Waterpipe smoking (WPS) has adverse health effects that include endothelial dysfunction with mechanisms involving oxidative stress and inflammation. Nonetheless, there is a scarcity of data on the direct impact of WPS on endothelial function. In this study, we assessed the in vitro effects of waterpipe smoke extract (WPSE) on aortic endothelial cell lines, namely the TeloHAEC. The WPSE markedly caused concentration- and time-dependent decreases in cellular viability. When compared with the control, at a concentration of 20 % and an incubation period of 48 h, the WPSE significantly increased the levels of lactate dehydrogenase, and markers of oxidative stress including thiobarbituric acid reactive substances, superoxide dismutase, catalase, and reduced glutathione. Moreover, the concentrations of proinflammatory cytokine (tumor necrosis factor alpha), and adhesion molecules (E-selectin and intercellular adhesion molecule-1) were also significantly augmented. Likewise, WPSE triggered mitochondrial dysfunction, DNA oxidative damage, as well as apoptosis in TeloHAEC cells. Similarly, cells cultured with WPSE have shown increased expression of phosphorylated nuclear factor-kappaB and hypoxia-inducible factor 1-alpha (HIF-1alpha). In conclusion, our study showed that WPSE triggers endothelial inflammation, oxidative stress, DNA damage, mitochondrial dysfunction, and apoptosis via mechanisms involving the activation of nuclear factor-kappaB and HIF-1alpha. Key words Waterpipe smoking, Aortic endothelial cells, Inflammation, Oxidative Stress.

• MeSH
• aorta * účinky léků   metabolismus   MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• endoteliální buňky * účinky léků   metabolismus   MeSH
• kouř * škodlivé účinky   MeSH
• kouření vodní dýmky * škodlivé účinky   metabolismus   MeSH
• lidé MeSH
• oxidační stres * účinky léků   MeSH
• poškození DNA účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Liver sinusoidal endothelial cells (LSECs) play a crucial role in regulating the hepatic function. Endoglin (ENG), a transmembrane glycoprotein, was shown to be related to the development of endothelial dysfunction. In this study, we hypothesized the relationship between changes in ENG expression and markers of liver sinusoidal endothelial dysfunction (LSED) during liver impairment. Male C57BL/6J mice aged 9-12 weeks were fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet (intrahepatic cholestasis) or choline-deficient l-amino acid defined high-fat diet (CDAA-HFD) (non-alcoholic steatohepatitis (NASH)). Significant increases in liver enzymes, fibrosis, and inflammation biomarkers were observed in both cholestasis and NASH. Decreased p-eNOS/eNOS and VE-cadherin protein expression and a significant increase in VCAM-1 and ICAM-1 expression were detected, indicating LSED in both mouse models of liver damage. A significant reduction of ENG in the DDC-fed mice, while a significant increase of ENG in the CDAA-HFD group was observed. Both DDC and CDAA-HFD-fed mice showed a significant increase in MMP-14 protein expression, which is related to significantly increased levels of soluble endoglin (sENG) in the plasma. In conclusion, we demonstrated that intrahepatic cholestasis and NASH result in an altered ENG expression, predominantly in LSECs, suggesting a critical role of ENG expression for the proper function of liver sinusoids. Both pathologies resulted in elevated sENG levels, cleaved by MMP-14 expressed predominantly from LSECs, indicating sENG as a liver injury biomarker.

