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Heterozygous familial hypercholesterolemia (HeFH) is a common autosomal-dominant inherited disorder associated with atherosclerotic cardiovascular disease (ASCVD). HeFH subjects have a higher lipoprotein(a), i.e. Lp(a), concentration than the general population. Patients with FH are exposed to elevated levels of LDL from birth and ox-LDL may induce other oxidation pathways. The aim of the study was to determine the levels of markers of oxidative stress and DNA damage in patients with HeFH and describe the effect of Lp(a) on the resulting damage. Higher DNA damage was identified in patients with HeFH compared to the normolipidemic ones, and ASCVD was associated with greater damage. Oxidative stress markers were elevated in HeFH patients; however, only ox-LDL was higher in the ASCVD group and its level correlated with DNA damage. A positive correlation was found between DNA damage and Lp(a) concentration in the HeFH patients. Higher levels of Lp(a) were associated with greater DNA damage, especially in patients with HeFH and ASCVD. In HeFH patients, the optimal Lp(a) cut-off point associated with ASCVD is > 23.45 nmol/L, i.e. much lower than for the general population; however this cut-off point needs validation in a larger group of HeFH patients. [ABSTRACT FROM AUTHOR]

Under physiological conditions, skin mast cells play an important role as guardians that quickly react to stimuli that disturb homeostasis. These cells efficiently support, fight infection, and heal the injured tissue. The substances secreted by mast cells allow for communication inside the body, including the immune, nervous, and blood systems. Pathologically non-cancerous mast cells participate in allergic processes but also may promote the development of autoinflammatory or neoplastic disease. In this article, we review the current literature regarding the role of mast cells in autoinflammatory, allergic, neoplastic skin disease, as well as the importance of these cells in systemic diseases with a pronounced course with skin symptoms. [ABSTRACT FROM AUTHOR]

Atherosclerosis and cardiovascular events can be prevented, or treated, using statin therapy, either alone or in combination with ezetimibe. Chronic inflammation, vascular proliferation, and the development of atherosclerosis are also influenced by 25-hydroxycholesterol (25-OHC). The aim of the study was to compare the direct pleiotropic effects of two commonly-used statins (atorvastatin, rosuvastatin), ezetimibe, and their combinations, on the mRNA expression of pro-inflammatory IL1β, IL-18 and IL-23 and anti-inflammatory TGFβ, IL-35 (EBI3, IL-12 subunits), IL-10 and IL-37, in endothelial cells damaged by 25-OHC. It also analyzed IL-35 expression at the protein level. HUVECs were stimulated with atorvastatin (5 μM), rosuvastatin (10 μM), ezetimibe (1.22 μM), atorvastatin-ezetimibe (5 μM + 1.22 μM) or rosuvastatin-ezetimibe (10 μM + 1.22 μM), with or without pre-incubation with 10 μg/mL 25-OHC. mRNA expression was analyzed by real-time PCR. The protein level of IL-35 was analyzed by ELISA. In the pre-stimulated HUVECs, atorvastatin and rosuvastatin decreased mRNA expression of IL1β, IL-18, IL-23, TGFβ, IL35 and increased mRNA expression of IL-10 and IL-37 compared to 25-OHC. Furthermore, only incubation with rosuvastatin and rosuvastatin-ezetimibe decreased IL-35 mRNA and protein levels. Ezetimibe down-regulated only IL1β. Treatment with rosuvastatin-ezetimibe and atorvastatin-ezetimibe reversed the effect of 25-OHC in IL1β, IL-18 and IL-35 mRNA expression. In conclusion, rosuvastatin has the strongest anti-inflammatory effects and is the best at reducing the effect of oxysterols. Both statins exert a greater anti-inflammatory effect than ezetimibe. The anti-inflammatory effect of the combination therapies appears to be based on the effects of the statins alone and not their combination with ezetimibe. [ABSTRACT FROM AUTHOR]

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]

