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      Development of an iron-selective antioxidant probe with protective effects on neuronal function

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          Abstract

          Iron accumulation, oxidative stress and calcium signaling dysregulation are common pathognomonic signs of several neurodegenerative diseases, including Parkinson´s and Alzheimer’s diseases, Friedreich ataxia and Huntington’s disease. Given their therapeutic potential, the identification of multifunctional compounds that suppress these damaging features is highly desirable. Here, we report the synthesis and characterization of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide, named CT51, which exhibited potent free radical neutralizing activity both in vitro and in cells. CT51 bound Fe 2+ with high selectivity and Fe 3+ with somewhat lower affinity. Cyclic voltammetric analysis revealed irreversible binding of Fe 3+ to CT51, an important finding since stopping Fe 2+/Fe 3+ cycling in cells should prevent hydroxyl radical production resulting from the Fenton-Haber-Weiss cycle. When added to human neuroblastoma cells, CT51 freely permeated the cell membrane and distributed to both mitochondria and cytoplasm. Intracellularly, CT51 bound iron reversibly and protected against lipid peroxidation. Treatment of primary hippocampal neurons with CT51 reduced the sustained calcium release induced by an agonist of ryanodine receptor-calcium channels. These protective properties of CT51 on cellular function highlight its possible therapeutic use in diseases with significant oxidative, iron and calcium dysregulation.

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          Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.

          Redox state is a term used widely in the research field of free radicals and oxidative stress. Unfortunately, it is used as a general term referring to relative changes that are not well defined or quantitated. In this review we provide a definition for the redox environment of biological fluids, cell organelles, cells, or tissue. We illustrate how the reduction potential of various redox couples can be estimated with the Nernst equation and show how pH and the concentrations of the species comprising different redox couples influence the reduction potential. We discuss how the redox state of the glutathione disulfide-glutathione couple (GSSG/2GSH) can serve as an important indicator of redox environment. There are many redox couples in a cell that work together to maintain the redox environment; the GSSG/2GSH couple is the most abundant redox couple in a cell. Changes of the half-cell reduction potential (E(hc)) of the GSSG/2GSH couple appear to correlate with the biological status of the cell: proliferation E(hc) approximately -240 mV; differentiation E(hc) approximately -200 mV; or apoptosis E(hc) approximately -170 mV. These estimates can be used to more fully understand the redox biochemistry that results from oxidative stress. These are the first steps toward a new quantitative biology, which hopefully will provide a rationale and understanding of the cellular mechanisms associated with cell growth and development, signaling, and reductive or oxidative stress.
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            The SH-SY5Y cell line in Parkinson’s disease research: a systematic review

            Parkinson’s disease (PD) is a devastating and highly prevalent neurodegenerative disease for which only symptomatic treatment is available. In order to develop a truly effective disease-modifying therapy, improvement of our current understanding of the molecular and cellular mechanisms underlying PD pathogenesis and progression is crucial. For this purpose, standardization of research protocols and disease models is necessary. As human dopaminergic neurons, the cells mainly affected in PD, are difficult to obtain and maintain as primary cells, current PD research is mostly performed with permanently established neuronal cell models, in particular the neuroblastoma SH-SY5Y lineage. This cell line is frequently chosen because of its human origin, catecholaminergic (though not strictly dopaminergic) neuronal properties, and ease of maintenance. However, there is no consensus on many fundamental aspects that are associated with its use, such as the effects of culture media composition and of variations in differentiation protocols. Here we present the outcome of a systematic review of scientific articles that have used SH-SY5Y cells to explore PD. We describe the cell source, culture conditions, differentiation protocols, methods/approaches used to mimic PD and the preclinical validation of the SH-SY5Y findings by employing alternative cellular and animal models. Thus, this overview may help to standardize the use of the SH-SY5Y cell line in PD research and serve as a future user’s guide. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0149-0) contains supplementary material, which is available to authorized users.
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              Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: Focusing on mitochondria

