Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role H2O2 produced main isoform Nox4. Therefore, we analysed impact genetic deletion Nox4 on atherosclerosis low-density lipoprotein receptor (Ldlr) knockout model.Ex vivo analysis function Mulvany myograph showed...

Tobacco smoking and hemodynamic forces are key stimuli for the development of endothelial dysfunction. As an alternative to smoking, next generation tobacco nicotine products (NGP) now widely used. However, little is known about their potential pro-inflammatory atherogenic effects on endothelium. In this study, we analyzed parameters function after exposure aqueous smoke extracts (AqE) a heated product (HTP), electronic cigarette (e-cig), conventional (3R4F) pure nicotine. All experiments...

Tobacco smoking and hemodynamic forces are key stimuli in the development of endothelial dysfunction atherosclerosis. High laminar flow has an atheroprotective effect on endothelium leads to a reduced response cells cardiovascular risk factors compared regions with disturbed or low flow. We hypothesize that high could delay caused by cigarette smoking. Primary human were stimulated increasing dosages aqueous smoke extract (CSEaq). CSEaq cell viability dose-dependent manner. The main mediator...

Recombinases have several potential advantages as genome editing tools compared to nucleases and other enzymes, but the process of engineering them efficiently recombine predetermined DNA targets demands considerable investment time labor. Here we sought harness zinc-finger DNA-binding domains (ZFDs) program recombinase binding by developing fusions, in which ZFDs are inserted into coding sequences. By screening libraries hybrid proteins, optimized insertion site, linker length, spacing ZFD...

Abstract Monocytes exhibiting a pro-inflammatory phenotype play key role in adhesion and development of atherosclerotic plaques. As an alternative to smoking, next-generation tobacco nicotine products (NGP) are now widely used. However, little is known about their effects on monocytes. We investigated cell viability, anti-oxidant gene protein expression THP-1 monocytes after exposure aqueous smoke extracts (AqE) heated product (HTP), electronic cigarette (e-cig), conventional (3R4F) pure...

PARP-inhibitors (PARPi) are an integral part of ovarian cancer treatment. However, overcoming acquired PARPi resistance or increasing the benefit in patients without homologous recombination deficiency (HRD) remains unmet clinical need. We sought to identify genetic modulators response, guiding pharmacological sensitization. CRISPR-Cas9 mediated loss-of-function screen with a focused sgRNA library revealed that DNA-demethylases JMJD1B/JMJD1C, targetable by small inhibitor methylstat, promote...

Abstract Tumor cells subvert immune surveillance by harnessing signals from checkpoints to acquire resistance. The protein PD ‐L1 is an important component in this process, and inhibition of elicits durable anti‐tumor responses a broad spectrum cancers. However, checkpoint that target known pathways not universally effective. A better understanding the genetic repertoire underlying these processes necessary expand our knowledge tumor immunity facilitate identification alternative targets....

Tobacco smoking is a risk factor for the development of atherosclerosis. One strategy to reduce harmful side effects tobacco next-generation and nicotine products. A crucial step in atherosclerosis activation adhesion monocytes. Remarkably, little known about direct cigarette on In this study, we developed methods determine detrimental aqueous smoke extract (CSEaq) from 3R4F reference cigarettes human monocytes vitro. First, tested cytotoxic CSEaq peripheral blood monocyte cell line derived...

Diabetes mellitus is an important risk factor for cardiovascular diseases. Clinical evidence supports a link between hyperglycemia, endothelial dysfunction, and vascular disorders. However, the precise molecular mechanisms causing dysfunction in diabetic patients remain unclear. An interesting novel mediator could be chicken ovalbumin upstream promoter-transcription II (COUP-TFII), which plays essential role glucose metabolism. COUP-TFII known to expressed venous cells. In this study, we...

The programmable CRISPR/Cas9 DNA nuclease is a versatile genome editing tool, but it requires the host cell repair machinery to alter genomic sequences. This fact leads unpredictable changes of at cut sites. Genome tools that can without causing double-strand breaks are therefore in high demand. Here, we show expression promoter-associated short guide (sg)RNAs together with dead Cas9 (dCas9) fused Krüppel-associated box domains (KRABd) combination transcription repression domain methyl...

with semi-fluid fsecal matted.Nothing was observed to account for the obstruction, and examination about be given up, when one of deceased's sons urged necessity examining rectum.An annular stricture latter found in its first portion, just below sacral promontory, puckering gut above it.The stenosis an inch length, calibre not greater than admit tip a man's little finger; it tore easily, as sloughing had commenced ; there ulcera- tion.

Tumor cells subvert immune surveillance or lytic stress by harnessing inhibitory signals. Hence, bispecific antibodies have been developed to direct CTLs the tumor site and foster immune-dependent cytotoxicity. Although applied with success, T cell–based immunotherapies are not universally effective partially because of expression pro-survival factors protecting them from apoptosis. Here, we report a CRISPR/Cas9 screen in human non-small cell lung cancer designed identify genes that confer...

The NADPH oxidase isoform NOX4 mainly produces H 2 O . Previously we could show, that is the major endothelial NOX and constitutively active. Regulation of formation reactive oxygen species involved in NO release. transcription factor NRF2 a key mediator cellular adaptation to redox stress. Therefore, regulation on transcriptional level by might be directly linked release function. Besides nitric oxide synthase (eNOS), role neuronal (nNOS) has been proposed. In this study, cells (HUVEC) were...

Endothelial dysfunction is one of the first steps in development atherosclerosis. This proinflammatory phenotype associated with decreased bioavailability nitric oxide and a corresponding expression profile endothelial cells. Tobacco smoking promotes atherosclerotic plaques local hemodynamic forces are key stimuli this process. Low laminar flow involved an unstable plaque phenotype, while high has atheroprotective role. The molecular mechanisms controlling stability response to tobacco...

The NADPH oxidase isoform NOX4 mainly produces H 2 O . Previously we could show, that is the major endothelial NOX and constitutively active. Regulation of formation reactive oxygen species are involved in NO release. transcription factor NRF2 a key mediator cellular adaptation to redox stress. Therefore, regulation on transcriptional level by might be directly linked release function. Besides nitric oxide synthase (eNOS), role neuronal (nNOS) has been proposed. In this study, cells (HUVEC)...

OBJECTIVE Hypercholesterolemia is an important risk factor of cardiovascular diseases. Lipoprotein apheresis efficient strategy to reduce the serum low-density lipoprotein (LDL)-cholesterol and lipoprotein(a) levels complications in patients with severe hypercholesterolemia. The underlying molecular mechanisms are not well-understood. In this study, we analyzed impact on gene expression human endothelial cells. METHODS Human cells were stimulated hypercholesterolemic before after apheresis....

The NADPH oxidase isoform NOX4 produces mainly hydrogen peroxide (H 2 O ). transcription factor NRF2 is a key mediator of cellular adaptation to redox stress. Regulation and formation H might be directly linked NO release. the major endothelial NOX considered constitutively active. on transcriptional level by release function. Endothelial cells (HUVEC) were constantly exposed high laminar shear stress (24h, 30dyn/cm This stimulates leads elongation in direction flow. Previously, we could...