Rred in the choroid; also correlation between cadmium accumulation and increase in zinc and copper levels in males was observed [5]. High zincTrace Elements in AMDFigure 1. Differences in the levels of aqueous humor trace elements (mmol/L) in group of patients with AMD and control group. doi:10.1371/purchase ZK-36374 journal.pone.0056734.gTrace Elements in AMDTable 4. Trace elements in patients with age-related macular degeneration (AMD) and patients with cataract and without AMD (control group).AMD Cadmium (mmol/L) Cobalt (mmol/L) Copper (mmol/L) Iron (mmol/L) Manganese (mmol/L) Selenium (mmol/L) Zinc (mmol/L) 0.9561.09 3.0060.61 30.7639.2 305.1637.5 2.2061.01 5,9261,90 24.17615.Patients without AMD 0.1260.16 1.1460.24 107.96133.5 131.3626.0 2.2461.69 7,6664,12 6.7864.GLM test value F = 26.15 F = 48.88 F = 23.24 F = 67.2 F = 1.10 F = 6.40 F = 0.Oltipraz chemical information Significance p,0.001 p,0.001 p,0001 p,0.001 not significant not significant not significantMean 6 standard deviation are displayed; p-value (2-tailed) is Bonferroni-corrected. The Mann-Whitney U test was used. doi:10.1371/journal.pone.0056734.tconcentration was also shown in macular sub-RPE deposits of patients with AMD [19]. Zinc may also be released from intracellular deposits of the RPE and photoreceptors due to apoptosis of these cells. These mechanisms may lead to elevated extracellular levels of this metal despite its suspected intracellular deficiency. As AMD was not a significant factor in a general linear model regarding zinc, the possible role of this trace element in the pathogenesis of AMD remains uncertain from the results of this study. We have reported elevated cobalt levels in patients with AMD. Cobalt can cause DNA fragmentation and activation of caspases, increased production of reactive oxygen species, and beta amyloid secretion [20]. A significant depletion of intracellular Zn2+ and Mg2+ after CoCl2 exposure has been described [21]. A substitution of magnesium ions by cobalt ions may result in the interruption of ATPases and the energy balance of the cell [22]. Ionic cobalt (Co2+) is known to exert hypoxia-like responses by stabilizing the alpha subunit of the hypoxia inducible transcription factor (HIF1) [23]. This results in changed gen transcription of encoding proteins that play key roles in angiogenesis, glucose and energy metabolism, cell survival and proliferation, iron metabolism, and vascular functions [24]. Comparative gene expression studies showed HIF1-mediated responses to be similar for hypoxia and CoCl2 exposure [25]. Although all these mechanisms have been described for the immediate toxicity of much higher cobalt concentrations than reported in our study, they might also play arole in a long-standing exposure to lower concentrations. We 15900046 could not find any published data on an involvement of cobalt toxicity in AMD pathogenesis. The major limitation of this pilot study is the relatively small sample size. Generally, a bias may be introduced by a convenient sampling approach; however, this seems unlikely in the present study due to the high prevalence of cataract in the general population and the case-control design. Our findings of significant alterations in aqueous humor metal levels in AMD-affected eyes support the hypothesis that their dysregulation may be involved in the pathogenesis of AMD. Knowledge of trace elements distribution, metabolism and toxicity will help to understand their role in the pathogenesis of AMD. Properly designed studies implementing biologically relev.Rred in the choroid; also correlation between cadmium accumulation and increase in zinc and copper levels in males was observed [5]. High zincTrace Elements in AMDFigure 1. Differences in the levels of aqueous humor trace elements (mmol/L) in group of patients with AMD and control group. doi:10.1371/journal.pone.0056734.gTrace Elements in AMDTable 4. Trace elements in patients with age-related macular degeneration (AMD) and patients with cataract and without AMD (control group).AMD Cadmium (mmol/L) Cobalt (mmol/L) Copper (mmol/L) Iron (mmol/L) Manganese (mmol/L) Selenium (mmol/L) Zinc (mmol/L) 0.9561.09 3.0060.61 30.7639.2 305.1637.5 2.2061.01 5,9261,90 24.17615.Patients without AMD 0.1260.16 1.1460.24 107.96133.5 131.3626.0 2.2461.69 7,6664,12 6.7864.GLM test value F = 26.15 F = 48.88 F = 23.24 F = 67.2 F = 1.10 F = 6.40 F = 0.Significance p,0.001 p,0.001 p,0001 p,0.001 not significant not significant not significantMean 6 standard deviation are displayed; p-value (2-tailed) is Bonferroni-corrected. The Mann-Whitney U test was used. doi:10.1371/journal.pone.0056734.tconcentration was also shown in macular sub-RPE deposits of patients with AMD [19]. Zinc may also be released from intracellular deposits of the RPE and photoreceptors due to apoptosis of these cells. These mechanisms may lead to elevated extracellular levels of this metal despite its suspected intracellular deficiency. As AMD was not a significant factor in a general linear model regarding zinc, the possible role of this trace element in the pathogenesis of AMD remains uncertain from the results of this study. We have reported elevated cobalt levels in patients with AMD. Cobalt can cause DNA fragmentation and activation of caspases, increased production of reactive oxygen species, and beta amyloid secretion [20]. A significant depletion of intracellular Zn2+ and Mg2+ after CoCl2 exposure has been described [21]. A substitution of magnesium ions by cobalt ions may result in the interruption of ATPases and the energy balance of the cell [22]. Ionic cobalt (Co2+) is known to exert hypoxia-like responses by stabilizing the alpha subunit of the hypoxia inducible transcription factor (HIF1) [23]. This results in changed gen transcription of encoding proteins that play key roles in angiogenesis, glucose and energy metabolism, cell survival and proliferation, iron metabolism, and vascular functions [24]. Comparative gene expression studies showed HIF1-mediated responses to be similar for hypoxia and CoCl2 exposure [25]. Although all these mechanisms have been described for the immediate toxicity of much higher cobalt concentrations than reported in our study, they might also play arole in a long-standing exposure to lower concentrations. We 15900046 could not find any published data on an involvement of cobalt toxicity in AMD pathogenesis. The major limitation of this pilot study is the relatively small sample size. Generally, a bias may be introduced by a convenient sampling approach; however, this seems unlikely in the present study due to the high prevalence of cataract in the general population and the case-control design. Our findings of significant alterations in aqueous humor metal levels in AMD-affected eyes support the hypothesis that their dysregulation may be involved in the pathogenesis of AMD. Knowledge of trace elements distribution, metabolism and toxicity will help to understand their role in the pathogenesis of AMD. Properly designed studies implementing biologically relev.