              Oxidative stress-induced lipid peroxidation has been associated with human physiology and diseases including cancer. Overwhelming data suggest that reactive lipid mediators generated from this process, such as 4-hydroxynonenal (4-HNE), are biomarkers for oxidative stress and important players for mediating a number of signaling pathways. The biological effects of 4-HNE are primarily due to covalent modification of important biomolecules including proteins, DNA, and phospholipids containing amino group. In this review, we summarize recent progress on the role of 4-HNE in pathogenesis of cancer and focus on the involvement of mitochondria: generation of 4-HNE from oxidation of mitochondria-specific phospholipid cardiolipin; covalent modification of mitochondrial proteins, lipids, and DNA; potential therapeutic strategies for targeting mitochondrial ROS generation, lipid peroxidation, and 4-HNE.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Investigation
                Role: Data curationRole: InvestigationRole: Methodology
                Role: Data curationRole: Investigation
                Role: Data curationRole: InvestigationRole: Methodology
                Role: Data curationRole: InvestigationRole: Methodology
                Role: Data curationRole: Methodology
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 December 2017
                2017
                : 12
                : 12
                : e0189043
                Affiliations
                [1 ] Biomedical Neuroscience Institute (BNI), Faculty of Medicine, Universidad de Chile, Santiago, Chile
                [2 ] Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile
                [3 ] Universidad Metropolitana de Ciencias de la Educación, Facultad de Ciencias Básicas, Departamento de Química, Santiago, Chile
                [4 ] Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile
                [5 ] Facultad de Ciencias Naturales y Matemáticas, Universidad de Ibagué, Ibagué, Colombia
                [6 ] Integrative Center for Applied Biology and Chemistry (CIBQA), Universidad Bernardo O’Higgins, Santiago, Chile
                [7 ] Department of Neuroscience, CEMC and ICBM, Faculty of Medicine, Universidad de Chile, Santiago, Chile
                North Carolina State University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                [¤]

                Current address: Facultad de Ciencias Naturales y Matemáticas, Universidad de Ibagué, Ibagué, Colombia

                Author information
                http://orcid.org/0000-0003-1256-9651
                Article
                PONE-D-17-24335
                10.1371/journal.pone.0189043
                5724820
                29228015
                c85598e7-5f5b-4add-9b99-33776c2d33aa
                © 2017 García-Beltrán et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 June 2017
                : 19 November 2017
                Page count
                Figures: 8, Tables: 0, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100002850, Fondo Nacional de Desarrollo Científico y Tecnológico;
                Award ID: 1140545
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002850, Fondo Nacional de Desarrollo Científico y Tecnológico;
                Award ID: 11140580
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002850, Fondo Nacional de Desarrollo Científico y Tecnológico;
                Award ID: 1130068
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002848, Comisión Nacional de Investigación Científica y Tecnológica;
                Award ID: 3140451
                Award Recipient :
                Funded by: Millennium Science Initiative (CL)
                Award ID: BNI P-09-015F
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100005853, Universidad de Chile;
                Award ID: U-APOYA 2236
                Award Recipient :
                This study was supported by the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT), Chile ( http://spl.conicyt.cl/auth/), which provided a postdoctoral research grant (N° 3149451) to Dr. Olimpo García-Beltrán; Fondo Nacional de Desarrollo Científico y Tecnológica (FONDECYT), Chile ( http://www.conicyt.cl/fondecyt/), which provided research grants to Cecilia Hidalgo (N° 1149545), Marco T. Núñez (N° 1130068) and Tatiana Adasme (N° 11140580); Instituto de Neurociencia Biomédica, Iniciativa Científica Milenio, Chile ( www.iniciativamilenio.cl/), which provided research funds to Cecilia Hidalgo (N° BNI P-09-015F). Financial support to Prof. Marco T Núñez was provided by the Program for Research, Faculty of Sciences (PAIFAC) and by U-APOYA 2236, VID, Universidad de Chile. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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