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  • Zweier, Jay L.  (7)
  • 1995-1999  (7)
  • Linguistics  (7)
  • Natural Sciences  (7)
  • 1
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 286, No. 5438 ( 1999-10-08), p. 304-306
    Abstract: Many human diseases are associated with the overproduction of oxygen free radicals that inflict cell damage. A manganese(II) complex with a bis(cyclohexylpyridine)-substituted macrocyclic ligand (M40403) was designed to be a functional mimic of the superoxide dismutase (SOD) enzymes that normally remove these radicals. M40403 had high catalytic SOD activity and was chemically and biologically stable in vivo. Injection of M40403 into rat models of inflammation and ischemia-reperfusion injury protected the animals against tissue damage. Such mimics may result in better clinical therapies for diseases mediated by superoxide radicals.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    RVK:
    RVK:
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 1999
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 2
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 1997
    In:  Proceedings of the National Academy of Sciences Vol. 94, No. 13 ( 1997-06-24), p. 6954-6958
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 13 ( 1997-06-24), p. 6954-6958
    Abstract: Superoxide (O 2⨪ ) and nitric oxide (NO) act to kill invading microbes in phagocytes. In macrophages NO is synthesized by inducible nitric oxide synthase (iNOS, NOS 2) from l -arginine ( l -Arg) and oxygen; however, O 2⨪ was thought to be produced mainly by NADPH oxidase. Electron paramagnetic resonance (EPR) spin trapping experiments performed in murine macrophages demonstrate a novel pathway of O 2⨪ generation. It was observed that depletion of cytosolic l -Arg triggers O 2⨪ generation from iNOS. This iNOS-mediated O 2⨪ generation was blocked by the NOS inhibitor N -nitro- l -arginine methyl ester or by l -Arg, but not by the noninhibitory enantiomer N -nitro- d -arginine methyl ester. In l -Arg-depleted macrophages iNOS generates both O 2⨪ and NO that interact to form the potent oxidant peroxynitrite (ONOO − ), which was detected by luminol luminescence and whose formation was blocked by superoxide dismutase, urate, or l -Arg. This iNOS-derived ONOO − resulted in nitrotyrosine formation, and this was inhibited by iNOS blockade. iNOS-mediated O 2⨪ and ONOO − increased the antibacterial activity of macrophages. Thus, with reduced l -Arg availability iNOS produces O 2⨪ and ONOO − that modulate macrophage function. Due to the existence of l -Arg depletion in inflammation, iNOS-mediated O 2⨪ and ONOO − may occur and contribute to cytostatic/cytotoxic actions of macrophages.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1997
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 1999
    In:  Proceedings of the National Academy of Sciences Vol. 96, No. 8 ( 1999-04-13), p. 4586-4591
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 96, No. 8 ( 1999-04-13), p. 4586-4591
    Abstract: EPR imaging has emerged as an important tool for noninvasive three-dimensional (3D) spatial mapping of free radicals in biological tissues. Spectral–spatial EPR imaging enables mapping of the spectral information at each spatial position, and, from the observed line width, the localized tissue oxygenation can be mapped. We report the development of EPR imaging instrumentation enabling 3D spatial and spectral–spatial EPR imaging of small animals. This instrumentation, along with the use of a biocompatible charcoal oximetry-probe suspension, enabled 3D spatial imaging of the gastrointestinal (GI) tract, along with mapping of oxygenation in living mice. By using these techniques, the oxygen tension was mapped at different levels of the GI tract from the stomach to the rectum. The results clearly show the presence of a marked oxygen gradient from the proximal to the distal GI tract, which decreases after respiratory arrest. This technique for in vivo mapping of oxygenation is a promising method, enabling the noninvasive imaging of oxygen within the normal GI tract. This method should be useful in determining the alterations in oxygenation associated with disease.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1999
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 1997
    In:  Science Vol. 275, No. 5306 ( 1997-03-14), p. 1649-1652
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 275, No. 5306 ( 1997-03-14), p. 1649-1652
    Abstract: NIH 3T3 fibroblasts stably transformed with a constitutively active isoform of p21 Ras , H-Ras V12 (v-H-Ras or EJ-Ras), produced large amounts of the reactive oxygen species superoxide (·O 2 − ). ·O 2 − production was suppressed by the expression of dominant negative isoforms of Ras or Rac1, as well as by treatment with a farnesyltransferase inhibitor or with diphenylene iodonium, a flavoprotein inhibitor. The mitogenic activity of cells expressing H-Ras V12 was inhibited by treatment with the chemical antioxidant N -acetyl-L-cysteine. Mitogen-activated protein kinase (MAPK) activity was decreased and c-Jun N-terminal kinase (JNK) was not activated in H-Ras V12 -transformed cells. Thus, H-Ras V12 -induced transformation can lead to the production of ·O 2 − through one or more pathways involving a flavoprotein and Rac1. The implication of a reactive oxygen species, probably ·O 2 − , as a mediator of Ras-induced cell cycle progression independent of MAPK and JNK suggests a possible mechanism for the effects of antioxidants against Ras-induced cellular transformation.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    RVK:
    RVK:
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 1997
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 5
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 1998
    In:  Proceedings of the National Academy of Sciences Vol. 95, No. 19 ( 1998-09-15), p. 11140-11145
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 19 ( 1998-09-15), p. 11140-11145
    Abstract: The polyamines are small organic cations that are absolutely required for eukaryotic cell growth. Although their growth requirements are well established, the molecular functions of the polyamines are ill-defined. Oxidative damage to DNA by reactive oxygen species is a continual problem that cells must guard against to survive. The polyamine spermine, which is normally found in millimolar concentrations in the nucleus, is shown here to function directly as a free radical scavenger, and adducts formed as a result of this function are identified. These data suggest that spermine is a major natural intracellular compound capable of protecting DNA from free radical attack.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1998
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Library Location Call Number Volume/Issue/Year Availability
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  • 6
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 1997
    In:  Proceedings of the National Academy of Sciences Vol. 94, No. 23 ( 1997-11-11), p. 12705-12710
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 23 ( 1997-11-11), p. 12705-12710
    Abstract: Although nitric oxide synthase (NOS) is widely considered as the major source of NO in biological cells and tissues, direct evidence demonstrating NO formation from the purified enzyme has been lacking. It was recently reported that NOS does not synthesize NO, but rather generates nitroxyl anion (NO − ) that is subsequently converted to NO by superoxide dismutase (SOD). To determine if NOS synthesizes NO, electron paramagnetic resonance (EPR) spectroscopy was applied to directly measure NO formation from purified neuronal NOS. In the presence of the NO trap Fe 2+ - N -methyl- d -glucamine dithiocarbamate, NO gives rise to characteristic EPR signals with g = 2.04 and a N = 12.7 G, whereas NO − is undetectable. In the presence of l -arginine ( l -Arg) and cofactors, NOS generated prominent NO signals. This NO generation did not require SOD, and it was blocked by the specific NOS inhibitor N -nitro- l -arginine methyl ester. Isotope-labeling experiments with l -[ 15 N]Arg further demonstrated that NOS-catalyzed NO arose from the guanidino nitrogen of l -Arg. Measurement of the time course of NO formation demonstrated that it paralleled that of l -citrulline. The conditions used in the prior study were shown to result in potent superoxide generation, and this may explain the failure to measure NO formation in the absence of SOD. These experiments provide unequivocal evidence that NOS does directly synthesize NO from l -Arg.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1997
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Library Location Call Number Volume/Issue/Year Availability
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  • 7
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 1998
    In:  Proceedings of the National Academy of Sciences Vol. 95, No. 8 ( 1998-04-14), p. 4556-4560
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 8 ( 1998-04-14), p. 4556-4560
    Abstract: Superoxide and superoxide-derived oxidants have been hypothesized to be important mediators of postischemic injury. Whereas copper,zinc-superoxide dismutase, SOD1, efficiently dismutates superoxide, there has been controversy regarding whether increasing intracellular SOD1 expression would protect against or potentiate cellular injury. To determine whether increased SOD1 protects the heart from ischemia and reperfusion, studies were performed in a newly developed transgenic mouse model in which direct measurement of superoxide, contractile function, bioenergetics, and cell death could be performed. Transgenic mice with overexpression of human SOD1 were studied along with matched nontransgenic controls. Immunoblotting and immunohistology demonstrated that total SOD1 expression was increased 10-fold in hearts from transgenic mice compared with nontransgenic controls, with increased expression in both myocytes and endothelial cells. In nontransgenic hearts following 30 min of global ischemia a reperfusion-associated burst of superoxide generation was demonstrated by electron paramagnetic resonance spin trapping. However, in the transgenic hearts with overexpression of SOD1 the burst of superoxide generation was almost totally quenched, and this was accompanied by a 2-fold increase in the recovery of contractile function, a 2.2-fold decrease in infarct size, and a greatly improved recovery of high energy phosphates compared with that in nontransgenic controls. These results demonstrate that superoxide is an important mediator of postischemic injury and that increasing intracellular SOD1 dramatically protects the heart from this injury. Thus, increasing intracellular SOD1 expression may be a highly effective approach to decrease the cellular injury that occurs following reperfusion of ischemic tissues.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1998
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Library Location Call Number Volume/Issue/Year Availability
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