Introduction: Fish tank granuloma is a rare dermatitis caused by Mycobacterium marinum. Infection occurs through contact of damaged skin with water or aquatic animals infected with these bacteria. Aim: It is likely that skin infection caused by M. marinum transmitted from Clarias gariepinus has as yet not been reported in literature. Our case report is presumably the first publication. Dermatoscopy as a useful method in the diagnosis of skin infections caused by atypical mycobacteria. Our article presents new dermatoscopic features of fish tank granuloma. Casestudy: The case report applies to a 30-year old, white, Caucasian man referred because of a single, well-demarcated plaque measuring 2 × 4 cm, localized on third finger on left hand above proximal phalanx, without subjective symptoms. The diagnosis was confirmed by medical history, dermoscopy and histopathological examination. Patient was successfully treated with sulfamethoxazole and trimethoprim. Results and discussion: Due to the fact that M. marinum infection is uncommon, in case of clinical suspicion it is necessary to perform skin biopsy, culture and tissue PCR analysis. Knowledge about the opportunities and limitations of theses laboratory tests is pivotal to reasonable clinical decision-making. Conclusions: Dermoscopy is useful to make a diagnosis, but there are still too few accounts in literature. The correct diagnosis determines the effective treatment. [ABSTRACT FROM AUTHOR]

Hodgkin's lymphoma (HL) belongs to the most radiosensitive and chemosensitive cancers. Combined modality therapy is the preferred treatment for patients with classical favorable early-stage HL. However, late toxicity still remains an issue. A modern approach in HL radiotherapy includes implementation of sophisticated and dedicated delivery techniques together with the lower doses and smaller fields, which allow for reduction of early and late toxicity. In recent years, the question on the need for complementary radiotherapy in the early stages of Hodgkin's lymphoma has been increasingly raised. The aim of the present review is to discuss the current role of radiotherapy and its potential future developments, with a focus on major clinical trials. [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]

Wstęp: Główną przyczyną umieralności w Polsce są choroby układu sercowo-naczyniowego. W patogenezie miażdżycy początkiem są zaburzenia funkcji śródbłonka naczyniowego, związane między innymi ze zwiększeniem ekspresji genów odpowiedzialnych za odkładanie się złogów w ścianie naczyń. W konsekwencji dochodzi do nasilenia reakcji wolnorodnikowych, a uwolnienie niestabilnej blaszki miażdżycowej może skutkować zakrzepicą, dlatego obecnie w leczeniu ostrego zespołu wieńcowego zaleca się terapię przeciwpłytkową. Cel: Celem badania była ocena właściwości plejotropowych związanych z działaniem antyoksydacyjnym nowoczesnych terapii przeciwpłytkowych - dabigatranu i rywaroksabanu w modelu uszkodzenia komórek śródbłonka naczyniowego żyły pępowinowej (human umbilical vein endothelial cells; HUVEC) utlenionym cholesterolem - 25 hydroksycholesterolu (25-OHC). Materiały i metody: Pęknięcia jedno- i dwuniciowe DNA oceniono przy użyciu wersji alkalicznej testu kometowego. Uszkodzenie oksydacyjne puryn i pirymidyn oceniono przy użyciu alkalicznej wersji testu kometowego z wykorzystaniem enzymów naprawczych: endonukleazy III (Nth) i ludzkiej 8-oksoguaninowej glikozylazy DNA (hOOG1). Generowanie reaktywnych form tlenu (RFT) określono za pomocą cytometrii przepływowej z wykorzystaniem sondy DCF. Wyniki: 25-hydroksycholesterol indukował pęknięcia jedno- i dwuniciowe DNA, w tym oksydacyjne uszkodzenia puryn i pirymidyn oraz zwiększał poziom RFT w HUVEC. Poziom RFT został obniżony zarówno przez dabigatran, jak i riwaroksaban. Natomiast tylko działanie dabigatranu było związane z całkowitą naprawą uszkodzeń DNA indukowanych przez oksysterol. Dabigatran zredukował poziom uszkodzeń oksydacyjnych pirymidyn indukowanych przez oksysterol do poziomu komórek kontrolnych. Podsumowanie: Wyniki niniejszego badania wskazują, że badane antykoagulanty indukowały pośrednią naprawę DNA poprzez hamowanie produkcji RFT. Ponadto wydaje się, że dabigatran ma wyższą aktywność przeciwutleniającą niż rywaroksaban. [ABSTRACT FROM AUTHOR]

