A Nonpeptidyl Mimic of Superoxide Dismutase with Therapeutic Activity in Rats

Salvemini, Daniela; Wang, Zhi Qiang; Zweíer, Jay L.; Samouilov, Alexandre; Macarthur, Heather; Misko, Thomas P.; Currie, Mark G.; Cuzzocrea, Salvatore; Sikorski, James A.; Riley, Dennis P.

doi:10.1126/science.286.5438.304

Cited by 476 publications

(332 citation statements)

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“…The supply and/or overexpression of exogenous SOD in rat models of intestinal ischemia significantly reduce injury (11,39,53). This finding suggests that maintenance of endogenous SOD may provide protection in GI/R.…”

Section: Discussionmentioning

confidence: 62%

“…The exogenous administration of SOD in a rat model of gastric ischemia-reperfusion increases luminal NO levels, suggesting that SOD-mediated protection is afforded by decreasing the local concentra-tion of superoxide that is available to react with NO (53). Because endogenous SOD levels are not adequate to quench the sudden surge in superoxide levels after reperfusion, attention has been directed toward the delivery of exogenous SOD (21,39). To date, factors mediating the regulation of endogenous SOD after ischemia-reperfusion have not been identified.…”

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confidence: 99%

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Role for complement in mediating intestinal nitric oxide synthase-2 and superoxide dismutase expression

Montalto

Hart

Jordan

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Role for complement in mediating intestinal nitric oxide synthase-2 and superoxide dismutase expression. Am J Physiol Gastrointest Liver Physiol 285: G197-G206, 2003. First published March 13, 2003 10.1152/ajpgi.00029.2003.-Inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD) play an important role in the pathology of ischemia-reperfusion. This study sought to determine if the proinflammatory effects of complement modulate iNOS and SOD in the rat after gastrointestinal ischemia and reperfusion (GI/R). An inhibitory or noninhibitory anti-complement component 5 (C5) monoclonal antibody (18A or 16C, respectively) was administered before GI/R. RT-PCR revealed a significant increase in intestinal iNOS mRNA compared with sham after GI/R that was attenuated significantly by 18A. Immunohistochemistry demonstrated increased iNOS protein expression within the intestinal crypts after GI/R. Cu/Zn SOD (mRNA and protein) was unaffected by GI/R, whereas Cu/Zn SOD activity was reduced significantly. Mn SOD protein expression was decreased significantly by GI/R. Anti-C5 preserved Cu/Zn SOD activity and Mn SOD protein expression. Staining for nitrotyrosine showed that anti-C5 treatment reduced protein nitration in the reperfused intestine. Immunohistochemistry demonstrated prominent phosphorylated (p) inhibitory factor-B (I B)-␣ staining of intestinal tissue after GI/R, whereas anti-C5 reduced p-I B-␣ expression. These data indicate that complement may mediate tissue damage during GI/R by increasing intestinal iNOS and decreasing the activity and protein levels of Cu/Zn SOD and Mn SOD, respectively. ischemia-reperfusion; inhibitory factor-B; interleukin-1␤ GASTROINTESTINAL ISCHEMIA-reperfusion (GI/R) is a common clinical problem in the settings of sepsis, hemorrhagic shock, vascular surgery, and small bowel transplantation (17, 21). GI/R causes gut dysfunction characterized by histological evidence of impaired gut motility, increased intestinal permeability, and mucosal injury (18). Numerous mediators have been implicated in GI/R injury, including cytokines (8,15,43,54,55) NF-B is maintained in a latent form in the cytoplasm of cells where it is complexed to inhibitory factor-B (I B) proteins (24). Upon activation of NF-B, I B is phosphorylated (p) by I B kinases at two conserved serine residues in the NH 2 terminus, which targets the protein for ubiquination and degradation by the proteosome. This rapidly frees NF-B to translocate to the nucleus, where it upregulates the transcription of a variety of adhesion molecules (ICAM-1 and VCAM-1), cytokines (TNF, IL-1, and IL-6), and enzymes (iNOS; see Refs. 24 and 37).NO has been implicated as a mediator of tissue damage in several models of intestinal disease, including reperfusion injury (26,47,48). NO can be produced by three nitric oxide synthase (NOS) isoforms (neuronal NOS, iNOS, and endothelial NOS). Specific inhibition of iNOS has been shown to attenuate NO production significantly and decrease intestinal injury, indicating that iNOS mediates the excessive p...