• MeSH
• acetamidy * MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• endoglin metabolismus   MeSH
• endoteliální buňky metabolismus   MeSH
• intrahepatální cholestáza * MeSH
• matrixová metaloproteinasa 14 MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nealkoholová steatóza jater * patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The endothelial-mesenchymal transition (EndMT) of endothelial progenitor cells (EPCs) plays a notable role in pathological vascular remodeling. Emerging evidence indicated that long non-coding RNA-regulator of reprogramming (linc-ROR) can promote epithelial-mesenchymal transition (EMT) in a variety of cancer cells. Nevertheless, the function of linc-ROR in EPC EndMT has not been well elucidated. The present study investigated the effect and possible mechanisms of function of linc-ROR on the EndMT of EPCs. A linc-ROR overexpression lentiviral vector (LV linc-ROR) or a linc-ROR short hairpin RNA lentiviral vector (LV-shlinc-ROR) was used to up or downregulate linc-ROR expression in EPCs isolated from human umbilical cord blood. Functional experiments demonstrated that LV-linc-ROR promoted the proliferation and migration of EPCs, but inhibited EPC angiogenesis in vitro. In the meantime, reverse transcription-quantitative PCR and western blotting results showed that the expression of the endothelial cell markers vascular endothelial-cadherin and CD31 was decreased, while the expression of the mesenchymal cell markers ?-smooth muscle actin and SM22? was increased at both mRNA and protein levels in LV-linc-ROR-treated EPCs, indicating that linc-ROR induced EPC EndMT. Mechanistically, the dual-luciferase reporter assay demonstrated that microRNA (miR/miRNA)-145 was a direct target of linc-ROR, and miR-145 binds to the 3'-untranslated region of Smad3. Moreover, LV-shlinc-ROR increased the expression of miR-145, but decreased the expression of Smad3. In conclusion, linc-ROR promotes EPC EndMT, which may be associated with the miR-145/Smad3 signaling pathway. Keywords: Endothelial progenitor cells, Endothelial to mesenchymal transition, Linc-ROR, MiR-145, Atherosclerosis.

• MeSH
• endotel-mezenchymální transformace MeSH
• endoteliální progenitorové buňky * metabolismus   MeSH
• epitelo-mezenchymální tranzice * MeSH
• kultivované buňky MeSH
• lidé MeSH
• mikro RNA * metabolismus   genetika   MeSH
• pohyb buněk fyziologie   MeSH
• proliferace buněk MeSH
• protein Smad3 * metabolismus   genetika   MeSH
• RNA dlouhá nekódující * genetika   metabolismus   MeSH
• signální transdukce * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Antigen-presenting cells (APCs) are master regulators of the immune response by directly interacting with T cells to orchestrate distinct functional outcomes. Several types of professional APC exist, including conventional dendritic cells, B cells and macrophages, and numerous other cell types have non-classical roles in antigen presentation, such as thymic epithelial cells, endothelial cells and granulocytes. Accumulating evidence indicates the presence of a new family of APCs marked by the lineage-specifying transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and demonstrates that these APCs have key roles in shaping immunity, inflammation and tolerance, particularly in the context of host-microorganism interactions. These RORγt+ APCs include subsets of group 3 innate lymphoid cells, extrathymic autoimmune regulator-expressing cells and, potentially, other emerging populations. Here, we summarize the major findings that led to the discovery of these RORγt+ APCs and their associated functions. We discuss discordance in recent reports and identify gaps in our knowledge in this burgeoning field, which has tremendous potential to advance our understanding of fundamental immune concepts.

