (50 mu M), and/or stable transfection of antiapoptotic protein, Bcl-2, was unable to afford protection against DNIC-induced apoptosis. The membrane-impermeable metal chelator, N-methyl-D-glucamine dithiocarbamate (MGD; 200 mu M), in the presence of DNIC significantly increased apoptosis, but had no effect on its own. Electron paramagnetic resonance studies showed that MGD led to rapid transformation of the extracellular DNIC into the stable impermeable NO-Fc-MGD complex and to a burst-type release of nitrosonium (NO+) equivalents in the extracellular space. These results suggest that in Jurkat cells, DNIC-thiosulfate induces Bcl-2- and caspase-independent apoptosis, which is probably secondary to local nitrosative stress at the cell surface. We hypothesize that the local release of nonheme Fe-NO species by activated macrophages may play a role in the killing of malignant cells that have high Bcl-2 levels. (c) 2005 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16631524
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    Keywords: CANCER ; IN-VITRO ; tumor ; BLOOD ; carcinoma ; SITE ; ENZYMES ; METABOLISM ; TISSUE ; PATIENT ; COMPLEX ; NITRIC-OXIDE ; COMPLEXES ; DNA ; CARCINOGENESIS ; colon ; CONTRAST ; BIOLOGY ; TARGET ; LESIONS ; MALIGNANCIES ; ESCHERICHIA-COLI ; REPAIR ; DAMAGE ; COLON-CANCER ; DNA-DAMAGE ; CANCER-PATIENTS ; INDIVIDUALS ; LIPID-PEROXIDATION ; OXIDATIVE STRESS ; CANCER PATIENTS ; free radicals ; colon cancer ; mRNA ; SCIENCE ; DNA damage ; BASE EXCISION-REPAIR ; P-32-postlabeling ; HUMAN-CELLS ; ONSET ; colorectal ; base excision repair ; 3,N-4-ETHENOCYTOSINE ; 1,N-2-Ethenoguanine ; 1,N-6-Ethenoadenine ; FATTY-ACID HYDROPEROXIDES ; LONG-PATCH ; PRIMARY SUBSTRATE
    Abstract: To assess the role of lipid peroxidation-induced DNA damage and repair in colon carcinogenesis, the excision rates and levels of 1,N-6-etheno-2'-deoxyadenosine (epsilon dA), 3,N-4-etheno-2'-deoxycytidine (epsilon dC), and 1,N-2-etheno-2'-deoxyguanosine (1,N-2-epsilon dG) were analyzed in polymorphic blood leukocytes (PBL) and resected colon tissues of 54 colorectal carcinoma (CRC) patients and PBL of 56 healthy individuals. In PBL the excision rates of 1,N-6-ethenoadenine (epsilon Ade) and 3,N-4-ethenocytosine (epsilon Cyt), measured by the nicking of oligodeoxynucleotide duplexes with single lesions, and unexpectedly also the levels of epsilon dA and 1,N-2-epsilon dG, measured by LC/MS/MS, were lower in CRC patients than in controls. In contrast the mRNA levels of repair enzymes, alkylpurine- and thymine-DNA glycosylases and abasic site endonuclease (APE1), were higher in PBL of CRC patients than in those of controls, as measured by QPCR. In the target colon tissues epsilon Ade and epsilon Cyt excision rates were higher, whereas the epsilon dA and epsilon dC levels in DNA, measured by P-32-postlabeling, were lower in tumor than in adjacent colon tissue, although a higher mRNA level was observed only for APE1. This suggests that during the onset of carcinogenesis, etheno adduct repair in the colon seems to be under a complex transcriptional and posttranscriptional control, whereby deregulation may act as a driving force for malignancy. (C) 2010 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20600828
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    Keywords: APOPTOSIS ; CELLS ; PROTEIN ; STRESS ; DAMAGE ; MITOCHONDRIA ; GEL-ELECTROPHORESIS ; free radicals ; DEHYDROGENASE ; REDOX REGULATION ; COMPLEX-I ; THIOREDOXIN SYSTEM ; BOVINE HEART-MITOCHONDRIA ; DT40 CELLS ; Electron transport chain ; Hydrogen peroxide ; Methionyl-tRNA synthetase ; Mitochondrial protein biosynthesis ; Thioredoxin 2
    Abstract: Reactive oxygen species (ROS) are released at the mitochondrial inner membrane by the electron transport chain (ETC). Increasing evidence suggests that mitochondrial H2O2 acts as a signaling molecule and participates in the (feedback) regulation of mitochondrial activity and turnover. It seems likely that key mitochondrial components contain redox-sensitive thiols that help to adapt protein function to changes in electron flow. However, the identity of most redox-regulated mitochondrial proteins remains to be defined. Thioredoxin 2 (Trx2) is the major protein-thiol-reducing oxidoreductase in the mitochondrial matrix. We used in situ mechanism-based kinetic trapping to identify disulfide-exchange interactions of Trx2 within functional mitochondria of intact cells. Mass spectrometry successfully identified known and suspected Trx2 target proteins and, in addition, revealed a set of new candidate target proteins. Our results suggest that the mitochondrial protein biosynthesis machinery is a major target of ETC-derived ROS. In particular, we identified mitochondrial methionyl-tRNA synthetase (mtMetRS) as one of the most prominent Trx2 target proteins. We show that an increase in ETC-derived oxidants leads to an increase in mtMetRS oxidation in intact cells. In conclusion, we find that in situ kinetic trapping provides starting points for future functional studies of intramitochondrial redox regulation.
