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      Pharmacological activation of NQO1 increases NAD + levels and attenuates cisplatin-mediated acute kidney injury in mice

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          Abstract

          Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD + is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD + levels by means of NAD(P)H:quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (β-lapachone) in wild-type and NQO1 −/− mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD +/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and β-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by β-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of β-lapachone in wild-type mice were completely abrogated in NQO1 −/− mice. Moreover, β-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD + levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury.

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          Most cited references55

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          Sirtuins in mammals: insights into their biological function.

          Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.
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            Negative control of p53 by Sir2alpha promotes cell survival under stress.

            The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha. These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.
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              Structure, Recognition, and Processing of Cisplatin-DNA Adducts.

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                Author and article information

                Journal
                Kidney Int
                Kidney Int
                Kidney International
                Nature Publishing Group
                0085-2538
                1523-1755
                March 2014
                11 September 2013
                : 85
                : 3
                : 547-560
                Affiliations
                [1 ]Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine , Iksan, Republic of Korea
                [2 ]Life Science Research Center, KT&G Life Sciences , Suwon, Republic of Korea
                [3 ]Department of Pathology, Kunsan Medical Center of Wonkwang University Hospital , Kunsan, Republic of Korea
                [4 ]Department of Internal Medicine, Wonkwang University School of Medicine , Iksan, Republic of Korea
                [5 ]Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology , Daejeon, Republic of Korea
                Author notes
                [* ]Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine , 344-2 Shinyong-dong, Iksan, Jeonbuk 570-749, Republic of Korea. E-mail: jeanso@ 123456wku.ac.kr
                [6]

                These authors contributed equally to this work as first authors.

                Article
                ki2013330
                10.1038/ki.2013.330
                3944666
                24025646
                093f8223-f560-4d41-8d6d-4dace6b55df8
                Copyright © 2013 International Society of Nephrology

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 04 January 2013
                : 10 June 2013
                : 13 June 2013
                Categories
                Basic Research

                Nephrology
                cisplatin,nad+,nephrotoxicity,nqo1,sirtuins
                Nephrology
                cisplatin, nad+, nephrotoxicity, nqo1, sirtuins

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