• MeSH
• antigen prezentující buňky metabolismus   MeSH
• endoteliální buňky MeSH
• jaderné receptory - podrodina 1, skupina F, člen 3 * metabolismus   MeSH
• lidé MeSH
• lymfocyty * MeSH
• přirozená imunita MeSH
• transportní proteiny metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Cardiovascular diseases are the most important cause of morbidity and mortality in the civilized world. Stenosis or occlusion of blood vessels leads not only to events that are directly life-threatening, such as myocardial infarction or stroke, but also to a significant reduction in quality of life, for example in lower limb ischemia as a consequence of metabolic diseases. The first synthetic polymeric vascular replacements were used clinically in the early 1950s. However, they proved to be suitable only for larger-diameter vessels, where the blood flow prevents the attachment of platelets, pro-inflammatory cells and smooth muscle cells on their inner surface, whereas in smaller-diameter grafts (6 mm or less), these phenomena lead to stenosis and failure of the graft. Moreover, these polymeric vascular replacements, like biological grafts (decellularized or devitalized), are cell-free, i.e. there are no reconstructed physiological layers of the blood vessel wall, i.e. an inner layer of endothelial cells to prevent thrombosis, a middle layer of smooth muscle cells to perform the contractile function, and an outer layer to provide innervation and vascularization of the vessel wall. Vascular substitutes with these cellular components can be constructed by tissue engineering methods. However, it has to be admitted that even about 70 years after the first polymeric vascular prostheses were implanted into human patients, there are still no functional small-diameter vascular grafts on the market. The damage to small-diameter blood vessels has to be addressed by endovascular approaches or by autologous vascular substitutes, which leads to some skepticism about the potential of tissue engineering. However, new possibilities of this approach lie in the use of modern technologies such as 3D bioprinting and/or electrospinning in combination with stem cells and pre-vascularization of tissue-engineered vascular grafts. In this endeavor, sex-related differences in the removal of degradable biomaterials by the cells and in the behavior of stem cells and pre-differentiated vascular cells need to be taken into account. Key words: Blood vessel prosthesis, Regenerative medicine, Stem cells, Footprint-free iPSCs, sr-RNA, Dynamic bioreactor, Sex-related differences.

• MeSH
• cévní protézy * MeSH
• lidé MeSH
• tkáňové inženýrství * metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Fuchs endothelial corneal dystrophy (FECD) is an age-related cause of vision loss, and the most common repeat expansion-mediated disease in humans characterised to date. Up to 80% of European FECD cases have been attributed to expansion of a non-coding CTG repeat element (termed CTG18.1) located within the ubiquitously expressed transcription factor encoding gene, TCF4. The non-coding nature of the repeat and the transcriptomic complexity of TCF4 have made it extremely challenging to experimentally decipher the molecular mechanisms underlying this disease. Here we comprehensively describe CTG18.1 expansion-driven molecular components of disease within primary patient-derived corneal endothelial cells (CECs), generated from a large cohort of individuals with CTG18.1-expanded (Exp+) and CTG 18.1-independent (Exp-) FECD. We employ long-read, short-read, and spatial transcriptomic techniques to interrogate expansion-specific transcriptomic biomarkers. Interrogation of long-read sequencing and alternative splicing analysis of short-read transcriptomic data together reveals the global extent of altered splicing occurring within Exp+ FECD, and unique transcripts associated with CTG18.1-expansions. Similarly, differential gene expression analysis highlights the total transcriptomic consequences of Exp+ FECD within CECs. Furthermore, differential exon usage, pathway enrichment and spatial transcriptomics reveal TCF4 isoform ratio skewing solely in Exp+ FECD with potential downstream functional consequences. Lastly, exome data from 134 Exp- FECD cases identified rare (minor allele frequency <0.005) and potentially deleterious (CADD>15) TCF4 variants in 7/134 FECD Exp- cases, suggesting that TCF4 variants independent of CTG18.1 may increase FECD risk. In summary, our study supports the hypothesis that at least two distinct pathogenic mechanisms, RNA toxicity and TCF4 isoform-specific dysregulation, both underpin the pathophysiology of FECD. We anticipate these data will inform and guide the development of translational interventions for this common triplet-repeat mediated disease.

