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      Therapeutic potential of N-acetylcysteine in acrylamide acute neurotoxicity in adult zebrafish

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          Abstract

          Two essential key events in acrylamide (ACR) acute neurotoxicity are the formation of adducts with nucleophilic sulfhydryl groups on cysteine residues of selected proteins in the synaptic terminals and the depletion of the glutathione (GSx) stores in neural tissue. The use of N-acetylcysteine (NAC) has been recently proposed as a potential antidote against ACR neurotoxicity, as this chemical is not only a well-known precursor of the reduced form of glutathione (GSH), but also is an scavenger of soft electrophiles such as ACR. In this study, the suitability of 0.3 and 0.75 mM NAC to protect against the neurotoxic effect of 0.75 mM ACR has been tested in vivo in adult zebrafish. NAC provided only a mild to negligible protection against the changes induced by ACR in the motor function, behavior, transcriptome and proteome. The permeability of NAC to cross blood-brain barrier (BBB) was assessed, as well as the ACR-scavenging activity and the gamma-glutamyl-cysteine ligase (γ-GCL) and acylase I activities. The results show that ACR not only depletes GSx levels but also inhibits it synthesis from NAC/cysteine, having a dramatic effect over the glutathione system. Moreover, results indicate a very low NAC uptake to the brain, probably by a combination of low BBB permeability and high deacylation of NAC during the intestinal absorption. These results strongly suggest that the use of NAC is not indicated in ACR acute neurotoxicity treatment.

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          Independent filtering increases detection power for high-throughput experiments.

          With high-dimensional data, variable-by-variable statistical testing is often used to select variables whose behavior differs across conditions. Such an approach requires adjustment for multiple testing, which can result in low statistical power. A two-stage approach that first filters variables by a criterion independent of the test statistic, and then only tests variables which pass the filter, can provide higher power. We show that use of some filter/test statistics pairs presented in the literature may, however, lead to loss of type I error control. We describe other pairs which avoid this problem. In an application to microarray data, we found that gene-by-gene filtering by overall variance followed by a t-test increased the number of discoveries by 50%. We also show that this particular statistic pair induces a lower bound on fold-change among the set of discoveries. Independent filtering-using filter/test pairs that are independent under the null hypothesis but correlated under the alternative-is a general approach that can substantially increase the efficiency of experiments.
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            The chemistry and biological activities of N-acetylcysteine.

            N-acetylcysteine (NAC) has been in clinical practice for several decades. It has been used as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication, doxorubicin cardiotoxicity, ischemia-reperfusion cardiac injury, acute respiratory distress syndrome, bronchitis, chemotherapy-induced toxicity, HIV/AIDS, heavy metal toxicity and psychiatric disorders. The mechanisms underlying the therapeutic and clinical applications of NAC are complex and still unclear. The present review is focused on the chemistry of NAC and its interactions and functions at the organ, tissue and cellular levels in an attempt to bridge the gap between its recognized biological activities and chemistry. The antioxidative activity of NAC as of other thiols can be attributed to its fast reactions with OH, NO2, CO3(-) and thiyl radicals as well as to restitution of impaired targets in vital cellular components. NAC reacts relatively slowly with superoxide, hydrogen-peroxide and peroxynitrite, which cast some doubt on the importance of these reactions under physiological conditions. The uniqueness of NAC is most probably due to efficient reduction of disulfide bonds in proteins thus altering their structures and disrupting their ligand bonding, competition with larger reducing molecules in sterically less accessible spaces, and serving as a precursor of cysteine for GSH synthesis. The outlined reactions only partially explain the diverse biological effects of NAC, and further studies are required for determining its ability to cross the cell membrane and the blood-brain barrier as well as elucidating its reactions with components of cell signaling pathways. Copyright © 2013 Elsevier B.V. All rights reserved.
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              Microtiter plate assay for the measurement of glutathione and glutathione disulfide in large numbers of biological samples.

              By combining the least complicated and expedient methods of sample handling with the sensitivity and specificity of the GSH assay by enzymatic recycling and the small volumes and software capabilities of microtiter plate technology we have devised a rapid, sensitive, and easy assay for GSH and GSSG in biological samples. The assay is sensitive to 5 pmol in sample volumes of 50 microliters, although other volumes could be used. The use of a computer-driven microplate with software capable of linear kinetic data storage and analysis on each well, Maxline series microplate readers and Softmax software, enables the user not only to assay large numbers of samples per day but also to have immediate calculated results. We suggest by examples that measurements of total GSH as well as changes in GSH:GSSG in vitro and in vivo are feasible with this technology.
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                Author and article information

                Contributors
                drpqam@cid.csic.es
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                11 November 2019
                11 November 2019
                2019
                : 9
                : 16467
                Affiliations
                [1 ]ISNI 0000 0004 1762 9198, GRID grid.420247.7, Institute for Environmental Assessment and Water Research (IDAEA-CSIC), ; Jordi Girona, 18, 08034 Barcelona, Spain
                [2 ]GRID grid.420192.c, Research and Development Center (CID-CSIC), ; Jordi Girona, 18, 08034 Barcelona, Spain
                [3 ]ISNI 0000 0001 1703 7780, GRID grid.424733.5, Department of Analytical Chemistry and Applied (Chromatography section), School of Engineering, , Institut Químic de Sarrià-Universitat Ramon Llull, ; Via Agusta 390, 08017 Barcelona, Spain
                [4 ]ISNI 0000 0001 0816 8287, GRID grid.260120.7, Institute for Genomics, Biocomputing & Biotechnology (IGBB), , Mississippi State University, ; Starkville, MS USA
                [5 ]ISNI 0000 0001 2174 6731, GRID grid.412872.a, Laboratorio de Toxicología Ambiental, Facultad de Química, , Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan s/n. Col. Residencial Colón, ; 50120 Toluca, Estado de México Mexico
                [6 ]ISNI 0000 0001 0637 9574, GRID grid.417553.1, Environmental Laboratory, , US Army Engineer Research and Development Center, ; Vicksburg, MS USA
                [7 ]ISNI 0000000121102151, GRID grid.6451.6, The Smoler Proteomics Center and the Department of Biology, , Technion-Israel Institute of Technology Haifa, ; 32000 Haifa, Israel
                Author information
                http://orcid.org/0000-0003-1451-4427
                http://orcid.org/0000-0001-7838-2027
                http://orcid.org/0000-0003-0504-3950
                http://orcid.org/0000-0002-7248-3449
                http://orcid.org/0000-0001-5256-1641
                Article
                53154
                10.1038/s41598-019-53154-w
                6848153
                31712630
                38954453-8097-4052-a974-d8c784aa42a5
                © The Author(s) 2019

                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
                : 12 July 2019
                : 28 October 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003030, Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants);
                Award ID: 2016 BP 00233
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100004415, North Atlantic Treaty Organization (NATO);
                Award ID: MD.SFPP 984777
                Award ID: MD.SFPP 984777
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100003339, Ministry of Economy and Competitiveness | Consejo Superior de Investigaciones Científicas (Spanish National Research Council);
                Award ID: CTM2017-83242-R
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                neurotoxicity syndromes,pharmacodynamics
                Uncategorized
                neurotoxicity syndromes, pharmacodynamics

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