    Type of Publication: Journal article published
    PubMed ID: 21295137
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    Abstract: The transcription factor nuclear factor-kappaB (NF-kappaB) mediates expression of key genes involved in innate immunity and inflammation. NF-kappaB activation has been repeatedly reported to be modulated by hydrogen peroxide (H2O2). Here, we show that the NF-kappaB-activating signaling adapter myeloid differentiation primary response gene 88 (MyD88) is highly sensitive to oxidation by H2O2 and may be redox-regulated in its function, thus facilitating an influence of H2O2 on the NF-kappaB signaling pathway. Upon oxidation, MyD88 forms distinct disulfide-linked conjugates which are reduced by the MyD88-interacting oxidoreductase nucleoredoxin (Nrx). MyD88 cysteine residues functionally modulate MyD88-dependent NF-kappaB activation, suggesting a link between MyD88 thiol oxidation state and immune signaling.
    Type of Publication: Journal article published
    PubMed ID: 27720842
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    Abstract: The genetically encoded probes roGFP2-Orp1 and Grx1-roGFP2 have been designed to be selectively oxidized by hydrogen peroxide (H2O2) and glutathione disulfide (GSSG), respectively. Both probes have demonstrated such selectivity in a broad variety of systems and conditions. In this study, we systematically compared the in vitro response of roGFP2, roGFP2-Orp1 and Grx1-roGFP2 to increasing amounts of various oxidant species that may also occur in biological settings. We conclude that the previously established oxidant selectivity is highly robust and likely to be maintained under most physiological conditions. Yet, we also find that hypochlorous acid, known to be produced in the phagocyte respiratory burst, can lead to non-selective oxidation of roGFP2-based probes at concentrations 〉/=2microM, in vitro. Further, we confirm that polysulfides trigger direct roGFP2 responses. A side-by-side comparison of all three probes can be used to reveal micromolar amounts of hypochlorous acid or polysulfides.