SGLT2 (Sodium-glucose Cotransporter-2) inhibitors are newer glucose-lowering drugs with many cardiovascular benefits that are not fully understood yet. Endothelial integrity plays a key role in cardiovascular homeostasis. 25-hydroxycholesterol (25-OHC), which is a proatherogenic stimuli that impairs endothelial barrier functions. VE-cadherin is an endothelial-specific protein crucial in maintaining endothelial integrity. The aim of this study was to assess the influence of SGLT2i on the integrity of endothelial cells interrupted by 25-OHC. We also aimed to evaluate whether this effect is associated with changes in the levels of VE-cadherin. We pre-incubated HUVECs with 10 μg/mL of 25-hydroxycholesterol (25-OHC) for 4 h and then removed it and incubated endothelial cells with 1 μM of empagliflozin, 1 μM canagliflozin, or 1 μM dapagliflozin for 24 h. The control group included HUVECs cultured with the medium or with 25-OHC 10 μg/mL. The integrity of endothelial cells was measured by the RTCA-DP xCELLigence system, and VE-cadherin was assessed in confocal microscopy. Our results show that SGLT2 inhibitors significantly increase endothelial integrity in comparison to medium controls, and they improve endothelial cell integrity interrupted by 25-OHC. This effect is associated with significant improvements in VE-cadherin levels. SGLT2i: empagliflozin, canagliflozin, and dapagliflozin have a beneficial effect on the endothelial cell integrity and VE-cadherin levels reduced by 25-OHC. [ABSTRACT FROM AUTHOR]

Psoriasis vulgaris is a common inflammatory skin disease with still unknown pathogenesis. In recent years, genetic and environmental factors have been mentioned as the main causes. Among environmental factors, many researchers are trying to investigate the role of mental health and its importance in the development of many diseases. In the pathophysiology of psoriasis, the role of the interaction between the nervous, endocrine, and immune systems are often emphasized. So far, no one has clearly indicated where the pathological process begins. One of the hypotheses is that chronic stress influences the formation of hormonal changes (lowering the systemic cortisol level), which favors the processes of autoimmunity. In inflammatory skin conditions, mast cells (MCs) are localized close to blood vessels and peripheral nerves, where they probably play an important role in the response to environmental stimuli and emotional stress. They are usually connected with a fast immune response, not only in allergies but also a protective response to microbial antigens. Among many cells of the immune system, MCs have receptors for the hormones of the hypothalamic–pituitary–adrenal (HPA) axis on their surface. In this review, we will try to take a closer look at the role of MCs in the pathophysiology of psoriasis. This knowledge may give the opportunity to search for therapeutic solutions. [ABSTRACT FROM AUTHOR]

We have determined the effect of glyphosate and aminomethylphosphonic acid (AMPA) on expression of genes involved in chromatin architecture in human peripheral blood mononuclear cells (PBMCs). The cells were incubated with glyphosate and AMPA in the concentrations ranging from 0.5 to 100 μM and from 0.5, to 250 μM, respectively. The expression profile of the following genes by quantitative Real-Time PCR was evaluated: Genes involved in the DNA methylation (DNMT1, DNMT3A) and DNA demethylation process (TET3) and those involved in chromatin remodeling: genes involved in the modification of histone methylation (EHMT1, EHMT2) and genes involved in the modification of histone deacetylation (HDAC3, HDAC5). Gene profiling showed that glyphosate changed the expression of DNMT1, DMNT3A, and HDAC3, while AMPA changed the expression of DNMT1 and HDAC3. The results also revealed that glyphosate at lower concentrations than AMPA upregulated the expression of the tested genes. Both compounds studied altered expression of genes, which are characteristic for the regulation of transcriptionally inactive chromatin. However, the unknown activity of many other proteins involved in chromatin structure regulation prevents to carry out an unambiguous evaluation of the effect of tested xenobiotics on the studied process. Undoubtedly, we have observed that glyphosate and AMPA affect epigenetic processes that regulate chromatin architecture. [ABSTRACT FROM AUTHOR]

