DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

Selenium concentration and cardiovascular disease risk: Mendelian randomization study

Abstract Background/Introduction Selenium has been associated with cardiovascular disease (CVD) risk in observational studies; however, the causality of the association remains unestablished. Purpose To examine the associations of selenium concentrations with 15 CVDs using Mendelian randomization analysis. Methods Genetic variants significantly associated with concentrations of toenail and blood (TAB) and blood selenium in mild linkage disequilibrium (r2 &amp;lt;0.3) were used as instrumental variables. Summary-level data for 15 CVDs were obtained from the UK Biobank study (n=367,561), FinnGen study (n=218,792), and six international consortia. The inverse variance weighted method accounting for linkage disequilibrium was used to estimate the associations. Results for one outcome from different sources were combined using the fixed effect meta-analysis method. Bonferroni correction was used to account for multiple testing, and associations with P value ≤0.003 (0.05 / 15 outcomes) were described as significant. Associations with P value between ≤0.05 and &amp;gt;0.003 were regarded as suggestive associations. Results Genetically predicted concentrations of TAB selenium were not significantly associated with the risk of the 15 CVDs. However, there were suggestive associations of genetically predicted higher concentrations of TAB selenium with increased risk of atrial fibrillation and peripheral artery disease. The odds ratio per one-unit increase in log-transformed concentrations of TAB selenium was 1.07 (95% confidence interval, 1.01–1.12; P=0.019) for atrial fibrillation and 1.20 (95% confidence interval, 1.05–1.38; P=0.008) for peripheral artery disease. We observed no associations between genetically predicted blood selenium concentrations and risk of the 15 CVDs. Conclusions Genetically predicted higher concentrations of TAB or blood selenium were not associated with a lower risk of CVD, which suggests that high selenium status may not prevent CVD development. The suggestive positive associations of TAB selenium with atrial fibrillation and peripheral artery disease warrants verification. Funding Acknowledgement Type of funding sources: None. </jats:sec

Biosynthesis of selenoproteins in cultured bovine mammary cells.

The biosynthesis of selenoproteins was studied in relation to milk formation and mammary cell biology by incubating the bovine mammary cell line MAC-T with (75Se)selenite. Intracellular proteins and proteins secreted into the cell culture medium were separated by 2D electrophoresis, the selenoproteins were detected by autoradiography, and the proteins were identified by MALDI-TOF. Approximately 35 75Se-containing spots were found in the cell proteins from MAC-T cells. Among them, one-third showed high intensity. The strongest spot was identified as glutathione peroxidase 1. About 20 spots were observed in protein precipitated from cell culture medium, one-third of them being distinctly visible. In an attempt to study a perturbation of the system, the effect of retinoic acid (RA) on the formation of selenoproteins was investigated. The concentration of 75Se in total cell protein was reduced by about 35% in cells cultured with RA compared with control cells, while the opposite effect was observed in protein precipitated from cell culture medium, which contained 60% more 75Se in RA-treated samples than in controls. There were also indications that RA might affect different selenoproteins in different ways. The methods described provide a promising approach for further studies of the regulation of selenoprotein formation in the mammary gland