• MeSH
• alternativní sestřih genetika   MeSH
• endoteliální buňky metabolismus   MeSH
• expanze trinukleotidových repetic * genetika   MeSH
• Fuchsova endoteliální dystrofie * genetika   MeSH
• lidé MeSH
• rohovkový endotel metabolismus   patologie   MeSH
• transkripční faktor 4 * genetika   metabolismus   MeSH
• transkriptom genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Coronary heart disease (CHD) is one of the most commonly seen cardiovascular conditions across the globe. Junctional cadherin 5 associated (JCAD) protein is found in the intercellular junctions of endothelial cells and linked to cardiovascular diseases. Nonetheless, the influence of JCAD on cardiomyocyte injury caused by CHD is unclear. A model of H2O2-induced H9c2 cell injury was constructed, and JCAD mRNA and protein levels were assessed by qRT-PCR and Western blot. The impacts of JCAD on the proliferation or apoptosis of H9c2 cells were explored by CCK-8 assay, Western blot and TUNEL staining. The effect of JCAD on the inflammatory response and vascular endothelial function of H9c2 cells was detected using ELISA kits. The levels of Wnt/β-catenin pathway-related proteins were assessed by Western blot. H2O2 treatment led to a rise in the levels of JCAD in H9c2 cells. Over-expression of JCAD promoted H2O2-induced cellular injury, leading to notably elevated contents of inflammatory factors, along with vascular endothelial dysfunction. In contrast to over-expression of JCAD, silencing of JCAD attenuated H2O2-induced cellular injury and inhibited apoptosis, inflammatory response and vascular endothelial dysfunction. Notably, JCAD could regulate the Wnt/β-catenin pathway, while DKK-1, Wnt/β-catenin pathway antagonist, counteracted the enhancing impact of JCAD over-expression on H2O2-induced H9c2 cell injury, further confirming that JCAD acts by regulating the Wnt/β-catenin pathway. In summary, over-expression of JCAD promoted H2O2-induced H9c2 cell injury by activating the Wnt/β-catenin pathway, while silencing of JCAD attenuated the H2O2-induced cell injury.

• MeSH
• apoptóza * účinky léků   MeSH
• beta-katenin metabolismus   MeSH
• buněčné linie MeSH
• down regulace * účinky léků   MeSH
• kadheriny metabolismus   MeSH
• kardiomyocyty * metabolismus   účinky léků   MeSH
• krysa rodu rattus MeSH
• peroxid vodíku * farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• signální dráha Wnt * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: AZURE was a 76-week, randomized, open-label, parallel-group, phase IIIb noninferiority study comparing the efficacy and safety of intravitreal aflibercept (IVT-AFL) in a treat-and-extend (T&E) regimen with fixed dosing in patients with neovascular age-related macular degeneration (nAMD) previously receiving IVT-AFL for ≥ 1 year. METHODS: Patients were aged ≥ 51 years and had completed ≥ 1 year of IVT-AFL treatment prior to enrollment (IVT-AFL once per month [- 1 or + 2 weeks] for 3 months followed by IVT-AFL every 2 months [6-12 weeks]). Patients were randomly assigned (1:1) to receive IVT-AFL 2 mg in either a T&E (minimum treatment interval of 8 weeks with no upper limit, adjusted according to functional and anatomic outcomes, as assessed by the investigator; n = 168), or a fixed dosing regimen (treatment every 8 weeks [± 3 days]; n = 168). The primary endpoint was best-corrected visual acuity (BCVA) change from baseline to week (W) 52. The key secondary endpoint was the proportion of patients maintaining vision (< 15-letter loss) at W52. RESULTS: The full analysis set comprised 332 patients (T&E: n = 165; fixed dosing: n = 167). Mean BCVA change (baseline to W52) was - 0.3 ± 7.5 vs. - 0.5 ± 8.4 letters (T&E vs. fixed dosing; least-squares mean difference [95% CI]: 0.22 [- 1.51 to 1.96] letters; P < 0.0001 for noninferiority test [5-letter margin]). From baseline to W52, 95.2% (T&E) and 94.0% (fixed dosing) of patients maintained vision. Mean central subfield thickness change from baseline to W52 was - 24 ± 55 (T&E) and - 33 ± 47 (fixed dosing) μm. Last treatment interval to W76 was ≥ 12 weeks for 37.0% of T&E patients. No new safety signals were identified. CONCLUSION: IVT-AFL T&E can achieve similar functional and anatomic outcomes to fixed dosing every 8 weeks over 52 weeks in patients with nAMD who have completed ≥ 1 year of treatment, while reducing treatment burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02540954.