Aminomethylphosphonic acid (AMPA) is a primary metabolite of glyphosate and amino-polyphosphonate. We have determined the effect of AMPA on selected epigenetic parameters and major cell cycle drivers in human peripheral blood mononuclear cells (PBMCs). The cells were incubated with AMPA at 0.5, 10 and 250 μM for 24 h. The performed analysis included: global DNA methylation by colorimetric measurement of 5-methylcytosine in DNA, methylation in the promoter regions of selected tumor suppressor genes (P16, P21, TP53) and proto-oncogenes (BCL2, CCND1) as well as the expression profile of the indicated genes by Real-Time PCR assays. The obtained results have revealed significant reduction of global DNA methylation level in PBMCs exposed to AMPA. Investigated xenobiotic changed methylation pattern of the P21 and TP53 suppressor gene promoters, but in case of other analyzed genes: P16, BCL2 and CCND1 no statistically significant changes have been noted. Gene profiling have shown that AMPA only changed the expression of CCND1. Summing up, our results have revealed a small potential disturbance in methylation processes and the absence of changes in expression of tested tumor suppressor genes (P16, P21, TP53) and protooncogenes (BCL2) in human PBMCs exposed to AMPA. Unlabelled Image • AMPA induced significant reduction of global DNA methylation level in human PBMCs. • AMPA altered methylation pattern of the P21 and TP53 gene promoters. • AMPA increased the expression of CCND1. • AMPA did not change the expression of tumor suppressor genes (P16, P21, TP53) and protooncogenes (BCL2). [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]

We have determined the effect of glyphosate on selected epigenetic parameters and major cell cycle drivers in human peripheral blood mononuclear cells (PBMCs). The cells were incubated with glyphosate at 0.5, 10 and 100 μM. The analysis included: global DNA methylation, methylation in the promoter regions of tumor suppressor genes (P16 , P21 , TP53) and proto-oncogenes (BCL2 , CCND1) by the Real-Time PCR and the expression profile of the indicated genes by Real-Time PCR. The obtained results have revealed significant reduction of global DNA methylation level in PBMCs exposed to glyphosate. Tested compound changed methylation pattern of the P21 and TP53 suppressor gene promoters, but in case of other analyzed genes: P16 , BCL2 and CCND1 we did not identify any statistically significant changes. Gene profiling showed that glyphosate changed the expression of genes involved in the regulation of cell cycle and apoptosis. Glyphosate decreased expression of P16 and TP53 as well as an increase in the expression of BCl2 , CCND1 and P21. Summing up, our results have shown a potential disturbance in methylation processes and gene expression in human PBMCs exposed to glyphosate, but the observed changes do not prejudge about the final metabolic effects, which are depended on many other factors. Unlabelled Image • Glyphosate significant reduction of global DNA methylation level in human PBMCs. • Glyphosate changes methylation pattern of the P21 and TP53 gene promoters. • Glyphosate changes the expression genes involved in regulation of cell cycle (CCND1 , P16 , P21 and TP53) and apoptosis (BCL2). [ABSTRACT FROM AUTHOR]

Atherosclerosis is associated with a haemostatic imbalance characterized by excessive activation of pro‐inflammatory and pro‐coagulant pathways. Non‐vitamin K antagonists oral anticoagulant (NOACs) may reduce the incidence of cardiovascular events, cerebral ischemia, thromboembolic events and atherosclerosis. Chronic inflammation, vascular proliferation and the development of atherosclerosis is also influenced by 25‐hydroxycholesterol (25‐OHC). The aim of the study was to assess the effect of rivaroxaban and dabigatran on the messenger RNA (mRNA) expression of anti‐inflammatory cytokines transforming growth factor β (TGF‐β), interleukin (IL)‐37, IL‐35 as well as of pro‐inflammatory cytokines IL‐18 and IL‐23, in endothelial cells damaged by 25‐OHC. Human umbilical vascular endothelial cells (HUVECs) were treated with 25‐OHC (10 μg/mL), rivaroxaban (100, 500 ng/mL), dabigatran (100, 500 ng/mL), 25‐OHC + rivaroxaban, and 25‐OHC + dabigatran. The mRNA expression of TGF‐β, IL‐37, IL‐35 subunits EBI3 and p35, IL‐18, and IL‐23 was analysed using real‐time polymerase chain reaction (PCR). The results showed that 25‐OHC decreased TGF‐β and IL‐37 mRNA expression and increased EBI3, p35, IL‐18, IL‐23 mRNA expression in endothelial cell as compared to an untreated control (P <.05). Messenger RNA expression of TGF‐β and IL‐37 significantly increased following stimulation with rivaroxaban and dabigatran as compared to an untreated control (P <.01). In HUVECs pre‐treated with oxysterol, rivaroxaban and dabigatran increased mRNA expression of TGF‐β, IL‐37 and decreased mRNA expression of EBI3, p35, IL‐23 and IL‐18 as compared to 25‐OHC (P <.01). Our finding suggests that both rivaroxaban and dabigatran inhibit the inflammatory activation caused by oxysterol in vitro. [ABSTRACT FROM AUTHOR]

Wstęp: Obecne podejście do leczenia cukrzycy nie koncentruje się już tylko na obniżeniu poziomu glukozy, ale również na plejotropowych działaniach leków hipoglikemizujących, które istotnie poprawiają rokowanie pacjentów chorujących na cukrzycę. Flozyny to leki hipoglikemizujące, które zmniejszają ryzyko zgonu z przyczyn sercowo-naczyniowych u pacjentów z cukrzycą typu II. Tak ogromne korzyści nie mogą wynikać tylko z obniżenia poziomu glukozy we krwi, a dokładny mechanizm nie jest w pełni poznany. W naszym badaniu chcemy lepiej poznać mechanizmy ateroprotekcyjne tych leków. Cel: Badanie ma na celu porównanie wpływu trzech inhibitorów SGLT2 (empagliflozyny, kanagliflozyny, dapagliflozyny) na wybrane parametry biorące udział w patogenezie miażdżycy. Materiały i Metody: Badanie zostało wykonane w modelu komórkowym in vitro. Komórki śródbłonka (HUVECs) były preinkubowane z 25-hydroksycholesterolem przez 4 godziny. Następnie, po usunięciu 25-hydroksycholesterolu komórki zostały poddane 24-godzinnej inkubacji z empagliflozyną (1 μM), kanagliflozyną (1 μM) lub dapagliflozyną (1 μM). Następnie została oceniona integralność komórek śródbłonka w systemie xCELLigence i ekspresja mRNA IL-6 i MCP-1. Wyniki: 25-hydroksycholesterol istotnie obniżył integralność komórek śródbłonka i zwiększył ekspresję mRNA IL-6 i MCP-1 w porównaniu z pożywką kontrolną. Następująca inkubacja komórek HUVEC z empagliflozyną (1 μM), kanagliflozyną (1 μM) lub dapagliflozyną (1 μM) znacząco złagodziła szkodliwy wpływ 25-hydroksycholesterolu na integralność bariery śródbłonkowej po 24 godzinach w systemie xCELLigence. Inkubacja komórek z inhibitorami SGLT2 spowodowała obniżenie ekspresji mRNA IL-6 i MCP-1 w real-time PCR w porównaniu do 25-hydroksycholesterolu. Podsumowanie: 25-hydroksycholesterol upośledza funkcje barierowe komórek śródbłonka i wywołuje w nich odpowiedź zapalną. Inhibitory SGLT2 wykazują działanie ateroprotekcyjne, które polega na poprawianiu funkcji barierowych komórek śródbłonka uszkodzonych przez 25-hydroksycholesterol wraz z towarzyszącym łagodzeniem odpowiedzi zapalnej. [ABSTRACT FROM AUTHOR]

Patients with diabetes are at higher risk of cardiovascular diseases and cognitive impairment. SGLT2 inhibitors (Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin, Sotagliflozin) are newer hypoglycemic agents with many pleiotropic effects. In this review, we discuss their neuroprotective potential. SGLT2 inhibitors (SGLT2i) are lipid-soluble and reach the brain/serum ratio from 0.3 to 0.5. SGLT receptors are present in the central nervous system (CNS). Flozins are not fully SGLT2-selective and have an affinity for the SGLT1 receptor, which is associated with protection against ischemia/reperfusion brain damage. SGLT2i show an anti-inflammatory and anti-atherosclerotic effect, including reduction of proinflammatory cytokines, M2 macrophage polarization, JAK2/STAT1 and NLRP3 inflammasome inhibition, as well as cIMT regression. They also mitigate oxidative stress. SGLT2i improve endothelial function, prevent remodeling and exert a protective effect on the neurovascular unit, blood-brain barrier, pericytes, astrocytes, microglia, and oligodendrocytes. Flozins are also able to inhibit AChE, which contributes to cognitive improvement. Empagliflozin significantly increases the level of cerebral BDNF, which modulates neurotransmission and ensures growth, survival, and plasticity of neurons. Moreover, they may be able to restore the circadian rhythm of mTOR activation, which is quite a novel finding in the field of research on metabolic diseases and cognitive impairment. SGLT2i have a great potential to protect against atherosclerosis and cognitive impairment in patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Dyslipidemia, atherosclerosis, and cardiovascular events can be prevented, or treated, using statins, alone or in combination with ezetimibe. The aim of the study was to compare the direct pleiotropic effects of two commonly-used statins (atorvastatin, rosuvastatin), ezetimibe and their combinations on endothelial cells damaged by oxidized cholesterol. HUVEC cultures were stimulated for 20 hours with atorvastatin (5 μM; 2793 ng/mL), rosuvastatin (10 μM; 4815 ng/mL), ezetimibe (1.22 μM; 500 ng/mL), atorvastatin plus ezetimibe (5 μM + 1.22 μM; 2793 ng/mL + 500 ng/mL) and rosuvastatin plus ezetimibe (10 μM + 1.22 μM; 4815 ng/mL + 500ng/mL) in separate groups, with or without 25-hydroxycholesterol pre-incubation (24.83 μM; 10 μg/mL; four hours then washout). HUVEC integrity was measured in the RTCA-DP xCELLigence system. The mRNA expression and protein levels of ZO-1, OCLN, ICAM-1 were analyzed by real-time PCR and ELISA. Pre-incubation with 25-OHC resulted in decreased endothelial cell integrity (p<0.001), decreased expression of ZO-1 mRNA (p<0.05) and protein levels (p<0.05), OCLN mRNA (p<0.05) and protein levels (p<0.05) and increased ICAM-1 mRNA (p<0.001) and protein levels (p<0.001) compared to the control group. Incubation with rosuvastatin (12h p<0.01; 24h p<0.001) and atorvastatin (only 12h p<0.05) restored HUVEC integrity. Subsequent incubation with rosuvastatin increased ZO-1 mRNA (p<0.001) and protein (p<0.001) levels. Subsequent addition of ezetimibe increased ZO-1 mRNA level (p<0.001) but not protein level. Furthermore, only incubation with rosuvastatin increased OCLN mRNA (p<0.05) and protein (p<0.05) levels. In each drug-stimulated group, both ICAM-1 mRNA and protein levels were reduced after initial incubation with oxysterol (p<0.05). 25-hydroxycholesterol disrupts endothelial integrity, decreases the mRNA and protein levels of tight junction, and increases those of intercellular adhesion molecules. Both rosuvastatin and atorvastatin can improve endothelial integrity, but only rosuvastatin can completely abolish the effect of oxysterol. The combination of statins with ezetimibe has less direct effect on the endothelial barrier than the statins alone. [ABSTRACT FROM AUTHOR]

