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Diabetes patients often suffer chronic vascular complications resulting from endothelial dysfunction, smooth muscle cell (SMC) proliferation, inflammation and disturbed oxidative balance. Empagliflozin is one of three approved sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes mellitus. was to determine the protective and repairing effect of EMPA in a model of vascular endothelial and SMC damage with 25-hydroxycholesterol (25-OHC). Human umbilical vascular endothelial cells (HUVECs) and SMCs were treated with compounds which induce DNA single-strand breaks (SSBs) and subjected to comet assay. Oxidative DNA damage was detected using endonuclease III (Nth) or human 8 oxoguanine DNA glycosylase (hOOG1). Reactive oxygen species (ROS) formation was determined by the fluorescence of a 6-carboxy-2′,7′-dichlorodihydrofluoresce probe in diacetate (H 2 DCFDA). 25-OHC-stimulated SMCs showed greater resistance to ROS generation and DNA damage compared to HUVECs. In both experimental models, EMPA treatment was associated with lower ROS production and DNA damage, including oxidative damage to purines and pyrimidines. This effect was not dose-dependent. EMPA was found to counteract this DNA damage by inhibiting ROS production. It appears that the EMPA induced indirect repair of DNA by inhibiting ROS production. [Display omitted] • 25-OHC-stimulated SMCs showed greater resistance to ROS generation compared to HUVECs. • 25-OHC-stimulated SMCs showed greater resistance to DNA damage compared to HUVECs. • EMPA treatment was associated with lower oxidative damage to purines and pyrimidines. • EMPA induced indirect repair of DNA by inhibiting ROS production. [ABSTRACT FROM AUTHOR]

Abstract Glyphosate is the most heavily applied among pesticides in the world, and thus human exposure to this substance continues to increase. WHO changed classification of glyphosate to probably cancerogenic to humans, thus there is urgent need to assess in detail genotoxic mechanism of its action. We have assessed the effect of glyphosate, its formulation (Roundup 360 PLUS) and its main metabolite (aminomethylphosphonic acid, AMPA) in the concentration range from 1 to 1000 μM on DNA damage in human peripheral blood mononuclear cells (PBMCs). The cells were incubated for 24 h. The compounds studied and formulation induced DNA single and double strand-breaks and caused purines and pyrimidines oxidation. None of compounds examined was capable of creating adducts with DNA, while those substances increased ROS (including •OH) level in PBMCs. Roundup 360 PLUS caused damage to DNA even at 5 μM, while glyphosate and particularly AMPA induced DNA lesions from the concentration of 250 μM and 500 μM, respectively. DNA damage induced by glyphosate and its derivatives increased in order: AMPA, glyphosate, Roundup 360 PLUS. We may conclude that observed changes were not associated with direct interaction of xenobiotics studied with DNA, but the most probably they occurred through ROS–mediated effects. Highlights • Glyphosate, Roundup 360 PLUS and AMPA induced DNA single and double strand-breaks. • The compounds studied caused purines and pyrimidines oxidation. • Glyphosate, Roundup and AMPA increased ROS level in PBMCs. • Glyphosate and Roundup increased.•OH level in peripheral blood mononuclear cells. • The compounds examined were not capable of creating adducts with DNA. [ABSTRACT FROM AUTHOR]

Background: Atherosclerotic plaques are unstable, and their release may result in thrombosis; therefore, currently, antiplatelet therapy with anticoagulants is recommended for the treatment of acute coronary syndrome. The aim of this study was to assess the effect of oxidized cholesterol on human umbilical vascular endothelial cells (HUVECs). The study also examines the protective and repairing effect of dabigatran and rivaroxaban in a model of vascular endothelial damage with 25-hydroxycholesterol (25-OHC). Methods: HUVECs were treated with compounds induce DNA single-strand breaks (SSBs) using the comet assay. Oxidative DNA damage was detected using endonuclease III (Nth) or human 8 oxoguanine DNA glycosylase (hOOG1). Reactive oxygen species (ROS) formation was determined using flow cytometry. Results: 25-hydroxycholesterol caused DNA SSBs, induced oxidative damage and increased ROS in the HUVECs; ROS level was lowered by dabigatran and rivaroxaban. Only dabigatran was able to completely repair the DNA SSBs induced by oxysterol. Dabigatran was able to reduce the level of oxidative damage of pyrimidines induced by oxysterol to the level of control cells. Conclusions: Observed changes strongly suggest that the tested anticoagulants induced indirect repair of DNA by inhibiting ROS production. Furthermore, dabigatran appears to have a higher antioxidant activity than rivaroxaban. [ABSTRACT FROM AUTHOR]