• MeSH
• injekce intravitreální MeSH
• lidé středního věku MeSH
• lidé MeSH
• makulární degenerace * farmakoterapie   MeSH
• receptory vaskulárního endoteliálního růstového faktoru * terapeutické užití   MeSH
• rekombinantní fúzní proteiny * terapeutické užití   MeSH
• senioři MeSH
• výsledek terapie MeSH
• zraková ostrost MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• hodnocení ekvivalence MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

Ciele: Dvojrozmerná „speckle tracking“ (2D ST) analýza umožňuje zhodnotenie deformácie myokardu a môže byť využitá v determinácii funkcie ľavej komory (ĽK) a ľavej predsiene (ĽP). Cieľom našej štúdie bolo porovnať výsledky globálneho longitudinálneho „strain“ ĽK (LV‐GLS) a „reservoir strain“ ĽP (R ‐LAS) medzi pacientami s akútnou dekompenzáciou chronického srdcového zlyhávania (SZ) a jedincami bez známeho kardiovaskulárneho ochorenia (KVO), a taktiež pozorovať zmeny v plazmatickej koncentrácii vaskulárneho endotelového rastového faktora (VEGF) počas liečby akútnej dekompenzácie SZ. Metódy: Realizovali sme pilotnú, prospektívnu, observačnú štúdiu zahŕňajúcu 16 pacientov prijatých pre akútnu dekompenzáciu SZ. Každý pacient absolvoval transtorakálne echokardiografické vyšetrenie (TTE) vrátane 2D ST analýzy s určením hodnôt LV‐GLS a R‐LAS. Pacienti boli rozdelení na základe hodnoty ejekčnej frakcie (EF) ĽK, pričom hodnota ≤ 40 % odlišovala SZ so zachovanou ejekčnou frakciou (SZpEF) – 10 pacientov, od SZ s redukovanou ejekčnou frakciou (SZrEF) – 6 pacientov. U každého pacienta boli odobraté dve vzorky venóznej krvi na vyšetrenie plazmatickej koncentrácie VEGF – pred liečbou a po liečbe. Kontrolná skupina pozostávala zo 16 jedincov bez KVO, u každého bolo realizované TTE vyšetrenie vrátane 2D ST analýzy. Výsledky: Zistili sme, že hodnoty parametrov LV‐GLS a R‐LAS boli signifikantne nižšie u oboch podskupín SZpEF aj SZrEF v porovnaní s kontrolnou skupinou (LV‐GLS: ‐13,4 ± 4,7 % vs. ‐19,7 ± 2,5 %, p < 0,05; R‐LAS: +12,2 ± 6,9 % vs. +40,3 ± 7,4 %, p < 0,05). Navyše, medzi SZrEF a SZpEF podskupinami bol zaznamenaný signifikantný rozdiel v parametri LV‐GLS (‐9,6 ± 3,2 % vs. ‐15,2 ± 4,3 %, p < 0,05), ale nie v parametri R ‐LAS (+13,7 ± 8,6 % vs. +11,4 ± 6,2 %). Plazmatické koncentrácie VEGF po liečbe boli signifikantne vyššie v podskupine so SZpEF v porovnaní s podskupinou so SZrEF (213 ± 161 pg/ml vs. 142 ± 130 pg/ml, p < 0,05). Záver: Naša štúdia preukázala signifikantný rozdiel v parametroch LV‐GLS a R ‐LAS u všetkých pacientov so SZ v porovnaní s kontrolnou skupinou. Taktiež bol dokázaný signifikantný rozdiel v parametri LV ‐GLS medzi SZrEF a SZpEF podskupinami. Bol preukázaný aj signifikantný rozdiel v plazmatickej koncentrácii VEGF po liečbe medzi oboma podskupinami.

