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Oxidative damage to DNA and antioxidant status in aging and age-related diseases

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Olinski R., Siomek A., Rozalski R., Gackowski D., Foksinski M., Guz J., Dziaman T., Szpila A., Tudek B.

2007

vol. 54

issue 1

11-26

Aging is a complex process involving morphologic and biochemical changes in single cells and in the whole organism. One of the most popular explanations of how aging occurs at the molecular level is the oxidative stress hypothesis. Oxidative stress leads in many cases to an age-dependent increase in the cellular level of oxidatively modified macromolecules including DNA, and it is this increase which has been linked to various pathological conditions, such as aging, carcinogenesis, neurodegenerative and cardiovascular diseases. It is, however, possible that a number of short-comings associated with gaps in our knowledge may be responsible for the failure to produce definite results when applied to understanding the role of DNA damage in aging and age-related diseases.

Cu,Zn-superoxide dismutase deficiency in mice leads to organ-specific increase in oxidatively damaged DNA and NF-κB1 protein activity

81%

Siomek A., Brzoska K., Sochanowicz B., Gackowski D., Rozalski R., Foksinski M., Zarakowska E., Szpila A., Guz J., Bartlomiejczyk T., Kalinowski B., Kruszewski M., Olinski R.

2010

vol. 57

issue 4

577-583

Earlier experimental studies have demonstrated that: i) Cu,Zn-superoxide dismutase deficiency leads to oxidative stress and carcinogenesis; ii) dysregulation of NF-κB pathway can mediate a wide variety of diseases, including cancer. Therefore, we decided, for the first time, to examine the level of oxidative DNA damage and the DNA binding activity of NF-κB proteins in SOD1 knockout, heterozygous and wild-type mice. Two kinds of biomarkers of oxidatively damaged DNA: urinary excretion of 8-oxodG and 8-oxoGua, and the level of oxidatively damaged DNA were analysed using HPLC-GC-MS and HPLC-EC. The DNA binding activity of p50 and p65 proteins in a nuclear extracts was assessed using NF-κB p50/p65 EZ-TFA transcription factor assay. These parameters were determined in the brain, liver, kidney and urine of SOD1 knockout, heterozygous and wild-type mice. The level of 8-oxodG in DNA was higher in the liver and kidney of knockout mice than in wild type. No differences were found in urinary excretion of 8-oxoGua and 8-oxodG between wild type and the SOD1-deficient animals. The activity of the p50 protein was higher in the kidneys, but surprisingly not in the livers of SOD1-deficient mice, whereas p65 activity did not show any variability. Our results indicate that in Cu,Zn-SOD-deficient animals the level of oxidative DNA damage and NF-κB1 activity are elevated in certain organs only, which may provide some explanation for organ-specific ROS-induced carcinogenesis.

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2 Acta Biochimica Polonica

1 2010

1 2007

2 Foksinski M.

2 Gackowski D.

2 Guz J.

2 Olinski R.

2 Rozalski R.

2 Siomek A.

2 Szpila A.

1 Bartlomiejczyk T.

1 Brzoska K.

1 Dziaman T.

1 Kalinowski B.

1 Kruszewski M.

1 Sochanowicz B.

1 Tudek B.

1 Zarakowska E.

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Oxidative damage to DNA and antioxidant status in aging and age-related diseases

Cu,Zn-superoxide dismutase deficiency in mice leads to organ-specific increase in oxidatively damaged DNA and NF-κB1 protein activity