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•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.
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.
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.
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.
Hybrid photovoltaic thermal (PVT) modules have gained more attention because of their benefits of higher total efficiency and lower gross area of installation in comparison with photovoltaic (PV) or ...solar thermal collectors (T). Although international standards for separate panels, photovoltaics, or thermal collectors are available, the lack of testing procedures for PVT panels is a problem, especially if a high level of integration between the two parts is implemented. In the paper, a new stand to test new PVT minimodules is proposed and verified. It allows a reduction of the influence of environmental conditions on the tested T or PVT structures. Research conducted on lamp configurations confirms the possibility of achieving a high uniformity of light intensity, with values close to the AM1.5 spectrum standard (1049 ± 34 W/m2). The first measurements of new PVT minimodules have proven their usefulness, as well as the potential of a new hybrid solution.
Central Giant Cell Granuloma constitutes approximately 7% of benign tumors of the jaws. The aggressive form of CGCG clinically behaves like a classic semi-malignant neoplasm. In the literature, the ...suggested method of treatment of aggressive forms of CGCG is curettage or resection with the margin of 0.5 cm. Surgical treatment, especially in the developmental age, entails disturbances in the growth and differentiation of tissues and deforms and disturbs the functioning of the stomatognathic system. Alternative treatment methods of the CGCG presented in this article lead to the patient avoiding a mutilating procedure and improve their quality of life. The aim was to present alternative method of treatment of aggressive forms of Central Giant Cell Lesion of the jaws-injections of dexamethasone into the tumor mass through drilled bony canals. Here, we present the three cases of aggressive forms of CGCG of jaws treated with dexamethasone injections into the tumor mass. Two cases resulted in regression of the tumor, which was confirmed in histologic evaluation after remodeling surgery. Those two patients were uneventful and showed no signs of tumor recurrence at 8 and 9 years of thorough follow-up, respectively. The third patient was qualified for the mandible resection due to the enlargement of the lesion and destruction of the cortical bone. According to our observations, if the proper patient discipline, and thorough, careful clinical and radiological examinations are provided, the dexamethasone injections could be a recommended method of treatment of intraosseous giant cell granuloma. The indication is restricted to the cases with preserved bony borders despite deformation. Additionally, leaving vital teeth in the lesion is also possible.
This paper examined the impact of optical fiber sensor design, and its integration to PVC (polyvinyl chloride) sheet piles, on deflection and strain monitoring. Optical fiber sensors based on ...Brillouin light backscattering (BLS) were prepared, as they can provide accurate strain and deflection measurement results. However, depending on the application of sheet piles systems, high deformation of PVC elements can be observed. Therefore, a fiber sensor design is not trivial. Three types of optical fiber coatings and their integration with PVC sheet piles were investigated. The effect on the value of compressive and tensile strain were analyzed. It has been experimentally proven that PVC sheet piles monitoring, based on BLS method, can be realized using optical fibers with 250 µm, 900 µm, and 3 mm coating diameter. Achieved results are in line with theory. Correction coefficient necessary for 900 µm and 3 mm coatings has been proposed and used to ensure proper strain measurement. It was found that 250 µm coating fiber based sensors can be utilized for PVC strain measurement under low deflection (>1.2 m beam length). On the other hand, sensors based on 3 mm coating fiber, due to a high level of linearity, can be applied to deflection distance measurement under high deformation.
Abstract
Background
Canine elbow dysplasia (CED) is a complex developmental skeletal disorder associated with a number of pathological conditions within the cubital joint. Because CED is a heritable ...disease, it is important to identify and remove the affected animals from breeding. The first objective of this study was to describe the prevalence of medial coronoid process disease (MCPD) without (MCD) or with (FMCP) fragmented medial coronoid process, osteochondrosis (OC) and/or osteochondritis dissecans (OCD), ununited anconeal process (UAP), radio-ulnar incongruence (INC R-U) and humero-ulnar incongruence (INC H-U) in dogs with the use of CT imaging. The second aim was to determine the influence of demographics on the prevalence of investigated pathologies in dogs with clinical evidence of elbow dysplasia.
