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Diabetes is one of the main health concerns, especially in developed countries. During the last few decades, the percentage of diabetic persons is constantly increasing. Although the genetic factors have a strong influence in the development of diabetes, environmental influence (physical inactivity, inadequate nutrition leading to obesity) also have an important impact. The main objective of this investigation was to evaluate the possible influence of organic sprouted whole wheat grain flourless bread Tonus® (product of Trivit, Becej, Serbia) on DNA damage at various stages of progression through type 2 diabetes mellitus (T2DM). In addition to control (non-diabetic) subjects we analyzed obese, pre-diabetic and diabetic patients, for a total of four experimental groups. All subjects used to eat Mediterranean diet for at least two years before being included in our study. In each of four groups we had five persons practicing the Mediterranean diet but instead of bread they consumed flourless bread Tonus®. The DNA damage was evaluated on peripheral blood mononuclear cells by alkaline single cell gel electrophoresis (Comet) assay at the very beginning (before starting the Tonus® bread diet), and after exactly the three months of consumption of Tonus® bread. Statistical analysis revealed that only in patients with type 2 diabetes, Tonus® bread intake led to decreased DNA damage compared to the level of DNA damage of these patients before they started Tonus® bread diet. We assume that decrease of body weight and hyperinsulinemia caused by Tonus® bread in the diet might be one of the main causes of decreased DNA damage.

Endocannabinoids act as a stress response system; simultaneously, the modulation of this system has emerged a novel approach for the therapy of cardiovascular disorders. We investigated the protective effects of the chronic administration of the fatty acid amide hydrolase inhibitor URB597 on morphology, pro-inflammatory and anti-inflammatory cytokine, the cytoplasm-nuclear distribution of JAK2/STAT3, and NF-κB and Nrf2/HO-1 signaling in the left ventricle of female and male rats exposed to chronic unpredictable stress. Our results show that URB597 treatment exhibits an antidepressant-like effect, decreases the heart/body weight ratio, prevents the hypertrophy of cardiomyocytes, and reduces the increased level of IL-6 in the wall of the left ventricle of stressed female and male rats. The phosphorylation levels of JAK2 and STAT3 in the ventricle of male rats treated with URB597 were declined, whereas in female rats the decrease of STAT3 was observed. In addition, URB597 reduced increased NF-κB in both females and males and increased the expression of Nrf2 and HO-1 protein in the cytosol of male rats, whereas did not affect their levels in females. Cardioprotective effects of URB597 could be linked to the ability to inhibit the JAK2 in males and the STAT3 inflammatory signaling pathways in both females and males., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The aim of this study was to investigate the effect of the cell differentiation status on the sensitivity to genotoxic insults. For this, we utilized the comet assay to test the DNA damage after treatment with 5 different substances with different mechanism of action in human promyelocytic HL60 cells with or without cell differentiation. A 4-hour MMS treatment induced a significant and concentration-dependent increase in DNA damage for both differentiated and undifferentiated cells, but the difference in sensitivity was only significant at the highest concentration. A 4-hour doxorubicin treatment did not induce DNA damage in differentiated HL60 cells, while it did in undifferentiated cells with its highest tested concentration. A one-hour etoposide treatment caused significant increase in DNA damage concentration dependently in both cell variants. This DNA damage was significantly higher in undifferentiated HL60 cells with several tested concentrations of etoposide. The treatment with the oxidizing substances hydrogen peroxide and potassium bromate yielded significant DNA damage induction in both undifferentiated and differentiated cells with no difference according to the differentiation status. Doxorubicin and etoposide are known to inhibit topoisomerase II. The activity of this enzyme has been shown to be higher in undifferentiated actively proliferating cells than in differentiated cells. This may be of relevance when exposures to topoisomerase-inhibiting compounds or the genotoxicity of compounds with unknown mechanism of action are assessed in routine testing., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Amitraz is formamidine pesticide widely used as insecticide and acaricide. In veterinary medicine, amitraz has important uses against ticks, mites and lice on animals. Also, amitraz is used in apiculture to control Varroa destructor. It this study, the alkaline Comet assay was used to evaluate DNA damaging effects of amitraz in human lymphocytes. Isolated human lymphocytes were incubated with varying concentrations of amitraz (0.035, 0.35, 3.5, 35 and 350 mu g/mL). The Comet assay demonstrated that all concentrations of amitraz caused statistically significant increase in the level of DNA damage, thus indicating that amitraz possesses genotoxic potential. The concentration of amitraz that produced the highest DNA damage (3.5 mu g/mL) was chosen for further analysis with the antioxidant catalase. The obtained results showed that co-treatment with antioxidant catalase (100 IU/mL or 500 IU/mL) significantly reduced the level of DNA damage, indicating the possible involvement of reactive oxygen species in DNA damaging effects of amitraz. Flow cytometric analysis revealed increase of the apoptotic index following treatment with amitraz. However, co-treatment with catalase reduced the apoptotic index, while treatment with catalase alone reduced the percentage of apoptotoc cells even in comparison with the negative control. Therefore, catalase had protective effects against ROS-mediated DNA damage and apoptosis.

