Relationship Between Anti-DFS70 Autoantibodies and Oxidative Stress

Background: The anti-DFS70 autoantibodies are one of the most commonly and widely described agent of unknown clinical significance, frequently detected in healthy individuals. It is not known whether the DFS70 autoantibodies are protective or pathogenic. One of the factors suspected of inducing the formation of anti-DFS70 antibodies is increased oxidative stress. We evaluated the coexistence of anti-DFS70 antibodies with selected markers of oxidative stress and investigated whether these antibodies could be considered as indirect markers of oxidative stress. Methods: The intensity of oxidative stress was measured in all samples via indices of free-radical damage to lipids and proteins such as total oxidant status (TOS), concentrations of lipid hydroperoxides (LPH), lipofuscin (LPS), and malondialdehyde (MDA). The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid concentration (UA), were also measured, as well as the activity of superoxide dismutase (SOD). Based on TOS and TAS values, the oxidative stress index (OSI) was calculated. All samples were also tested with indirect immunofluorescence assay (IFA) and 357 samples were selected for direct monospecific anti DFS70 enzyme-linked immunosorbent assay (ELISA) testing. Results: The anti-DFS70 antibodies were confirmed by ELISA test in 21.29% of samples. Compared with anti-DFS70 negative samples we observed 23% lower concentration of LPH (P =.038) and 11% lower concentration of UA (P =.005). TOS was 20% lower (P =.014). The activity of SOD was up to 5% higher (P =.037). The Pearson correlation showed weak negative correlation for LPH, UA, and TOS and a weak positive correlation for SOD activity. Conclusion: In samples positive for the anti-DFS70 antibody a decreased level of oxidative stress was observed, especially in the case of samples with a high antibody titer. Anti-DFS70 antibodies can be considered as an indirect marker of reduced oxidative stress or a marker indicating the recent intensification of antioxidant processes

Mitotic Slippage and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres

Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of TP53-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-MB-231 cell line treated with doxorubicin (DOX). We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle.: This work was supported by a grant from the European Regional Development Fund (ERDF) projects No. 1.1.1.2/VIAA/3/19/463 for K.S., partly from No. 1.1.1.1/18/A/099 for J.E and D.P., partly supported by the Polish National Science Center grant UMO-2015/17/B/NZ3/03531 for E.S., grant from the Ministerio de Ciencia, Innovación y Universidades of Spain (Grant: SAF2017-89791-R) for P.P., and the Natural Sciences PhD Student Scholarship from the University of Latvia Foundation to N.M.V

Structural characterization of agmatine at physiological conditions

Abstract The present work aims at determining the structure–activity relationships (SAR’s) which rule the biological function of agmatine (4-(aminobutyl)guanidinium, AGM), a biogenic amine produced by decarboxylation of arginine. Its structural preferences, both as an isolated molecule and in aqueous solution (namely at physiological conditions) were ascertained, by vibrational (Raman) spectroscopy coupled to theoretical (density functional) calculations. An evaluation of mitochondrial functions (membrane potential (??), mitochondrial swelling, and cytochrome c release) in rat liver mitochondria (RLM) was also carried out. The results thus obtained, coupled to the conformational analysis performed for the distinct polyamine protonation states, allowed to individualize the agmatine structures which interact with the mitochondrial site responsible for its transport and for the protection against mitochondrial permeability transition (MPT) induction, as well as to gain information on the specific mechanisms involved

Prevalence and loads of torquetenovirus (TTV) in the European MARK-AGE Study Population

Torquetenovirus (TTV) viremia has been associated with increased mortality risk in the elderly population. This work aims to investigate TTV viremia as a potential biomarker of immunosenescence. We compared levels of circulating TTV in 1,813 participants of the MARK-AGE project, including human models of delayed (offspring of centenarians - GO) and premature (Down syndrome - DS) immunosenescence. The TTV load was positively associated with age, CMV antibody levels and the Cu/Zn ratio, and negatively associated with platelets, total cholesterol and total IgM. TTV viremia was highest in DS and lowest in GO, with intermediate levels in the SGO (spouses of GO) and RASIG (randomly recruited age-stratified individuals from the general population) populations. In the RASIG population, TTV DNA loads showed a slight negative association with CD3+T-cells and CD4+T-cells. Finally, males with 654log TTV copies/ml had a higher risk of having a CD4/CD8 ratio<1 than those with lower viremia (OR = 2.85, 95%CI: 1.06-7.62), as well as reduced CD3+ and CD4+T-cells compared to males with lower replication rates (<4log), even after adjusting for CMV infection. In summary, differences in immune system preservation are reflected in the models of delayed and premature immunosenescence, displaying the best and worst control over TTV replication, respectively. In the general population TTV loads were negatively associated with CD4+ cell counts, with an increased predisposition for an inverted CD4/CD8 ratio for individuals with TTV loads 654log copies/ml, thus promoting an immune risk phenotype