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      The Effect of Preoperative Melatonin on Nuclear Erythroid 2-Related Factor 2 Activation in Patients Undergoing Coronary Artery Bypass Grafting Surgery

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          Abstract

          During and after coronary artery bypass grafting (CABG), oxidative stress occurs. Finding an effective way to improve antioxidant response is important in CABG surgery. It has been shown that patients with coronary heart disease have a low Melatonin production rate. The present study aimed to investigate the effects of Melatoninon nuclear erythroid 2-related factor 2(Nrf2) activity in patients undergoing CABG surgery. Thirty volunteers undergoing CABG were randomized to receive 10 mg oral Melatonin (Melatonin group, n = 15) or placebo (placebo group, n = 15) before sleeping for 1 month before surgery. The activated Nrf2 was measured twice by DNA-based ELISA method in the nuclear extract of peripheral blood mononuclear cells of patients before aortic clumps and 45 minutes after CABG operation. Melatonin administration was associated with a significant increase in both plasma levels of Melatonin and Nrf2 concentration in Melatonin group compared to placebo group, respectively (15.2 ± 4.6 pmol/L, 0.28 ± 0.01 versus 1.1 ± 0.59 pmol/L, 0.20 ± 0.07, P < 0.05). The findings of the present study provide preliminary data suggesting that Melatonin may play a significant role in the potentiation of the antioxidant defense and attenuate cellular damages resulting from CABG surgery via theNrf2 pathway.

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          Molecular mechanisms of Nrf2-mediated antioxidant response.

          Nrf2 is the key transcription factor regulating the antioxidant response. Nrf2 signaling is repressed by Keap1 at basal condition and induced by oxidative stress. Keap1 is recently identified as a Cullin 3-dependent substrate adaptor protein. A two-sites binding "hinge & latch" model vividly depicts how Keap1 can efficiently present Nrf2 as substrate for ubiquitination. Oxidative perturbation can impede Keap1-mediated Nrf2 ubiquitination but fail to disrupt Nrf2/Keap1 binding. Nrf2 per se is a redox-sensitive transcription factor. A new Nrf2-mediated redox signaling model is proposed based on these new discoveries. Free floating Nrf2 protein functions as a redox-sensitive probe. Keap1 instead functions as a gate keeper to control the availability of Nrf2 probes and thus regulates the overall sensitivity of the redox signaling. Copyright 2008 Wiley-Liss, Inc.
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            Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance.

            Melatonin has been shown to protect against oxidative stress in various, highly divergent experimental systems. There are many reasons for its remarkable protective potential. Signaling effects comprise the upregulation of antioxidant enzymes, such as superoxide dismutases, peroxidases, and enzymes of glutathione supply, down-regulation of prooxidant enzymes, such as nitric oxide synthases and lipoxygenases, and presumably also the control of quinone reductase 2. Other mechanisms are based on direct interactions with several reactive oxygen and nitrogen species. Among these reactions, the capacity of easily undergoing single-electron transfer reactions is of particular importance. Electron donation by melatonin is not only an aspect of direct radical scavenging, but additionally represents the basis for formation of the protective metabolites AFMK (N1-ace-tyl-N2-formyl-5-methoxykynuramine) and AMK (N1-acetyl-5-methoxykynuramine). Recent investigations on mitochondrial metabolism indicate that melatonin as well as AMK are capable of supporting the electron flux through the respiratory chain, of preventing the breakdown of the mitochondrial membrane potential, and of decreasing electron leakage, thereby reducing the formation of superoxide anions. Radical avoidance is a new line of investigation, which exceeds mitochondrial actions and also comprises antiexcitatory effects and contributions to the maintenance of internal circadian phase relationships.
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              Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence.

              Melatonin (N-acetyl-5-methoxytryptamine), an endogenously produced indole found throughout the animal kingdom, was recently reported, using a variety of techniques, to be a scavenger of a number of reactive oxygen and reactive nitrogen species both in vitro and in vivo. Initially, melatonin was discovered to directly scavenge the high toxic hydroxyl radical (*OH). The methods used to prove the interaction of melatonin with the *OH included the generation of the radical using Fenton reagents or the ultraviolet photolysis of hydrogen peroxide (H202) with the use of spin-trapping agents, followed by electron spin resonance (ESR) spectroscopy, pulse radiolysis followed by ESR, and several spectrofluorometric and chemical (salicylate trapping in vivo) methodologies. One product of the reaction of melatonin with the *OH was identified as cyclic 3-hydroxymelatonin (3-OHM) using high-performance liquid chromatography with electrochemical (HPLC-EC) detection, electron ionization mass spectrometry (EIMS), proton nuclear magnetic resonance (1H NMR) and COSY 1H NMR. Cyclic 3-OHM appears in the urine of humans and other mammals and in rat urine its concentration increases when melatonin is given exogenously or after an imposed oxidative stress (exposure to ionizing radiation). Urinary cyclic 3-OHM levels are believed to be a biomarker (footprint molecule) of in vivo *OH production and its scavenging by melatonin. Although the data are less complete, besides the *OH, melatonin in cell-free systems has been shown to directly scavenge H2O2, singlet oxygen (1O2) and nitric oxide (NO*), with little or no ability to scavenge the superoxide anion radical (O2*-) In vitro, melatonin also directly detoxifies the peroxynitrite anion (ONOO-) and/or peroxynitrous acid (ONOOH), or the activated form of this molecule, ONOOH*; the product of the latter interaction is proposed to be 6-OHM. How these in vitro findings relate to the in vivo antioxidant actions of melatonin remains to be established. The ability of melatonin to scavenge the lipid peroxyl radical (LOO*) is debated. The weight of the evidence is that melatonin is probably not a classic chain-breaking antioxidant, since its ability to scavenge the LOO* seems weak. Its ability to reduce lipid peroxidation may stem from its function as a preventive antioxidant (scavenging initiating radicals), or yet unidentified actions. In sum, in vitro melatonin acts as a direct free radical scavenger with the ability to detoxify both reactive oxygen and reactive nitrogen species; in vivo, it is an effective pharmacological agent in reducing oxidative damage under conditions in which excessive free radical generation is believed to be involved.
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                Author and article information

                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OXIMED
                Oxidative Medicine and Cellular Longevity
                Hindawi Publishing Corporation
                1942-0900
                1942-0994
                2013
                8 April 2013
                : 2013
                Affiliations
                1Department of Physiology, Physiology Research Centre, Isfahan University of Medical Sciences, Hezar Jerib Avenue, Isfahan 73461-8174, Iran
                2Medical Student Research Center, Medical School, Isfahan University of Medical Sciences, Isfahan 73461-8174, Iran
                3Students' Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                4Medical Student Research Center, Medical School, Shahrekord University of Medical Sciences, Shahrekord, Iran
                5Department of Cardiac Surgery, Isfahan Medical School, Isfahan University of Medical Sciences, Isfahan 73461-8174, Iran
                Author notes
                *Mohsen Mirmohammad-Sadeghi: mmsadeghi_iumhs@ 123456yahoo.com

                Academic Editor: Daniela Giustarini

                Article
                10.1155/2013/676829
                3649755
                23691266
                Copyright © 2013 Shaghayegh Haghjooy Javanmard et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Clinical Study

                Molecular medicine

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