Statins, also known as HMG-CoA reductase inhibitors, are one of the most potently prescribed and thoroughly researched medications, predominantly utilized for managing cardiovascular diseases by modulating serum cholesterol levels. Despite the well-documented efficacy of statins in reducing overall mortality via attenuating the risk of cardiovascular diseases, notable interindividual variability in therapeutic responses persists as such variability could compromise the lipid-lowering efficacy of the drug, potentially increasing susceptibility to adverse effects or attenuating therapeutic outcomes.This phenomenon has catalysed a growing interest in the scientific community to explore common genetic polymorphisms within genes that encode for pivotal enzymes within the pharmacokinetic pathways of statins. In our review, we focus to provide insight into potentially clinically relevant polymorphisms associated with statins' pharmacokinetic participants and assess their consequent implications on modulating the therapeutic outcomes of statins among distinct genetic carrier • Statins pharmacokinetics involves several superfamilies of enzymes such as CYP, UGT, SLCO, ABC. • Numerous polymorphisms within genes encoding CYP, UGT, SLCO, ABC have been studied for their impact on altering statins efficacy. • Our Review provides aninsight into modulatory effect of gene polymorphisms on lipid-lowering effect of statins. [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]

Wstęp: Heterozygotyczna hipercholesterolemia rodzinna (heterozygous familial hypercholesterolemia; HeFH) charakteryzuje się podwyższonym poziomem cholesterolu lipoprotein o niskiej gęstości (LDL-C), zwiększającym ryzyko chorób sercowo-naczyniowych. Pacjenci z HeFH, stanowią szczególną grupę chorych, u których osiągnięcie pożądanych wartości LDL-C za pomocą standardowych schematów leczenia nie jest możliwe. Inhibitory PCSK9 (PCSK9i) stanowią nową alternatywę w intensyfikacji leczenia hipolipemizującego. Cel: Celem badań było określenie poziomu uszkodzeń DNA w jednojądrzastych komórkach krwi obwodowej pacjentów z HeFH, a także potencjalnego wpływu PCSK9i na zmniejszenie powstałych uszkodzeń. Materiały i Metody: Materiałem do badań były jednojądrzaste komórki krwi obwodowej pobranej od pacjentów z HeFH (n=16), którzy zostali zakwalifikowani do programu leczenia PCSK9i (ICD-10 E78.01, I21, I22, I25). Poziom uszkodzeń jedno-i dwuniciowych DNA został oznaczony za pomocą wersji alkalicznej testu kometowego, zarówno przed leczeniem, jak i po 6 miesiącach terapii PCSK9i. Grupą kontrolną stanowili pacjenci z normolipidemią (n=7), nie poddani terapii hipolipemizującej. Wyniki/Dyskusja/Podsumowanie: Pacjenci z HeFH charakteryzują się występowaniem uszkodzeń DNA. Otrzymane wyniki sugerują, że stosowanie PCSK9i w tej grupie chorych zmniejsza poziom uszkodzeń DNA, w porównaniu z poziomem uszkodzeń DNA przed włączeniem terapii hipolipemizującej, ale nie do poziomu uszkodzeń DNA zaobserwowanych w grupie pacjentów z normolipidemią. Dlatego też, niezbędne wydają się być dalsze badania wyjaśniające mechanizm wpływu PCSK9i na redukcję uszkodzeń DNA u pacjentów z HeFH. [ABSTRACT FROM AUTHOR]

