Oxidative DNA damage and cellular sensitivity to oxidative stress in human autoimmune diseases.

Bashir, Samina; Harris, G.; Denman, Michael; Blake, David R.; Winyard, Paul G.

doi:10.1136/ard.52.9.659

Cited by 231 publications

(140 citation statements)

References 44 publications

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“…5,6 Smoking and systemic inflammatory disease can induce formation of 8-OHdG in peripheral leukocyte DNA. 37,38 angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have also been shown to reduce DNA damage of lymphocytes in experimental chronic renal failure. 39 Therefore, to reduce oxidation as much as possible to identify the differences in lymphocyte 8-OHdG levels mainly as a result of intravenous iron therapy, it was of the utmost importance to exclude these confounders in this study.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Iron Exacerbates Oxidative DNA Damage in Peripheral Blood Lymphocytes in Chronic Hemodialysis Patients

Kuo

Hung

Wei

et al. 2008

Journal of the American Society of Nephrology

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Patients undergoing maintenance hemodialysis have elevated markers of oxidative stress, but the reasons for this are not fully understood. Intravenous administration of iron, which many of these patients receive, may provoke the generation of bioactive iron, which enhances oxidative stress and lipid peroxidation. In this study, 110 hemodialysis patients were randomly assigned to five groups that were administered single intravenous doses of iron sucrose, ranging from 20 to 500 mg. A time-and dosage-dependent rise in lymphocyte 8-hydroxy-2Ј-deoxyguanosine (8-OHdG) levels in lymphocyte DNA, a marker of oxidative DNA damage, with a significant increase at 2 h after intravenous iron of Ն200 mg (P Ͻ 0.05). Four weeks later, patients were randomly assigned to weekly iron sucrose (100 mg of elemental iron) or saline for 12 wk, and 89 patients completed the study. Mean lymphocyte 8-OHdG content was significantly higher in patients receiving intravenous iron compared with control subjects (P Ͻ 0.05), especially in those with ferritin levels Ͼ500 g/L. In addition, flow cytometric techniques revealed increased production of reactive oxygen species in lymphocytes among those treated with intravenous iron. Treatment with intravenous iron but not saline was also associated with decreased plasma ascorbate and ␣-tocopherol levels and increased oxidized glutathione/reduced glutathione ratio (P Ͻ 0.05). In summary, intravenous iron sucrose provokes oxidative damage to peripheral blood lymphocyte DNA in hemodialysis patients, especially among those with high levels of ferritin. 19: 181719: -182619: , 200819: . doi: 10.1681 Cumulative evidence indicates that oxidative stress frequently occurs in patients undergoing maintenance hemodialysis (HD) as a result of a decrease of antioxidant defenses and an overproduction of reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide, hydroxyl radical, and hypochlorous acid. 1-4 Direct measurement of ROS is difficult because of its lower plasma levels and shorter half-life; however, measurement of oxidative byproducts combined with the assessment of antioxidant levels become more feasible. Oxidative damage to cellular constituents, such as membrane lipids, protein, and DNA, are fingerprints of oxidative byproducts. Recently, investigators disclosed that 8-hydroxy 2Ј-deoxyguanosine (8-OHdG) is one of the most abundant oxidative DNA products and a sensitive DNA damage marker because it can be detected by a HPLC electrochemical detection method in the femtomole range. 5,6 Our previous J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Intravenous Iron Exacerbates Oxidative DNA Damage in Peripheral Blood Lymphocytes in Chronic Hemodialysis Patients

Kuo

Hung

Wei

et al. 2008

Journal of the American Society of Nephrology

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“…Even the presence of only a small percentage of oxidized cardiolipin molecules in a microtiter well could lead to the appearance of antibody binding to "native" cardiolipin. By analogy, are other subtle modifications of native molecules, such as cholesterol or DNA, responsible for binding of anticholesterol (69) and anti-DNA antibodies (70,71)? Could such common and subtle oxidation-derived modifications be present on both DNA and cardiolipin, for example, and could these epitopes be responsible for the reported ability of some anticardiolipin antibodies to bind to DNA?…”

Section: Discussionmentioning

confidence: 99%

Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein.

Hörkkö¹,

Miller²,

Dudl³

et al. 1996

J. Clin. Invest.

299

118

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The optimal clinical management of patients with antiphospholipid antibody syndrome (APS) is uncertain because of a lack of an underlying hypothesis to explain why antiphospholipid autoantibodies (aPL) form to such ubiquitous compounds as phospholipids (PL). In this paper, we demonstrate that many, if not most, aPL are actually directed at neoepitopes of oxidized PL, or neoepitopes generated by adduct formation between breakdown products of oxidized PL and associated proteins. Each cardiolipin (CL) molecule contains four unsaturated fatty acids and is highly susceptible to oxidation, particularly upon exposure to air. Yet, standard anticardiolipin antibodies (aCL) immunoassays routinely bind CL to microtiter wells by evaporation of the ethanol solvent overnight at 4 Њ C. Using a variety of techniques, we demonstrated that rapid oxidation occurs when CL is plated and exposed to air. Sera from apo E-deficient mice, which have high autoantibody titers to oxidized low density lipoprotein, showed a striking time-dependent increase in binding to CL that was exposed to air for increasing periods of time. Monoclonal antibodies to oxidized LDL, cloned from the apo E-deficient mice, also bound to oxidized CL. Both sera and affinity-purified aCL-IgG from APS patients bound to CL progressively as it was oxidized. However, the monoclonal antibodies from apo E-deficient mice, or sera or aCL-IgG from APS patients did not bind to a reduced CL analog that was unable to undergo peroxidation. These data demonstrate that many aPL are directed at neoepitopes of oxidized phospholipids, and suggest that oxidative events may be important in the pathophysiology of APS. In turn, this suggests new therapeutic strategies, possibly including intensive antioxidant therapy.

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“…The development of the 32P-postlabeling assay resulted in significant advances in our ability to measure carcinogen exposure in human tissues (55,61), and now approximately 40% of published studies have used this assay to detect DNA adducts ( Figure 1). The Figure 2A), and lower 80HG levels were observed in Japanese populations, as compared with western (European/US) populations (1,3,12,25,31,36,42,44,45,50,58,72 (12,25,31,45,72), buffy coat (1,36), mononuclear cells (44,50), and lymphocytes (3,42,58) by either GC-MS (3,44,58) (12,31,44). Smoking status was not defined.…”

Section: Introductionmentioning

confidence: 99%

DNA Adducts: Endogenous and Induced

Povey

2000

Toxicol Pathol

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Oxidative DNA damage and cellular sensitivity to oxidative stress in human autoimmune diseases.

Cited by 231 publications

References 44 publications

Intravenous Iron Exacerbates Oxidative DNA Damage in Peripheral Blood Lymphocytes in Chronic Hemodialysis Patients

Intravenous Iron Exacerbates Oxidative DNA Damage in Peripheral Blood Lymphocytes in Chronic Hemodialysis Patients

Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein.

DNA Adducts: Endogenous and Induced

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