Brominated flame retardants (BFRs) are the compounds used in the industry in order to decrease flammability of various everyday products. The use of BFRs leads to migration of these substances into the environment, which results in the exposure of humans to their action. Although BFRs are widespread in human surrounding, the effect of these compounds on human body has been very poorly assessed. The purpose of this study was to evaluate cytotoxic effects as well as oxidative potential of selected bromophenolic flame retardants such as tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), 2,4,6-tribromophenol (2,4,6-TBP) and pentabromophenol (PBP) on human peripheral blood mononuclear cells (PBMCs) that are crucial for proper functioning of the immune system. The cells were treated with the substances studied in the concentrations ranging from 0.0001 to 100 μg/mL for 1 h or 24 h. The results have shown that the compounds examined reduced PBMCs viability and ATP level as well as increased reactive oxygen species (including hydroxyl radical) formation. Moreover, the substances tested induced lipid peroxidation and caused oxidative damage to proteins in the incubated cells. It has also been noticed that the greatest changes were provoked by tetrabromobisphenol A, while the weakest by TBBPS, which is used as a substitute of TBBPA in the manufacture. • Cytotoxic and oxidative effects of selected bromophenolic FRs on human PBMCs were studied. • TBBPA, TBBPS, 2,4,6-TBP and PBP exhibited cytotoxic and oxidative potential in PBMCs. • BFRs examined decreased cell viability and depleted intracellular ATP level. • BFRs studied increased ROS level and caused damage to lipids and proteins in PBMCs. • The greatest changes were noted for TBBPA, whereas the weakest for TBBPS. [ABSTRACT FROM AUTHOR]

• Statins regulate ROS and NO synthesis through microRNA expression. • Ezetimibe inhibits ROS synthesis and limits apoptosis through Akt/GSK-3β pathway. • DKK-1 is a potentially new metabolic target for statin atherosclerosis treatment. • Statins inhibit NLRP3 Inflammasome by PXR receptor activation in HUVECs. • Statins improve diabetic vasculopathy by ERK5-Nrf2 pathway stimulation. Statin therapy is the gold standard in the treatment of dyslipidemia. Understanding the mechanisms of action of these drugs provides an opportunity to define new therapeutic goals for pharmacotherapy in patients with atherosclerotic lesions. The present review indicates the existence of previously unknown therapeutic targets for statins, such as Krüppel-like Factor 2 (KLF-2), Cystathionine γ lyase (CSE) and the microRNA regulating eNOS activity and synthesis; nuclear PXR receptor and EB transcription factor regulating Inflammasome NLRP3 activity; the Dickkopf-related protein 1 (DKK-1), which inhibits the WNT signalling pathway; the peroxisome proliferator-activated receptor (PPAR-γ) in vascular smooth muscle cells (VSMCs), which regulates the cell cycle, and the ERK5-Nrf2 pathway, which reduces the level of harmful advanced glycation end-products (AGE) in VSMCs during diabetic vasculopathy. Importantly, our review includes a number of promising discoveries, specifically those related to the effects of miR-221, miR-222 and miR-27b on the structure, synthesis and activity of eNOS, such as microRNA-based therapies, which offer promise in future targeted therapies. In contrast to numerous experiments confirming the pleiotropic effect of statins, there is still insufficient evidence on the pleiotropic effect of ezetimibe, which goes beyond its basic inhibitory effect on intestinal cholesterol absorption. However, recent studies indicate that this effect is limited to inhibiting macrophage migration, decreasing VCAM-1 expression and reducing the levels of reactive oxygen species. Defining new therapeutic goals for pharmacotherapy in patients with atherosclerotic lesions and ensuring effective treatment of dyslipidemia and its associated cardiovascular complications requires a thorough understanding of both the mechanisms of action of these drugs and of atherosclerosis itself. [ABSTRACT FROM AUTHOR]