Aims: Two-dimensional speckle tracking (2D ST) analysis provides assessment of myocardial deformation and can be used as a diagnostic tool to determine the function of the left ventricle (LV) and the left atrium (LA). This study aimed to compare global longitudinal strain of LV (LV-GLS) and reservoir strain of LA (R-LAS) results between patients hospitalised for acute decompensation of heart failure (HF) and individuals with no known cardiovascular disease (CVD); and to observe the plasma concentration of vascular endothelial growth factor (VEGF) with treatment of acute decompensation of HF. Methods: We performed a pilot, prospective and observational study involving 16 patients hospitalised for acute decompensation of HF. Each patient underwent transthoracic echocardiography (TTE) with 2D ST and the values of LV-GLS and R-LAS were obtained. The patients were divided into 2 subgroups according to the value of the left ventricular ejection fraction (EF) using a cut-off value of ≤ 40% to distinguish heart failure with preserved ejection fraction (HFpEF) - 10 patients, from heart failure with reduced ejection fraction (HFrEF) - 6 patients. Two samples of venous blood, one before and one after treatment, were also taken in each patient to be examined for the plasma concentration of VEGF. The control involved 16 persons without a history of CVD, each of whom underwent 2D ST analysis as well. Results: We found that LV-GLS and R-LAS were significantly lower in both HFpEF and HFrEF subgroups in comparison with the control (LV-GLS: -13.4±4.7 % vs. -19.7±2.5 %, p < 0.05; R-LAS: +12.2±6.9 % vs. +40.3±7.4 %, p < 0.05). Furthermore, there was a significant difference in LV-GLS (-9.6±3.2 % vs. -15.2±4.3 %, p<0.05), but not in R-LAS (+13.7±8.6 % vs. +11.4±6.2 %) between HFrEF and HFpEF subgroups. The VEGF plasma concentrations after treatment were significantly greater in the HFpEF compared to the HFrEF group (213±161 pg/ml vs. 142±130 pg/ml, p<0.05). Conclusion: Our study showed a significant difference in LV-GLS and R-LAS in all patients with HF compared to the control. There was also a significant difference in LV-GLS between the HFrEF and HFpEF subgroups. Ultimately, there was also a significant difference in the VEGF plasma concentrations after treatment between the subgroups.

• MeSH
• lidé MeSH
• pozorovací studie jako téma MeSH
• srdeční selhání * MeSH
• vaskulární endoteliální růstové faktory * analýza   MeSH
• Check Tag
• lidé MeSH

Vascular ageing, characterized by structural and functional changes in blood vessels of which arterial stiffness and endothelial dysfunction are key components, is associated with increased risk of cardiovascular and other age-related diseases. As the global population continues to age, understanding the underlying mechanisms and developing effective therapeutic interventions to mitigate vascular ageing becomes crucial for improving cardiovascular health outcomes. Therefore, this review provides an overview of the current knowledge on pharmacological modulation of vascular ageing, highlighting key strategies and promising therapeutic targets. Several molecular pathways have been identified as central players in vascular ageing, including oxidative stress and inflammation, the renin-angiotensin-aldosterone system, cellular senescence, macroautophagy, extracellular matrix remodelling, calcification, and gasotransmitter-related signalling. Pharmacological and dietary interventions targeting these pathways have shown potential in ameliorating age-related vascular changes. Nevertheless, the development and application of drugs targeting vascular ageing is complicated by various inherent challenges and limitations, such as certain preclinical methodological considerations, interactions with exercise training and sex/gender-related differences, which should be taken into account. Overall, pharmacological modulation of endothelial dysfunction and arterial stiffness as hallmarks of vascular ageing, holds great promise for improving cardiovascular health in the ageing population. Nonetheless, further research is needed to fully elucidate the underlying mechanisms and optimize the efficacy and safety of these interventions for clinical translation.

• MeSH
• lidé MeSH
• oxidační stres MeSH
• signální transdukce MeSH
• stárnutí buněk MeSH
• stárnutí * metabolismus   MeSH
• tuhost cévní stěny * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH