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Antioxidant Defense, Redox Homeostasis, and Oxidative Damage in Children With Ataxia Telangiectasia and Nijmegen Breakage Syndrome.

ABSTRACT: Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) belong to a group of primary immunodeficiency diseases (PI) characterized by premature aging, cerebral degeneration, immunoglobulin deficiency and higher cancer susceptibility. Despite the fact that oxidative stress has been demonstrated in vitro and in animal models of AT and NBS, the involvement of redox homeostasis disorders is still unclear in the in vivo phenotype of AT and NBS patients. Our study is the first to compare both enzymatic and non-enzymatic antioxidants as well as oxidative damage between AT and NBS subjects. Twenty two Caucasian children with AT and twelve patients with NBS were studied. Enzymatic and non-enzymatic antioxidants - glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase-1 (SOD) and uric acid (UA); redox status-total antioxidant capacity (TAC) and ferric reducing ability of plasma (FRAP); and oxidative damage products-8-hydroxy-2'-deoxyguanosine (8-OHdG), advanced glycation end products (AGE), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE) protein adducts, and 8-isoprostanes (8-isop) were evaluated in serum or plasma samples. We showed that CAT, SOD and UA were significantly increased, while TAC and FRAP levels were statistically lower in the plasma of AT patients compared to controls. In NBS patients, only CAT activity was significantly elevated, while TAC was significantly decreased as compared to healthy children. We also showed higher oxidative damage to DNA (?8-OHdG), proteins (?AGE, ?AOPP), and lipids (?4-HNE, ?8-isop) in both AT and NBS patients. Interestingly, we did not demonstrate any significant differences in the antioxidant defense and oxidative damage between AT and NBS patients. However, in AT children, we showed a positive correlation between 8-OHdG and the ?-fetoprotein level as well as a negative correlation between 8-OHdG and IgA. In NBS, AGE was positively correlated with IgM and negatively with the IgG level. Summarizing, we demonstrated an imbalance in cellular redox homeostasis and higher oxidative damage in AT and NBS patients. Despite an increase in the activity/concentration of some antioxidants, the total antioxidant capacity is overwhelmed in children with AT and NBS and predisposes them to more considerable oxidative damage. Oxidative stress may play a major role in AT and NBS phenotype.

SUBMITTER: Maciejczyk M

PROVIDER: S-EPMC6776633 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:Nijmegen breakage syndrome (NBS) is a rare autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies. Due to a founder mutation in the underlying NBN gene (c.657_661del5) the disease is encountered most frequently among Slavic populations. The principal clinical manifestations of the syndrome are: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The NBN gene codes for nibrin which, as part of a DNA repair complex, plays a critical nuclear role wherever double-stranded DNA ends occur, either physiologically or as a result of mutagenic exposure. Laboratory findings include: (1) spontaneous chromosomal breakage in peripheral T lymphocytes with rearrangements preferentially involving chromosomes 7 and 14, (2) sensitivity to ionizing radiation or radiomimetics as demonstrated in vitro by cytogenetic methods or by colony survival assay, (3) radioresistant DNA synthesis, (4) biallelic hypomorphic mutations in the NBN gene, and (5) absence of full-length nibrin protein. Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome). In fact, NBS was most commonly confused with Fanconi anaemia and LIG4 syndrome. Genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies.

Project description:Oxidative stress is a key pathogenic factor in both neurogenerative and metabolic diseases. However, its contribution in the brain complications of insulin resistance is still not well understood. Therefore, the aim of this study was the evaluation of redox homeostasis and oxidative damage in the hypothalamus and cerebral cortex of insulin-resistant and control rats. 16 male Wistar rats were divided into two equal groups (n = 8): the control and high fat diet group (HFD). Prooxidant enzymes (xanthine oxidase and NADPH oxidase); enzymatic and nonenzymatic antioxidants [glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase-1 (SOD-1), and uric acid (UA)]; and oxidative damage products [advanced glycation end products (AGE), 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] as well as the total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and total ferric reducing ability of sample (FRAP) were evaluated in the hypothalamus and cerebral cortex as well as serum/plasma of HFD-fed and control rats. The activity of prooxidant enzymes was significantly increased in the cerebral cortex and hypothalamus of HFD-fed rats vs. control rats. Additionally, we have showed enhanced antioxidant efficiency in the hypothalamus (?CAT, ?UA, ?TAC, and ?FRAP) and cerebral cortex (?GPx, ?CAT, ?SOD-1, ?UA, ?TAC, and ?FRAP) of HFD-fed rats. All of the oxidative damage markers (AGE, 4-HNE, MDA, 8-OHdG, and OSI) were significantly increased in the cerebral cortex of insulin-resistant rats, while only 4-HNE and MDA were markedly higher in the hypothalamus of the HFD group. Summarizing, the results of our study indicate an adaptive brain response to the increased production of free radicals under insulin resistance conditions. Despite the increase in antioxidative defense systems, this mechanism does not protect both brain structures from oxidative damages. However, the cerebral cortex is more susceptible to oxidative stress caused by HFD.

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Antioxidant Defense, Redox Homeostasis, and Oxidative Damage in Children With Ataxia Telangiectasia and Nijmegen Breakage Syndrome.

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