Recent data showed that dabigatran can reduce not only procoagulatory effects but also block proinflammatory stimuli by inhibiting the expression of cytokines and chemokines and reducing thrombin-induced endothelial permeability. The aim of our study was to assess the effect of dabigatran on the integrity and inflammatory properties of endothelial cells stimulated by 25-hydroxycholesterol (25-OHC, oxysterol). HUVECs (Human Umbilical Vein Endothelial Cells) were stimulated with 25-hydroxycholesterol 10 µg/ml, dabigatran 100 ng/ml or 500 ng/ml and 25-hydroxycholesterol + dabigatran (100 ng/ml, 500 ng/ml). HUVEC integrity and permeability was measured in the RTCA-DP xCELLigence system and by the paracellular flux system. The mRNA expression of ICAM-1, VEGF, IL-33, MCP-1 and TNF-α was analyzed by Real-time PCR. Cell apoptosis and viability was measured by flow cytometry. VEGF protein concentration was assessed in supernatants by ELISA. VE-cadherin expression in endothelial cells was evaluated by confocal microscopy. Pre-stimulation of HUVECs with 25-OHC decreased endothelial cell integrity (p < 0.001) and increased the expression of IL-33, ICAM-1, MCP-1, VEGF, TNF-α mRNA (p < 0.01) compared to unstimulated controls. Following stimulation of HUVECs with dabigatran 100 ng/ml or 500 ng/ml restored HUVEC integrity interrupted by 25-OHC (p < 0.001). In HUVECs pre-stimulated with oxysterol, dabigatran stimulation decreased mRNA expression of the proinflammatory cytokines IL-33 and TNF-α, chemokines MCP-1 ICAM-1 and VEGF (p < 0.01). Dabigatran 500 mg/ml+ 25-OHC increased the endothelial expression of VE-cadherin as compared to 25-OHC (p < 0.01). Our findings suggest that dabigatran stabilizes the endothelial barrier and inhibits the inflammation caused by oxysterol. The effect of stimulation: 25-hydroxycholesterol (10 µg/ml)(A), dabigatran (100, 500 ng/ml) + 25-hydroxycholesterol (10 µg/ml)(B) on the barrier function and immune profile of Human Umbilical Vein Endothelial Cells (HUVECs). [Display omitted] • Dabigatran may reverse damaging effect of the 25-OHC on endothelial cells. • Dabigatran stabilized endothelial barrier interrupted by 25-OHC. • Dabigatran decreased the mRNA expression of ICAM-1, VEGF, IL-33, MCP-1 and TNFα elevated by 25-OHC in HUVECs. [ABSTRACT FROM AUTHOR]

Introduction: There are five basic types of sensation: vibration, poses, gentle touch, pain and temperature. The literature says that to study gentle sensation can be used cotton ball or finger. It is important that the therapist dosed stimulus was reproducible. Aim of sthe study: Aim of this study was to measure the gentle touch sensation in healthy subjects for 21 points developed by researchers Material and methods: Examined 28 students Silesian Medical University in Katowice 21 women and 7 men. The age of respondents x = 21,1±1,8. On both hands and forearms of respondents indicated 21 points developed by the researchers. The researcher pointed randomly selected point. The purpose of the respondents was to identify the place where they felt the touch. If examined incorrectly described the location of the point, researcher measured a difference with centimeter tape. The results were put in database and statistically analyzed in Statistica 8. Results: Differences in the level of statistical significance was observed when comparing the mean scores of variations point 13 is located in the middle of the forearm to the side of both forearms. Conclusions: Observed changes may indicate a more precise feeling the gentle touch in the middle of the lateral side of the forearm. [ABSTRACT FROM AUTHOR]

The virus responsible for the current COVID-19 pandemic is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a new virus with high infectivity and moderate mortality. The major clinical manifestation of COVID-19 is interstitial pneumonia, which may progress to acute respiratory distress syndrome (ARDS). However, the disease causes a potent systemic hyperin-flammatory response, i.e., a cytokine storm or macrophage activation syndrome (MAS), which is associated with thrombotic complications. The complexity of the disease requires appropriate intensive treatment. One of promising treatment is statin administration, these being 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that exert pleiotropic anti-inflammatory effects. Recent studies indicate that statin therapy is associated with decreased mortality in COVID-19, which may be caused by direct and indirect mechanisms. According to literature data, statins can limit SARS-CoV-2 cell entry and replication by inhibiting the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The cytokine storm can be ameliorated by lowering serum IL-6 levels; this can be achieved by inhibiting Toll-like receptor 4 (TLR4) and modulating macrophage activity. Statins can also reduce the complications of COVID-19, such as thrombosis and pulmonary fibrosis, by reducing serum PAI-1 levels, attenuating TGF-β and VEGF in lung tissue, and improving endothelial function. Despite these benefits, statin therapy may have side effects that should be considered, such as elevated creatinine kinase (CK), liver enzyme and serum glucose levels, which are already elevated in severe COVID-19 infection. The present study analyzes the latest findings regarding the benefits and limitations of statin therapy in patients with COVID-19. [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]