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      Cisplatin-induced Kidney Dysfunction and Perspectives on Improving Treatment Strategies

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          Abstract

          Cisplatin is one of the most widely used and highly effective drug for the treatment of various solid tumors; however, it has dose-dependent side effects on the kidney, cochlear, and nerves. Nephrotoxicity is the most well-known and clinically important toxicity. Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced nephrotoxicity. Even though the establishment of cisplatin-induced nephrotoxicity can be alleviated by diuretics and pre-hydration of patients, the prevalence of cisplatin nephrotoxicity is still high, occurring in approximately one-third of patients who have undergone cisplatin therapy. Therefore it is imperative to develop treatments that will ameliorate cisplatin-nephrotoxicity. In this review, we discuss the mechanisms of cisplatin-induced renal toxicity and the new strategies for protecting the kidneys from the toxic effects without lowering the tumoricidal activity.

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          Most cited references71

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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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            Mechanisms of Cisplatin Nephrotoxicity

            Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention.
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              Mammalian SIRT1 represses forkhead transcription factors.

              The NAD-dependent deacetylase SIR2 and the forkhead transcription factor DAF-16 regulate lifespan in model organisms, such as yeast and C. elegans. Here we show that the mammalian SIR2 ortholog SIRT1 deacetylates and represses the activity of the forkhead transcription factor Foxo3a and other mammalian forkhead factors. This regulation appears to be in the opposite direction from the genetic interaction of SIR2 with forkhead in C. elegans. By restraining mammalian forkhead proteins, SIRT1 also reduces forkhead-dependent apoptosis. The inhibition of forkhead activity by SIRT1 parallels the effect of this deacetylase on the tumor suppressor p53. We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.
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                Author and article information

                Journal
                Electrolyte Blood Press
                Electrolyte Blood Press
                EBP
                Electrolytes & Blood Pressure : E & BP
                The Korean Society of Electrolyte Metabolism
                1738-5997
                2092-9935
                December 2014
                31 December 2014
                : 12
                : 2
                : 55-65
                Affiliations
                Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, Korea.
                Author notes
                Corresponding Author: Hong-Seob So, Ph.D. Department of Microbiology, Wonkwang University School of Medicine, 344-2 Shinyong-dong, Iksan, Jeonbuk 570-749, Korea. Tel: +82-63-850-6950, Fax: +82-63-855-6777, jeanso@ 123456wku.ac.kr
                Article
                10.5049/EBP.2014.12.2.55
                4297704
                25606044
                6e21e47f-168e-41a5-bc34-057eee40253b
                Copyright © 2014 The Korean Society of Electrolyte Metabolism

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 November 2014
                : 05 December 2014
                Funding
                Funded by: National Research Foundation of Korea
                Award ID: 2011-0028866
                Award ID: 2011-0030715
                Categories
                Review

                Cardiovascular Medicine
                cisplatin,chemotherapy,nephrotoxicity,nad+
                Cardiovascular Medicine
                cisplatin, chemotherapy, nephrotoxicity, nad+

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