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      Folate Deficiency Triggered Apoptosis of Synoviocytes: Role of Overproduction of Reactive Oxygen Species Generated via NADPH Oxidase/Mitochondrial Complex II and Calcium Perturbation

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          Abstract

          Despite a plethora of literature has documented that osteoarthritis (OA) is veritably associated with oxidative stress-mediated chondrocyte death and matrix degradation, yet the possible involvement of synoviocyte abnormality as causative factor of OA has not been thoroughly investigated. For this reason, we conduct the current studies to insight into how synoviocytes could respond to an episode of folate-deprived (FD) condition. First, when HIG-82 synoviocytes were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature mediated through FD-evoked overproduction of reactive oxygen species (ROS) and drastically released of cytosolic calcium (Ca 2+) concentrations. Next, we uncovered that FD-evoked ROS overproduction could only be strongly suppressed by either mitochondrial complex II inhibitors (TTFA and carboxin) or NADPH oxidase (NOX) inhibitors (AEBSF and apocynin), but not by mitochondrial complex I inhibitor (rotenone) and mitochondrial complex III inhibitor (antimycin A). Interestingly, this selective inhibition of FD-evoked ROS by mitochondrial complex II and NOX inhibitors was found to correlate excellently with the suppression of cytosolic Ca 2+ release and reduced the magnitude of the apoptotic TUNEL-positive cells. Taken together, we present the first evidence here that FD-triggered ROS overproduction in synoviocytes is originated from mitochondrial complex II and NOX. Both elevated ROS in tandem with cytosolic Ca 2+ overload serve as final arbitrators for apoptotic lethality of synoviocytes cultivated under FD condition. Thus, folate supplementation may be beneficial to patients with OA.

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          Most cited references34

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          Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.

          It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke. To assess the relationship of homocysteine concentrations with vascular disease risk. MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators. Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete. Data from 30 prospective or retrospective studies involving a total of 5073 IHD events and 1113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression. Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 micromol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk. This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.
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            Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity.

            Elevated plasma levels of the sulfur-containing amino acid homocysteine increase the risk for atherosclerosis, stroke, and possibly Alzheimer's disease, but the underlying mechanisms are unknown. We now report that homocysteine induces apoptosis in rat hippocampal neurons. DNA strand breaks and associated activation of poly-ADP-ribose polymerase (PARP) and NAD depletion occur rapidly after exposure to homocysteine and precede mitochondrial dysfunction, oxidative stress, and caspase activation. The PARP inhibitor 3-aminobenzamide (3AB) protects neurons against homocysteine-induced NAD depletion, loss of mitochondrial transmembrane potential, and cell death, demonstrating a requirement for PARP activation and/or NAD depletion in homocysteine-induced apoptosis. Caspase inhibition accelerates the loss of mitochondrial potential and shifts the mode of cell death to necrosis; inhibition of PARP with 3AB attenuates this effect of caspase inhibition. Homocysteine markedly increases the vulnerability of hippocampal neurons to excitotoxic and oxidative injury in cell culture and in vivo, suggesting a mechanism by which homocysteine may contribute to the pathogenesis of neurodegenerative disorders.
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              Physiology of folate and vitamin B12 in health and disease.

              Folate is a water-soluble B-vitamin and enzymatic cofactor that is necessary for the synthesis of purine and thymidine nucleotides and for the synthesis of methionine from homocysteine. Impairment of folate-mediated one-carbon metabolic pathways can result from B-vitamin deficiencies and/or single nucleotide polymorphisms, and increases risk for pathologies, including cancer and cardiovascular disease, and developmental anomalies including neural tube defects. Although several well validated metabolic and genomic biomarkers for folate deficiency exist, our understanding of the biochemical and genetic mechanisms whereby impaired folate metabolism increases risk for developmental anomalies and disease is limited, as are the mechanisms whereby elevated folate intake protects against these pathologies. Therefore, current initiatives to increase folate intakes in human populations to ameliorate developmental anomalies and prevent disease, while effective, lack predictive value with respect to unintended adverse outcomes.
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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
                15 January 2016
                2016
                : 11
                : 1
                : e0146440
                Affiliations
                [1 ]Department of Physical Medicine and Rehabilitation, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan
                [2 ]Department of Nursing, Chang-Gung University of Science and Technology, Chia-Yi, Taiwan
                [3 ]Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
                [4 ]Center of Advanced Integrative Sports Medicine, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan
                [5 ]Department of Microbiology, Immunology and Biopharmaceuticals, Collage of Life Sciences, National Chiayi University, Chiayi City 60004, Taiwan
                [6 ]Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
                [7 ]Department of Physical therapy, Hung Kuang University, Taichung, Taiwan
                [8 ]Translational Research Laboratory, Cancer Center, Taipei Medical University and Hospital, Taipei, Taiwan
                School of Medicine and Health Sciences, University of North Dakota, UNITED STATES
                Author notes

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

                Conceived and designed the experiments: HCH FJL PJC TZL CHC. Performed the experiments: HCH WMC JYW YWC CCH KHC CZH RHY. Analyzed the data: JYW CHC. Contributed reagents/materials/analysis tools: HCH WMC CHC. Wrote the paper: TZL CHC.

                Article
                PONE-D-15-04453
                10.1371/journal.pone.0146440
                4714898
                26771387
                c652ef46-9568-42c4-aa15-cfc417b134ff
                © 2016 Hsu 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
                : 6 March 2015
                : 17 December 2015
                Page count
                Figures: 8, Tables: 0, Pages: 21
                Funding
                This study was supported by Chang Gung Memorial Hospital, R.O.C. (CMRPG6B0471, W.M.C.) and in part by National Science Council, Taiwan (NSC 102-2320-B-415-005-MY3; National Science Council’s, C.H.C.). 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
                Medicine and Health Sciences
                Hematology
                Anemia
                Megaloblastic Anemia
                Folate Deficiency
                Computer and Information Sciences
                Data Acquisition
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Cartilage
                Chondrocytes
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Cartilage
                Chondrocytes
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Connective Tissue Cells
                Chondrocytes
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Connective Tissue Cells
                Chondrocytes
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Connective Tissue Cells
                Chondrocytes
                Biology and Life Sciences
                Cell Biology
                Oxidative Stress
                Research and analysis methods
                Bioassays and physiological analysis
                Biochemical analysis
                Colorimetric assays
                MTT assay
                Research and analysis methods
                Bioassays and physiological analysis
                Biochemical analysis
                Enzyme assays
                MTT assay
                Research and Analysis Methods
                Spectrum Analysis Techniques
                Spectrophotometry
                Cytophotometry
                Flow Cytometry
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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