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      The association between serum uric acid and glaucoma severity in primary angle closure glaucoma: a retrospective case-control study

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          Abstract

          Uric acid (UA) is a major antioxidant molecule and has been hypothesized to have a protective effect on the central nervous system against oxidative damage. We prospectively investigated the serum concentration of UA in primary angle closure glaucoma (PACG), and explored the association between serum concentration of UA and the severity of PACG. Using a retrospective case-control study design, 886 PACG subjects and 994 control subjects who attended the Eye & ENT Hospital of Fudan University, were eligible for this study. Glaucoma severity was classified as mild (MD ≤ 6.00 dB), moderate (12 dB ≥ MD > 6 dB) and severe (MD > 12 dB) based on the MD (mean deviation). The levels of UA were significantly lower ( p = 0.025) in PACG (0.286 ± 0.082 mmol/l) compared with control (0.295 ± 0.085 mmol/l). The mean serum UA levels were lowest in the severe group (0.281 ± 0.074 mmol/l) followed by moderate (0.282 ± 0.080 mmol/l) and mild (0.297 ± 0.090 mmol/l) with significant differences among the three groups ( p = 0.032). In multivariate regression analysis, there was a significant negative correlation between UA level and vertical cup-disc ratio (B = −0.165, p = 0.035). Significantly lower serum UA concentration in PACG and its negative association with disease severity presented it as an important candidate in reaction to oxidative stress in glaucoma pathogenesis.

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          The role of oxidative stress in glaucoma.

          DNA damage is related to a variety of degenerative diseases such as cancer, atherosclerosis and neurodegenerative diseases, depending on the tissue affected. Increasing evidence indicates that reactive oxygen species (ROS) play a key role in the pathogenesis of primary open angle glaucoma (POAG), the main cause of irreversible blindness worldwide. Oxidative DNA damage is significantly increased in the ocular epithelium regulating aqueous humor outflow, i.e., the trabecular meshwork (TM), of glaucomatous patients compared to controls. The pathogenic role of ROS in glaucoma is supported by various experimental findings, including (a) resistance to aqueous humor outflow is increased by hydrogen peroxide by inducing TM degeneration; (b) TM possesses remarkable antioxidant activities, mainly related to superoxide dismutase-catalase and glutathione pathways that are altered in glaucoma patients; and (c) intraocular-pressure increase and severity of visual-field defects in glaucoma patients parallel the amount of oxidative DNA damage affecting TM. Vascular alterations, which are often associated with glaucoma, could contribute to the generation of oxidative damage. Oxidative stress, occurring not only in TM but also in retinal cells, appears to be involved in the neuronal cell death affecting the optic nerve in POAG. The highlighting of the pathogenic role of ROS in POAG has implications for the prevention of this disease as indicated by the growing number of studies using genetic analyses to identify susceptible individuals and of clinical trials testing the efficacy of antioxidant drugs for POAG management.
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            Uric acid-iron ion complexes. A new aspect of the antioxidant functions of uric acid.

            In order to survive in an oxygen environment, aerobic organisms have developed numerous mechanisms to protect against oxygen radicals and singlet oxygen. One such mechanism, which appears to have attained particular significance during primate evolution, is the direct scavenging of oxygen radicals, singlet oxygen, oxo-haem oxidants and hydroperoxyl radicals by uric acid. In the present paper we demonstrate that another important 'antioxidant' property of uric acid is the ability to form stable co-ordination complexes with iron ions. Formation of urate-Fe3+ complexes dramatically inhibits Fe3+-catalysed ascorbate oxidation, as well as lipid peroxidation in liposomes and rat liver microsomal fraction. In contrast with antioxidant scavenger reactions, the inhibition of ascorbate oxidation and lipid peroxidation provided by urate's ability to bind iron ions does not involve urate oxidation. Association constants (Ka) for urate-iron ion complexes were determined by fluorescence-quenching techniques. The Ka for a 1:1 urate-Fe3+ complex was found to be 2.4 X 10(5), whereas the Ka for a 1:1 urate-Fe2+ complex was determined to be 1.9 X 10(4). Our experiments also revealed that urate can form a 2:1 complex with Fe3+ with an association constant for the second urate molecule (K'a) of approx. 4.5 X 10(5). From these data we estimate an overall stability constant (Ks approximately equal to Ka X K'a) for urate-Fe3+ complexes of approx. 1.1 X 10(11). Polarographic measurements revealed that (upon binding) urate decreases the reduction potential for the Fe2+/Fe3+ half-reaction from -0.77 V to -0.67 V. Thus urate slightly diminishes the oxidizing potential of Fe3+. The present results provide a mechanistic explanation for our previous report that urate protects ascorbate from oxidation in human blood. The almost saturating concentration of urate normally found in human plasma (up to 0.6 mM) represents 5-10 times the plasma ascorbate concentration, and is orders of magnitude higher than the 'free' iron ion concentration. These considerations point to the physiological significance of our findings.
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              Oxidative deoxyribonucleic acid damage in the eyes of glaucoma patients.

              Little is known about the molecular mechanisms responsible for the development of glaucoma, the leading cause of irreversible blindness worldwide. Some investigators have hypothesized that oxidative damage may be involved. We evaluated oxidative deoxyribonucleic acid (DNA) damage, in terms of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), in the eyes of glaucoma patients. Levels of 8-OH-dG were measured in the trabecular meshwork region from 42 patients with glaucoma and 45 controls of similar age and sex. Genotypes of glutathione S-transferase isoenzymes (GSTM1 and GSTT1) were assessed by polymerase chain reaction in the same DNA samples. Levels of 8-OH-dG were significantly higher in glaucoma patients than in controls. Oxidative DNA damage in patients with glaucoma correlated significantly with intraocular pressure; in patients with primary open-angle glaucoma, it also correlated with visual field defects. GSTT1 was similar in the two groups, and had no effect on 8-OH-dG levels. Conversely, 8-OH-dG levels were significantly higher in GSTM1-null than in GSTM1-positive subjects. The GSTM1-null genotype was significantly more common in patients with primary open-angle glaucoma than in controls. Oxidative DNA damage is significantly increased in the trabecular meshwork of glaucoma patients. GSTM1 gene deletion, which has been associated with an increased risk of cancer at various sites and molecular lesions in atherosclerosis, predisposes to more severe oxidative DNA damage in glaucoma patients. These findings may contribute to understanding the pathogenesis of glaucoma and may be useful in the prevention and treatment of this disease.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                10 January 2017
                1 December 2016
                : 8
                : 2
                : 2816-2824
                Affiliations
                1 Department of Clinical Laboratory, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shangai, China
                2 Department of Ophthalmology and Visual Science, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shangai, China
                3 State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China
                4 Key Laboratory of Myopia, Ministry of Health (Fudan University), Shangai, China
                5 Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shangai, China
                Author notes
                Correspondence to: Wenjun Cao, wgkjyk@ 123456aliyun.com
                Article
                13745
                10.18632/oncotarget.13745
                5356844
                27926530
                c83791ec-7e61-4a7a-938a-5efda9b7b67c
                Copyright: © 2017 Li 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
                : 20 September 2016
                : 23 November 2016
                Categories
                Research Paper

                Oncology & Radiotherapy
                primary angle closure glaucoma,serum,uric acid,oxidative stress
                Oncology & Radiotherapy
                primary angle closure glaucoma, serum, uric acid, oxidative stress

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