    Type of Publication: Journal article published
    PubMed ID: 28242229
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    Keywords: CELLS ; EXPRESSION ; GROWTH ; BLOOD ; Germany ; RISK ; RNA ; RISK-FACTORS ; LESIONS ; PLASMA ; risk factors ; smoking ; LDL ; OVEREXPRESSION ; PERIPHERAL-BLOOD ; COX-2 ; LIPOPROTEINS ; N-ACETYL-CYSTEINE ; inflammation ; HYPERCHOLESTEROLEMIA ; SERUM ; ELISA ; free radicals ; MATRIX METALLOPROTEINASES ; ATHEROSCLEROTIC LESIONS ; GLUTAMATE LEVELS ; hyperlipoproteinemia ; NITRIC-OXIDE-SYNTHASE ; OXIDIZED LOW-DENSITY
    Abstract: Cyclooxygenase (COX)-2 is expressed in macrophages of arteriosclerotic lesions and promotes inflammation. We investigated whether COX-2 is already expressed in peripheral blood mononuclear cells (PBMCs) of subjects possessing risk-related factors, such as in smokers and hyperlipidemics. PBMCs were isolated from the venous blood of normolipidemic nonsmokers (NL-NSM; n = 15), normolipidemic smokers (NL-SM; n = 12), hyperlipidemic nonsmokers (HL-NSM; n = 10), and hyperlipidemic smokers (HL-SM; n = 10). RNA from PBMCs was used for RT-PCR. Plasma concentrations of oxidized low-density lipoproteins (oxLDL) were rneasured by ELISA, those of glutamate and cystine by HPLC. The results show that COX-2 expression in PBMCs was significantly increased in the groups with cardiovascular risk factors (NL-SM, HL-SM, HL-NSM) compared with NL-NSM. COX-2 expression in PBMCs was positively Correlated with concentrations of total serum cholesterol, oxLDL, glutamate, or cystine. We suggest that the elevated COX-2 expression indicates a priming of PBMCs as a response to a systemic pro-oxidative and proinflammatory shift in subjects with cardiovascular risk factors, which might also contribute to growth and instability of arteriosclerotic lesions. (C) 2004 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15607906
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  • 10
    Keywords: CANCER ; CELLS ; BLOOD ; CELL ; Germany ; human ; IN-VIVO ; VIVO ; DISEASE ; DISEASES ; DNA adducts ; NEW-YORK ; RISK ; METABOLISM ; TISSUE ; ACCURACY ; validation ; ACCUMULATION ; DNA ; MECHANISM ; RISK-FACTORS ; CARCINOGENESIS ; BASE ; BIOMARKERS ; TISSUES ; mechanisms ; BIOLOGY ; MOLECULAR-BIOLOGY ; FORM ; immunohistochemistry ; HUMANS ; ASSAY ; STRESS ; risk factors ; GAS ; mass spectrometry ; TANDEM MASS-SPECTROMETRY ; cancer risk ; DAMAGE ; MASS-SPECTROMETRY ; PRODUCT ; DNA-DAMAGE ; ADDUCTS ; DIETARY ; RISK ASSESSMENT ; OXIDATIVE STRESS ; WHITE BLOOD-CELLS ; MASSES ; PERFORMANCE LIQUID-CHROMATOGRAPHY ; DNA-ADDUCTS ; molecular biology ; molecular ; lipid peroxidation ; PERSISTENT ; review ; RE ; PRODUCTS ; LEADS ; LEVEL ; biomarker ; methods ; DNA ADDUCT ; USA ; CINNAMON LEC RATS ; RISK-FACTOR ; in vivo ; CANCER-RISK ; carcinogenic ; SWITCHING LC/APCI-MS/MS ; HOMEOSTASIS ; 1,N-2-PROPANODEOXYGUANOSINE ADDUCTS ; URINARY-EXCRETION ; lipid ; DIETARY FATTY-ACID ; exocyclic etheno-,Propano-,Malondialdehyde adducts ; P-32 POSTLABELING METHOD
    Abstract: Persistent oxidative stress and excess lipid peroxidation (LPO), induced by inflammatory processes, impaired metal storage, and/or dietary imbalance, cause accumulations and massive DNA damage. This massive DNA damage, along with deregulation of cell homeostasis, leads to malignant diseases. Reactive aldehydes produced by LPO, such as 4-hydroxy-2-nonenal, malondialdehyde, acrolein, and crotonaldehyde, react directly with DNA bases or generate bifunctional intermediates which form exocyclic DNA adducts. Modification of DNA bases by these electrophiles, yielding proinutagenic exocyclic adducts, is thought to contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. Ultrasensitive detection methods have facilitated studies of the concentrations of promutagenic DNA adducts in human tissues, white blood cells, and urine, where they are excreted as modified nucleosides and bases. Thus, immunoaffinity-P-32-postlabeling, high-performance liquid chromatography-electrochemical detection, gas chromatography-mass spectrometry, liquid chromatography-tandem mass spectrometry, immunoslotblot assay, and immunohistochemistry have made it possible to detect background concentrations of adducts arising from endogenous LPO products in vivo and studies of their role in carcinogenesis. These background adduct levels in asymptomatic human tissues occur in the order of 1 adduct /10(8) and in organs affected by cancer-prone inflammatory diseases these can be 1 or 2 orders of magnitude higher. In this review, we critically discuss the accuracy of the available methods and their validation and summarize studies in which measurement of exocyclic adducts suggested new mechanisms of cancer causation, providing potential biomarkers for cancer risk assessment in humans with cancer-prone diseases. (c) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17854706
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