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Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

Role for complement in mediating intestinal nitric oxide synthase-2 and superoxide dismutase expression

Montalto

Hart

Jordan

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Nitration of intracellular proteins was inhibited by removal of superoxide formation via inhibition of vascular cell NADPH oxidases a well-recognized source of cytokine-triggered superoxide in these cells (7)(8)(9). Furthermore, superoxide scavenging similarly ablated intracellular nitration, as noted in studies using the specific superoxide dismutase mimetic M40403 (39). Thus, peroxynitrite, the reaction product of nitric oxide and superoxide, is the likely proximal species responsible for nitrating tyrosine residues in proteins after stimulation in this model.…”

Section: Discussionmentioning

confidence: 79%

Expression of Inducible Nitric-oxide Synthase and Intracellular Protein Tyrosine Nitration in Vascular Smooth Muscle Cells

Fries

Paxinou

Themistocleous

et al. 2003

Journal of Biological Chemistry

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A significant increase in the induction of inducible nitric-oxide synthase (iNOS) protein expression and in the levels of nitrite plus nitrate was observed in rat aortic smooth muscle cells (RASMCs) stably transfected with catalase (RASMC-2C2) as compared with empty vector-transfected RASMC-V4 cells after exposure to cytokines and lipopolysaccharide. The increased expression of iNOS protein in the RASMC-2C2 cells was associated with a significant activation of nuclear transcription factor B, one of the transcriptional regulators of iNOS expression. The induction of iNOS was also accompanied by increased protein tyrosine nitration in both cell types as revealed by immunocytochemical staining and high pressure liquid chromatography with on-line electrospray ionization tandem mass spectrometry. Nitrotyrosine formation was inhibited by 1400W, an iNOS inhibitor, by 4-(2-aminoethyl) benzenesulfonyl fluoride, an inhibitor of NADPH oxidase, and by the superoxide dismutase mimetic M40403, but not by the peroxidase inhibitor 4-aminobenzoic hydrazide. Electron microscopy using affinity-purified anti-nitrotyrosine antibodies revealed labeling at the cytosolic side of the rough endoplasmic reticulum membranes, in the nucleus, occasionally in mitochondria, and consistently within the fibrillar layer underneath the plasma membrane. Collectively, the data in this model system indicate that hydrogen peroxide, by inhibiting the activation of nuclear transcription factor B, prevents iNOS expression, whereas superoxide contributes in a precise pattern of intracellular protein tyrosine nitration.

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“…Its 2S,21S B. Mn(II) cyclic polyamines in suppressing oxidative stress in vivo and in vitro M40403 is thus far the most studied cyclic polyamine in vivo. It suppressed inflammation in a variety of models: carrageenan-induced pleurisy mouse model (75), rat model of septic shock (198), E. coli lipopolysaccharide serotype 0111:B4 (LPS)-induced cytokine production by cultured rat alveolar macrophages (233), inflammatory pain in a carrageenan model of paw edema (230,277,329), guinea-pig model of allergic asthma-like reactions (207), rodent model of colitis (74), myocardial ischemia-reperfusion injury (208,343), chronic hypoxia-induced pulmonary hypertension (86), and so on. M40403 also was reported to provide protection against radiation-induced mucositis in the Syrian golden hamsters.…”

Section: A Sod-like Activitymentioning

confidence: 99%

“…Riley et al (21,204,269,277) developed Mn complexes with cyclic polyamines=tetraaza crown ethers as catalysts for O 2 ·À dismutation (Fig. 9).…”

Section: A Sod-like Activitymentioning

confidence: 99%

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

459

689

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Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO 3 _ À , peroxyl radical, and less efficiently H 2 O 2 . By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and=or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877-918.

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A Nonpeptidyl Mimic of Superoxide Dismutase with Therapeutic Activity in Rats

Cited by 476 publications

References 27 publications

Role for complement in mediating intestinal nitric oxide synthase-2 and superoxide dismutase expression

Role for complement in mediating intestinal nitric oxide synthase-2 and superoxide dismutase expression

Expression of Inducible Nitric-oxide Synthase and Intracellular Protein Tyrosine Nitration in Vascular Smooth Muscle Cells

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

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