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      N-Acetyl Cysteine Depletes Reactive Oxygen Species and Prevents Dental Monomer-Induced Intrinsic Mitochondrial Apoptosis In Vitro in Human Dental Pulp Cells

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          Abstract

          Purpose

          To investigate the involvement of intrinsic mitochondrial apoptosis in dental monomer-induced cytotoxicity and the influences of N-acetyl cysteine (NAC) on this process.

          Methods

          Human dental pulp cells (hDPCs) were exposed to several dental monomers in the absence or presence of NAC, and cell viability, intracellular redox balance, morphology and function of mitochondria and key indicators of intrinsic mitochondrial apoptosis were evaluated using various commercial kits.

          Results

          Dental monomers exerted dose-dependent cytotoxic effects on hDPCs. Concomitant to the over-production of reactive oxygen species (ROS) and depletion of glutathione (GSH), differential changes in activities of superoxide dismutase, glutathione peroxidase, and catalase were detected. Apoptosis, as indicated by positive Annexin V/propidium iodide (PI) staining and activation of caspase-3, was observed after dental monomer treatment. Dental monomers impaired the morphology and function of mitochondria, and induced intrinsic mitochondrial apoptosis in hDPCs via up-regulation of p53, Bax and cleaved caspase-3, and down-regulation of Bcl-2. NAC restored cell viability, relieved oxidative stress and blocked the apoptotic effects of dental monomers.

          Conclusions

          Dental monomers induced oxidative stress and mitochondrial intrinsic apoptosis in hDPCs. NAC could reduce the oxidative stress and thus protect hDPCs against dental monomer-induced apoptosis.

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          Most cited references 36

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          Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.

          Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.
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            Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.

            Bcl-2 protein is able to repress a number of apoptotic death programs. To investigate the mechanism of Bcl-2's effect, we examined whether Bcl-2 interacted with other proteins. We identified an associated 21 kd protein partner, Bax, that has extensive amino acid homology with Bcl-2, focused within highly conserved domains I and II. Bax is encoded by six exons and demonstrates a complex pattern of alternative RNA splicing that predicts a 21 kd membrane (alpha) and two forms of cytosolic protein (beta and gamma). Bax homodimerizes and forms heterodimers with Bcl-2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of Bcl-2. These data suggest a model in which the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus.
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              Role of reactive oxygen species (ROS) in apoptosis induction.

              Reactive oxygen species (ROS) and mitochondria play an important role in apoptosis induction under both physiologic and pathologic conditions. Interestingly, mitochondria are both source and target of ROS. Cytochrome c release from mitochondria, that triggers caspase activation, appears to be largely mediated by direct or indirect ROS action. On the other hand, ROS have also anti-apoptotic effects. This review focuses on the role of ROS in the regulation of apoptosis, especially in inflammatory cells.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                25 January 2016
                2016
                : 11
                : 1
                Affiliations
                [1 ]State Key Laboratory of Military Stomatology, Department of Prosthodontics, School of Stomatology, the Fourth Military Medical University, Xi’an, PR China
                [2 ]Shaanxi Key Laboratory of Military Stomatology, Xi’an, Shaanxi, PR China
                [3 ]State Key Laboratory of Military Stomatology, Department of Operative Dentistry and Endodontics, School of Stomatology, the Fourth Military Medical University, Xi’an, PR China
                [4 ]Department of Orthopaedic Oncology, Xijing Hospital Affiliated to the Fourth Military Medical University, Xi’an, PR China
                [5 ]Department of Orthopaedic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, PR China
                [6 ]State Key Laboratory of Military Stomatology, Department of Orthodontics, School of Stomatology, the Fourth Military Medical University, Xi’an, PR China
                [7 ]State Key Laboratory of Military Stomatology, Department of General and Emergency, School of Stomatology, the Fourth Military Medical University, Xi’an, PR China
                National Cheng Kung University, TAIWAN
                Author notes

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

                Conceived and designed the experiments: SM JC. Performed the experiments: YJ YW. Analyzed the data: LS JL QL. Contributed reagents/materials/analysis tools: LH YL QS FY HY HL. Wrote the paper: YJ SM JC.

                Article
                PONE-D-15-34629
                10.1371/journal.pone.0147858
                4726696
                26808507
                © 2016 Jiao 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.

                Page count
                Figures: 8, Tables: 0, Pages: 20
                Product
                Funding
                This study was financially supported by grant 2015JQ8301 (principal investigator SM) from the Natural Science Foundation of Shaanxi Province, grant 81130078 (principal investigator JC), grant 81300927 (principal investigator SM), grant 81272072 (principal investigator LS) and grant 81200816 (principal investigator LH) from the National Nature Science Foundation of China, and Program No. IRT13051 from the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Biology and Life Sciences
                Biochemistry
                Bioenergetics
                Energy-Producing Organelles
                Mitochondria
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Energy-Producing Organelles
                Mitochondria
                Biology and Life Sciences
                Cell Biology
                Oxidative Stress
                Biology and Life Sciences
                Biotechnology
                Physical Sciences
                Chemistry
                Chemical Reactions
                Oxidation-Reduction Reactions
                Physical Sciences
                Chemistry
                Electrochemistry
                Oxidation-Reduction Reactions
                Biology and Life Sciences
                Biochemistry
                Oxidative Damage
                Reactive Oxygen Species
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cytoplasm
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Membrane Proteins
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized

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