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      Serum Paraoxonase 1 Activity and Lipid Peroxidation Levels in Patients with Age-Related Macular Degeneration

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          Our objective was to investigate antioxidant paraoxonase 1 (PON1) activity together with malondialdehyde (MDA) levels to evaluate oxidative stress in patients with age-related macular degeneration (AMD), an important cause of blindness in the elderly population. Serum PON1 activity and MDA levels were analyzed in 37 patients with AMD and compared with 29 healthy controls using a spectrophotometric method. Serum MDA levels were significantly higher in the patient group (2.76 ± 1.28 nmol/ml) than controls (1.00 ± 0.36 nmol/ml; p < 0.001), whereas PON1 activity was lower in the patient group (132.27 ± 63.39 U/l) than controls (312.13 ± 136.23 U/l; p < 0.001). There was a negative correlation between MDA and PON1 levels (r = –0.470, p < 0.001). We conclude that the observed increase in MDA levels may be related to decreased PON1 activity; the present data also demonstrated that an obvious negative correlation between PON1 activity and MDA levels exists in patients with AMD. PON1 is also an antioxidant agent, therefore effective antioxidant therapy to inhibit lipid peroxidation is necessary and agents to increase PON1 activity may be a therapeutic option in AMD.

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          Most cited references 26

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          Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase.

          HDL levels are inversely related to the risk of developing atherosclerosis. In serum, paraoxonase (PON) is associated with HDL, and was shown to inhibit LDL oxidation. Whether PON also protects HDL from oxidation is unknown, and was determined in the present study. In humans, we found serum HDL PON activity and HDL susceptibility to oxidation to be inversely correlated (r2 = 0.77, n = 15). Supplementing human HDL with purified PON inhibited copper-induced HDL oxidation in a concentration-dependent manner. Adding PON to HDL prolonged the oxidation lag phase and reduced HDL peroxide and aldehyde formation by up to 95%. This inhibitory effect was most pronounced when PON was added before oxidation initiation. When purified PON was added to whole serum, essentially all of it became HDL-associated. The PON-enriched HDL was more resistant to copper ion-induced oxidation than was control HDL. Compared with control HDL, HDL from PON-treated serum showed a 66% prolongation in the lag phase of its oxidation, and up to a 40% reduction in peroxide and aldehyde content. In contrast, in the presence of various PON inhibitors, HDL oxidation induced by either copper ions or by a free radical generating system was markedly enhanced. As PON inhibited HDL oxidation, two major functions of HDL were assessed: macrophage cholesterol efflux, and LDL protection from oxidation. Compared with oxidized untreated HDL, oxidized PON-treated HDL caused a 45% increase in cellular cholesterol efflux from J-774 A.1 macrophages. Both HDL-associated PON and purified PON were potent inhibitors of LDL oxidation. Searching for a possible mechanism for PON-induced inhibition of HDL oxidation revealed PON (2 paraoxonase U/ml)-mediated hydrolysis of lipid peroxides (by 19%) and of cholesteryl linoleate hydroperoxides (by 90%) in oxidized HDL. HDL-associated PON, as well as purified PON, were also able to substantially hydrolyze (up to 25%) hydrogen peroxide (H2O2), a major reactive oxygen species produced under oxidative stress during atherogenesis. Finally, we analyzed serum PON activity in the atherosclerotic apolipoprotein E-deficient mice during aging and development of atherosclerotic lesions. With age, serum lipid peroxidation and lesion size increased, whereas serum PON activity decreased. We thus conclude that HDL-associated PON possesses peroxidase-like activity that can contribute to the protective effect of PON against lipoprotein oxidation. The presence of PON in HDL may thus be a major contributor to the antiatherogenicity of this lipoprotein.
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            Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration.

            Oxidative stress is believed to contribute to the pathogenesis of many diseases, including age-related macular degeneration (AMD). Although the vision loss of AMD results from photoreceptor damage in the central retina, the initial pathogenesis involves degeneration of RPE cells. Evidence from a variety of studies suggests that RPE cells are susceptible to oxidative damage. Mitochondrial DNA (mtDNA) is particularly prone to oxidative damage compared to nuclear DNA (nDNA). Using the quantitative PCR assay, a powerful tool to measure oxidative DNA damage and repair, we have shown that human RPE cells treated with H(2)O(2) or rod outer segments resulted in preferential damage to mtDNA, but not nDNA; and damaged mtDNA is not efficiently repaired, leading to compromised mitochondrial redox function as indicated by the MTT assay. Thus, the susceptibility of mtDNA to oxidative damage in human RPE cells, together with the age-related decrease of cellular anti-oxidant system, provides the rationale for a mitochondria-based model of AMD.
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              Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration.

              Age-related macular degeneration (AMD) is the leading cause of severe central visual impairment among the elderly and is associated both with environmental factors such as smoking and with genetic factors. Here, 167 unrelated AMD patients were screened for alterations in ABCR, a gene that encodes a retinal rod photoreceptor protein and is defective in Stargardt disease, a common hereditary form of macular dystrophy. Thirteen different AMD-associated alterations, both deletions and amino acid substitutions, were found in one allele of ABCR in 26 patients (16%). Identification of ABCR alterations will permit presymptomatic testing of high-risk individuals and may lead to earlier diagnosis of AMD and to new strategies for prevention and therapy.

                Author and article information

                S. Karger AG
                December 2005
                21 December 2005
                : 220
                : 1
                : 12-16
                Departments of aBiochemistry and Clinical Biochemistry, bOphthalmology and cInternal Medicine, Medical Faculty, Erciyes University, Kayseri, Turkey
                89269 Ophthalmologica 2006;220:12–16
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 1, References: 47, Pages: 5
                Original Paper


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