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      Molecular Insights into the Interaction of RONS and Thieno[3,2-c]pyran Analogs with SIRT6/COX-2: A Molecular Dynamics Study

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          Abstract

          SIRT6 and COX-2 are oncogenes target that promote the expression of proinflammatory and pro-survival proteins through a signaling pathway, which leads to increased survival and proliferation of tumor cells. However, COX-2 also suppresses skin tumorigenesis and their relationship with SIRT6, making it an interesting target for the discovery of drugs with anti-inflammatory and anti-cancer properties. Herein, we studied the interaction of thieno[3,2-c]pyran analogs and RONS species with SIRT6 and COX-2 through the use of molecular docking and molecular dynamic simulations. Molecular docking studies revealed the importance of hydrophobic and hydrophilic amino acid residues for the stability. The molecular dynamics study examined conformational changes in the enzymes caused by the binding of the substrates and how those changes affected the stability of the protein-drug complex. The average RMSD values of the backbone atoms in compounds 6 and 10 were calculated from 1000 ps to 10000 ps and were found to be 0.13 nm for both compounds. Similarly, the radius of gyration values for compounds 6 and 10 were found to be 1.87 ± 0.03 nm and 1.86 ± 0.02 nm, respectively. The work presented here, will be of great help in lead identification and optimization for early drug discovery.

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          Oxidative stress in the pathogenesis of skin disease.

          Skin is the largest body organ that serves as an important environmental interface providing a protective envelope that is crucial for homeostasis. On the other hand, the skin is a major target for toxic insult by a broad spectrum of physical (i.e. UV radiation) and chemical (xenobiotic) agents that are capable of altering its structure and function. Many environmental pollutants are either themselves oxidants or catalyze the production of reactive oxygen species (ROS) directly or indirectly. ROS are believed to activate proliferative and cell survival signaling that can alter apoptotic pathways that may be involved in the pathogenesis of a number of skin disorders including photosensitivity diseases and some types of cutaneous malignancy. ROS act largely by driving several important molecular pathways that play important roles in diverse pathologic processes including ischemia-reperfusion injury, atherosclerosis, and inflammatory responses. The skin possesses an array of defense mechanisms that interact with toxicants to obviate their deleterious effect. These include non-enzymatic and enzymatic molecules that function as potent antioxidants or oxidant-degrading systems. Unfortunately, these homeostatic defenses, although highly effective, have limited capacity and can be overwhelmed thereby leading to increased ROS in the skin that can foster the development of dermatological diseases. One approach to preventing or treating these ROS-mediated disorders is based on the administration of various antioxidants in an effort to restore homeostasis. Although many antioxidants have shown substantive efficacy in cell culture systems and in animal models of oxidant injury, unequivocal confirmation of their beneficial effects in human populations has proven elusive.
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            Incidence estimate of nonmelanoma skin cancer in the United States, 2006.

            To estimate the incidence of nonmelanoma skin cancer (NMSC) in the US population in 2006 and secondarily to indicate trends in numbers of procedures for skin cancer treatment. A descriptive analysis of population-based claims and US Census Bureau data combined with a population-based cross-sectional survey using multiple US government data sets, including the Centers for Medicare and Medicaid Services Fee-for-Service Physicians Claims databases, to calculate totals of skin cancer procedures performed for Medicare beneficiaries in 1992 and from 1996 to 2006 and related parameters. The National Ambulatory Medical Care Service database was used to estimate NMSC-related office visits. We combined these to estimate totals of new skin cancer diagnoses and affected individuals in the overall US population. The total number of procedures for skin cancer in the Medicare fee-for-service population increased by 76.9% from 1 158 298 in 1992 to 2 048 517 in 2006. The age-adjusted procedure rate per year per 100 000 beneficiaries increased from 3514 in 1992 to 6075 in 2006. From 2002 to 2006 (the years for which the databases allow procedure linkage to patient demographics and diagnoses), the number of procedures for NMSC in the Medicare population increased by 16.0%. In this period, the number of procedures per affected patient increased by 1.5%, and the number of persons with at least 1 procedure increased by 14.3%. We estimate the total number of NMSCs in the US population in 2006 at 3 507 693 and the total number of persons in the United States treated for NMSC at 2 152 500. The number of skin cancers in Medicare beneficiaries increased dramatically over the years 1992 to 2006, due mainly to an increase in the number of affected individuals. Using nationally representative databases, we provide evidence of much higher overall totals of skin cancer diagnoses and patients in the US population than previous estimates. These data give the most complete evaluation to date of the underrecognized epidemic of skin cancer in the United States.
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              Effect of lipid peroxidation on membrane permeability of cancer and normal cells subjected to oxidative stress† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c5sc02311d Click here for additional data file.

              Molecular dynamics simulations suggest that the cholesterol-induced stability of lipid membranes during lipid peroxidation offers an explanation for the observed selectivity of plasma treatments towards cancer cells.
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                Author and article information

                Contributors
                dharmendra30oct@gmail.com
                kmh0515@gachon.ac.kr
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                19 March 2018
                19 March 2018
                2018
                : 8
                : 4777
                Affiliations
                [1 ]ISNI 0000 0004 0647 2973, GRID grid.256155.0, College of Pharmacy, , Gachon University of Medicine and Science, ; 191, Hambangmoe-ro, Yeonsu-gu, Incheon, 21936 Republic of Korea
                [2 ]ISNI 0000 0004 4681 1140, GRID grid.463267.2, Department of Biochemistry, , All India Institute of Medical Science, ; Jodhpur, Rajasthan 342005 India
                [3 ]ISNI 0000 0004 1764 2536, GRID grid.444471.6, Department of Chemistry, , Malaviya National Institute of Technology, ; Jawaharlal Nehru Marg, Jaipur, 302017 India
                [4 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Faculty of Biochemistry and Molecular Medicine Aapistie, , University of Oulu, 7A, ; Oulu, 90220 Finland
                [5 ]ISNI 0000 0004 0533 0009, GRID grid.411202.4, Plasma Bioscience Research Center/Department of Electrical and Biological Physics, , Kwangwoon University, ; 20 Kwangwon-Ro, Nowon-Gu, Seoul, 139-701 Republic of Korea
                [6 ]ISNI 0000 0001 2181 989X, GRID grid.264381.a, School of Pharmacy, , Sungkyunkwan University, ; Suwon, 16419 Republic of Korea
                [7 ]ISNI 0000 0001 0790 3681, GRID grid.5284.b, Present Address: Department of Chemistry, , Research group PLASMANT, University of Antwerp, ; BE-2610 Wilrijk-Antwerp, Belgium
                Author information
                http://orcid.org/0000-0003-1102-1993
                http://orcid.org/0000-0002-2718-5637
                Article
                22972
                10.1038/s41598-018-22972-9
                5859274
                29556059
                ddfbb899-861d-4af8-a69c-56f29396eac0
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 December 2017
                : 5 March 2018
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