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      Retinal Cell Death Caused by Sodium Iodate Involves Multiple Caspase-Dependent and Caspase-Independent Cell-Death Pathways

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          Abstract

          Herein, we have investigated retinal cell-death pathways in response to the retina toxin sodium iodate (NaIO 3) both in vivo and in vitro. C57/BL6 mice were treated with a single intravenous injection of NaIO 3 (35 mg/kg). Morphological changes in the retina post NaIO 3 injection in comparison to untreated controls were assessed using electron microscopy. Cell death was determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining. The activation of caspases and calpain was measured using immunohistochemistry. Additionally, cytotoxicity and apoptosis in retinal pigment epithelial (RPE) cells, primary retinal cells, and the cone photoreceptor (PRC) cell line 661W were assessed in vitro after NaIO 3 treatment using the ApoToxGlo™ assay. The 7-AAD/Annexin-V staining was performed and necrostatin (Nec-1) was administered to the NaIO 3-treated cells to confirm the results. In vivo, degenerating RPE cells displayed a rounded shape and retracted microvilli, whereas PRCs featured apoptotic nuclei. Caspase and calpain activity was significantly upregulated in retinal sections and protein samples from NaIO 3-treated animals. In vitro, NaIO 3 induced necrosis in RPE cells and apoptosis in PRCs. Furthermore, Nec-1 significantly decreased NaIO 3-induced RPE cell death, but had no rescue effect on treated PRCs. In summary, several different cell-death pathways are activated in retinal cells as a result of NaIO 3.

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          Most cited references33

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          An alternative, nonapoptotic form of programmed cell death.

          The term apoptosis often has been used interchangeably with the term programmed cell death. Here we describe a form of programmed cell death that is distinct from apoptosis by the criteria of morphology, biochemistry, and response to apoptosis inhibitors. Morphologically, this alternative form of programmed cell death appears during development and in some cases of neurodegeneration. Despite its lack of response to caspase inhibitors and Bcl-x(L), we show that this form of cell death is driven by an alternative caspase-9 activity that is Apaf-1-independent. Characterization of this alternative form of programmed cell death should lead to new insight into cell death programs and their roles in development and degeneration.
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            Expression of cone-photoreceptor-specific antigens in a cell line derived from retinal tumors in transgenic mice.

            To examine an immortalized mouse retinal cell line (661W) for markers characteristic of photoreceptor cells and validate its photoreceptor origin. The 661W cells were cloned from retinal tumors of a transgenic mouse line that expresses the simian virus (SV) 40 T antigen under control of the human interphotoreceptor retinol-binding protein (IRBP) promoter. Morphologic, immunocytochemical, and immunoblot analyses were performed to characterize these cells. Total cellular protein was used for immunoblot analysis of various photoreceptor-specific proteins. 661W cells grew as a monolayer and exhibited processes characteristic of neuronal cells. Immunoblot analysis showed that 661W cells expressed SV40 T antigen, blue and green cone pigments, transducin, and cone arrestin. Immunocytochemical detection of blue and green opsins showed distribution throughout the cell, the nucleus included. However, these cells did not express rod-specific antigens, such as opsin and arrestin or rod- and cone-specific proteins such as phosducin, peripherin/rds, and ROM1. Furthermore, the cells did not express RPE65, a cone- and RPE-cell-specific protein. 661W cells demonstrate cellular and biochemical characteristics exhibited by cone photoreceptor cells. These cells also resemble neuronal cells with their spindlelike processes and should serve as a useful alternative in vitro model for the study of cone photoreceptor cell biology and associated diseases.
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              Does autophagy contribute to cell death?

              Autophagy (specifically macroautophagy) is an evolutionarily conserved catabolic process where the cytoplasmic contents of a cell are sequestered within double membrane vacuoles, called autophagosomes, and subsequently delivered to the lysosome for degradation. Autophagy can function as a survival mechanism in starving cells. At the same time, extensive autophagy is commonly observed in dying cells, leading to its classification as an alternative form of programmed cell death. The functional contribution of autophagy to cell death has been a subject of great controversy. However, several recent loss-of-function studies of autophagy (atg) genes have begun to address the roles of autophagy in both cell death and survival. Here, we review the emerging evidence in favor of and against autophagic cell death, discuss the possible roles that autophagic degradation might play in dying cells, and identify salient issues for future investigation.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                03 July 2015
                July 2015
                : 16
                : 7
                : 15086-15103
                Affiliations
                [1 ]Department of Ophthalmology, Inselspital, University of Bern, Bern 3010, Switzerland; E-Mails: jasmin.balmer@ 123456ndcn.ox.ac.uk (J.B.); s.roberti@ 123456gmx.net (S.R.)
                [2 ]Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
                [3 ]Department of Cell Biology, the University of Oklahoma Health Sciences Center, University of Oklahoma, Oklahoma City, OK 73104, USA; E-Mail: rahel-zulliger@ 123456ouhsc.edu
                [4 ]Department for Clinical Research, University of Bern, Bern 3010, Switzerland
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: volker.enzmann@ 123456insel.ch ; Tel.: +41-31-632-8935; Fax: +41-31-632-4882.
                Article
                ijms-16-15086
                10.3390/ijms160715086
                4519888
                26151844
                1166039e-6314-4412-9506-92eac3f61483
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 April 2015
                : 04 June 2015
                Categories
                Article

                Molecular biology
                sodium iodate,cell death,retinal pigment epithelium,photoreceptors,apoptosis,necrosis,in vivo,in vitro

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