Results
In this retrospective study, CT data records of 169 dogs of different breeds presented to the small animal veterinary clinic from 2012 to 2018 were included. 69.23% of dogs diagnosed with CED were young (≤ 2 years old). The mean age of dogs presented with INC R-U was 1.68 ± 1.82 years, while in dogs without INC R-U the mean age was 2.64 ± 2.59 years. The mean age of dogs with INC H-U was 1.94 ± 2.06 years, while without INC H-U 3.29 ± 2.09 years. Labrador Retrievers, German Shepherd and Bernese Mountain dogs were most frequently presented with CED-associated lameness. In 122 dogs OA of varying severity was found.
Conclusion
INC H-U, FMCP and MCD were among the most frequently found components of CED found in the present study. OCD and UAP were the least frequently diagnosed. Dogs presented with INC R-U and INC H-U were significantly younger than dogs without these CED components. Boxers, Dog de Bordeaux, American Staffordshire terriers and mixed-breed dogs were diagnosed later in life than the other breeds. OA of varying severity was found in 72.18% of dogs. Males accounted for more than 75% of the study population.
The objective of this study was to compare oxidative stress indices in 24 patients (mean ± SD age 71 ± 13 years) undergoing surgical aortic valve replacement (SAVR) versus transcatheter aortic valve ...replacement (TAVR). Serum total antioxidant capacity (TAC), copper/zinc ratio (Cu/Zn), activity of lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances (TBARS) were assessed at four different time-points: pre-procedure, immediately post-procedure, and one day and two days after the procedure. All oxidative stress parameters were comparable in both groups pre-procedure. TAC decreased significantly when assessed immediately after procedures in both groups (
< 0.001); however, the magnitude of the reduction was more pronounced after SAVR (88% decrease from baseline: 1.8 ± 0.1 vs. 0.2 ± 0.03 mM) compared to TAVR procedures (53% decrease from baseline: 1.9 ± 0.1 vs. 1.0 ± 0.1 mM;
< 0.001). TAC returned to baseline two days after TAVR in all patients, but was still reduced by 55% two days after SAVR. In concordance, TBARS levels and Cu/Zn ratio increased significantly with maximum levels immediately after procedures in both groups (
< 0.001), but the magnitude of the increase was significantly higher in SAVR compared to TAVR (TBARS: 3.93 ± 0.61 µM vs. 1.25 ± 0.30 µM,
= 0.015; Cu/Zn ratio: 2.33 ± 0.11 vs. 1.80 ± 0.12;
< 0.001). Two days after the procedure, TBARS levels and the Cu/Zn ratio returned to baseline after TAVR, with no full recovery after SAVR. TAVR is associated with a lesser redox imbalance and faster recovery of antioxidant capacity compared to SAVR.
Vascular endothelial cells (EC) are constantly exposed to endo- and exogenous compounds, which may disturb EC function. One of the protecting mechanisms against chemicals consists of drug ...metabolizing enzymes and transporter proteins regulated by nuclear receptors and transcription factors. Therefore, the aim of the current study was to assess the regulation of nuclear receptors and their coordinated genes in Human Umbilical Vein Endothelial Cells (HUVEC).
HUVEC were exposed to TCDD (10 nM), oltipraz (100 μM) and simvastatin (1 μM) for 24 h. Gene expressions were evaluated using quantitative real-time PCR. The protein expression levels were determined by Western blotting. Enzymatic activity of CYP1A1/CYP1B1 was assessed by luciferin-labelled CYPs substrate.
Our study confirmed that nuclear receptor AhR and nuclear factor Nrf2 are highly expressed in HUVECs. Treatment of HUVECs with TCDD (AhR inducer) resulted in a significant induction of AHR target genes CYP1A1, CYP1B1 and NQO1. Oltipraz (Nrf2 inducer) also markedly increased expression of NQO1 but did not affect Nrf2 mRNA nor protein levels. Under simvastatin stimulation PXR and NRF2 target transcripts were not altered, however AHR-regulated genes: CYP1A1, CYP1B1 and MDR1 were significantly induced. Western blot analysis confirmed CYP1B1 induction in TCDD-treated HUVECs, but not in the simvastatin group. Moreover, HUVEC exposure to TCDD resulted in induction of CYP1A1/CYP1B1 enzymatic activity.
This study revealed functional expression of AhR and Nrf2 in HUVECs. Moreover, it was defined that simvastatin induced AhR and its related genes.
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