Post-mitotic neurons are typically terminally differentiated and in a quiescent status. However, in Alzheimer disease (AD), many neurons display ectopic re-expression of cell cycle-related proteins. Cyclin-dependent kinase 11 (CDK11) mRNA produces a 110-kDa protein (CDK11(p110)) throughout the cell cycle, a 58-kDa protein (CDK11(p58)) that is specifically translated from an internal ribosome entry site and expressed only in the G(2)/M phase of the cell cycle, and a 46-kDa protein (CDK11(p46)) that is considered to be apoptosis specific. CDK11 is required for sister chromatid cohesion and the completion of mitosis. In this study, we found that the expression patterns of CDK11 vary such that cytoplasmic CDK11 is increased in AD cellular processes, compared to a pronounced nuclear expression pattern in most controls. We also investigated the effect of amyloid precursor protein (APP) on CDK11 expression in vitro by using M17 cells overexpressing wild-type APP and APP Swedish mutant phenotype and found increased CDK11 expression compared to empty vector. In addition, amyloid-β(25-35) resulted in increased CDK11 in M17 cells. These data suggest that CDK11 may play a vital role in cell cycle re-entry in AD neurons in an APP-dependent manner, thus presenting an intriguing novel function of the APP signaling pathway in AD.

Cytogenetic analysis of the X chromosome in phytohaemagglutinin stimulated peripheral blood lymphocytes was evaluated in 12 sporadic Alzheimer disease (AD) patients and in 11 healthy subjects. For chromosome analysis two methods were used: (1) standard analysis of G-banded metaphase chromosomes and; (2) fluorescent in situ hybridization (FISH) for the detection of the X chromosome centromeric region in interphase nuclei. Cytogenetic analysis revealed that the X chromosome expresses premature centromere division (PCD) in AD females in 10.53% of metaphase cells and in 15.22% of interphase nuclei. In AD men the percentages were 3.98 and 6.06%, respectively. X chromosome PCD in the female control group showed a percentage of 7.46% in metaphase cells and 9.35% in interphase nuclei and in male controls the percentages were 2.84% in metaphases and 5.54% in interphase nuclei. The results of FISH analysis showed that PCD could occur much earlier than metaphase of mitosis, i.e. in interphase of the cell cycle, immediately after replication. The FISH method can be used for PCD verification in all phases of the cell cycle in various disorders including AD.

Metabolic changes in the phenolic groups of steroidal oestrogens accompanied by the generation of quinones and reactive oxygen species underlie their mutagenic effects. Although nonsteroidal hormones and related compounds have not been thoroughly investigated for genotoxicity, some of them also contain phenolic groups that could be involved in redox cycling. Therefore, the aim of the present study was to evaluate the possible DNA damaging effects of the thyroid hormone, triiodothyronine (T3), and the neurotransmitter, noradrenaline (NA), in human lymphocytes using the Comet assay. After dose-response investigations, doses of 100 microM T3 and 550 microM of NA, producing clear DNA damaging effects and good cell viability, were chosen for further experiments with the antioxidant, catalase. Since the scavenging enzyme catalase reduced the DNA damaging effects of T3 and NA, it can be concluded that T3 and NA induced DNA damage mainly via the production of reactive oxygen species. Therefore, the mechanism of mutagenic action of both steroidal hormones and nonsteroidal compounds, T3 and NA, imply the creation of oxidative stress and subsequent DNA damage with reactive oxygen species and, possibly, with reactive hormone derivatives created during their redox cycling., (Copyright 2003 Wiley-Liss, Inc.)

Background: Epidemiologic data and animal experiments strongly implicate that steroid hormones are involved in the process of malignant transformation due to their capability to stimulate mitotic division and/or elevate the level of mutations in susceptible cells., Methods: The objectives of this investigation were to evaluate the effects of 17beta estradiol in sister-chromatid exchange (SCE) test on cultured human peripheral blood lymphocytes. The lowest concentration of 17beta estradiol used in this experiment (10(-10) M) was calculated as comparable with the physiologic blood level of 17beta estradiol in women. Three experimental concentrations corresponded to minimal (7 x 10(-8) M), average (3.5 x 10(-6) M), and maximal (7 x 10(-6) M) therapeutic doses in human medicine. In addition, the highest concentrations exceed maximal therapeutic dose 10-fold (7 x 10(-5) M) and 30-fold (2.1 x 10(-4) M), respectively., Results: The obtained results indicate that estradiol significantly elevates SCE per cell frequency at all concentrations applied except at the lowest one. However, estradiol has not influenced mitotic activity of cultured human lymphocytes significantly., Conclusions: It can be concluded that 17beta estradiol expressed genotoxic effects and therefore might represent a human health risk.