Glioblastomas are aggressive brain tumors for which effective therapy is still lacking, resulting in dismal survival rates. These tumors display significant phenotypic plasticity, harboring diverse cell populations ranging from tumor core cells to dispersed, highly invasive cells. Neuron navigator 3 (NAV3), a microtubule-associated protein affecting microtubule growth and dynamics, is downregulated in various cancers, including glioblastoma, and has thus been considered a tumor suppressor. In this study, we challenge this designation and unveil distinct expression patterns of NAV3 across different invasion phenotypes. Using glioblastoma cell lines and patient-derived glioma stem-like cell cultures, we disclose an upregulation of NAV3 in invading glioblastoma cells, contrasting with its lower expression in cells residing in tumor spheroid cores. Furthermore, we establish an association between low and high NAV3 expression and the amoeboid and mesenchymal invasive phenotype, respectively, and demonstrate that overexpression of NAV3 directly stimulates glioblastoma invasive behavior in both 2D and 3D environments. Consistently, we observed increased NAV3 expression in cells migrating along blood vessels in mouse xenografts. Overall, our results shed light on the role of NAV3 in glioblastoma invasion, providing insights into this lethal aspect of glioblastoma behavior.
- MeSH
- fenotyp * MeSH
- glioblastom * patologie genetika metabolismus MeSH
- invazivní růst nádoru * genetika MeSH
- lidé MeSH
- membránové proteiny MeSH
- mikrotubuly metabolismus MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory mozku * patologie genetika metabolismus MeSH
- pohyb buněk genetika fyziologie MeSH
- proteiny nervové tkáně metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: We aimed to evaluate the prognostic impact of renal insufficiency and fluctuation of glomerular filtration observed during hospitalization for heart failure (HF). METHODS: We followed 3,639 patients hospitalized for acute HF and assessed the mortality risk associated with moderate or severe renal insufficiency, either permanent or transient. RESULTS: After adjustment, severe renal failure defined as estimated glomerular filtration (eGFR) <30 mL/min indicates ≈60% increase in 5-year mortality risk. Similar risk also had patients with only transient decline of eGFR to this range. In contrast, we did not observe any apparent mortality risk attributable to mild/moderate renal insufficiency (eGFR 30-59.9 mL/min), regardless of whether it was transient or permanent. CONCLUSION: Even transient severe renal failure during hospitalization indicates poor long-term prognosis of patients with manifested HF. In contrast, only moderate renal insufficiency observed during hospitalization has no additive long-term mortality impact.
- MeSH
- hodnoty glomerulární filtrace MeSH
- hospitalizace MeSH
- ledviny MeSH
- lidé MeSH
- prognóza MeSH
- renální insuficience * komplikace MeSH
- srdeční selhání * komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Short- and medium-chain chlorinated paraffins (SCCPs and MCCPs) are environmental contaminants known for their persistence and bioaccumulation in fatty tissues. SCCPs are considered potential carcinogens and endocrine disruptors, with similar effects expected for MCCPs. This study investigated the body burden of SCCPs and MCCPs in residents of two regions of the Czech Republic with different levels of industrial pollution. Blood serum samples from 62 individuals in Ceske Budejovice (control area) and Ostrava (industrial area) were analysed. The results showed higher concentrations of SCCPs (<120-650 ng/g lipid weight (lw)) and MCCPs (<240-1530 ng/g lw) in Ostrava compared to Ceske Budejovice (SCCPs: <120-210 ng/g lw, MCCPs: <240-340 ng/g lw). The statistical analysis revealed no significant correlations between chemical concentrations and demographic variables such as age, BMI, or gender. The findings are consistent with European and Australian studies but significantly lower than levels reported in China. This is the first comprehensive survey of SCCPs and MCCPs in human blood serum in the Czech Republic and the second study in Europe. The data collected in this study are essential for assessing SCCPs and MCCPs. They will contribute to a better understanding the potential health risks associated with exposure to these chemicals.
- Publikační typ
- časopisecké články MeSH
The gut microbiota influences the reactivity of the immune system, and Parabacteroides distasonis has emerged as an anti-inflammatory commensal. Here, we investigated whether its lysate could prevent severe forms of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in mice and how this preventive strategy affects the gut microbiota and immune response. Lysate of anaerobically cultured P. distasonis (Pd lysate) was orally administered to C57BL/6 mice in four weekly doses. One week later, EAE was induced and disease severity was assessed three weeks after induction. Fecal microbiota changes in both vehicle- and Pd lysate-treated animals was analyzed by 16S V3-V4 amplicon sequencing and qPCR, antimicrobial peptide expression in the intestinal mucosa was measured by qPCR, and immune cell composition in the mesenteric and inguinal lymph nodes was measured by multicolor flow cytometry. Pd lysate significantly delayed the development of EAE and reduced its severity when administered prior to disease induction. EAE induction was the main factor in altering the gut microbiota, decreasing the abundance of lactobacilli and segmented filamentous bacteria. Pd lysate significantly increased the intestinal abundance of the genera Anaerostipes, Parabacteroides and Prevotella, and altered the expression of antimicrobial peptides in the intestinal mucosa. It significantly increased the frequency of regulatory T cells, induced an anti-inflammatory milieu in mesenteric lymph nodes, and reduced the activation of T cells at the priming site. Pd lysate prevents severe forms of EAE by triggering a T regulatory response and modulating T cell priming to autoantigens. Pd lysate could thus be a future modulator of neuroinflammation that increases the resistance to multiple sclerosis.
- MeSH
- Bacteroidetes imunologie MeSH
- encefalomyelitida autoimunitní experimentální * imunologie prevence a kontrola MeSH
- myši inbrední C57BL * MeSH
- myši MeSH
- střevní mikroflóra * imunologie MeSH
- střevní sliznice imunologie mikrobiologie metabolismus MeSH
- T-lymfocyty imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Adrenergic activation of protein kinase A (PKA) in cardiac muscle targets the sarcolemma, sarcoplasmic reticulum, and contractile apparatus to increase contractile force and heart rate. In the thin filaments of the contractile apparatus, cardiac troponin I (cTnI) Ser22 and Ser23 in the cardiac-specific N-terminal peptide (NcTnI: residues 1 to 32) are the targets for PKA phosphorylation. Phosphorylation causes a 2-3 fold decrease of affinity of cTn for Ca2+ associated with a higher rate of Ca2+ dissociation from cTnC leading to a faster relaxation rate of the cardiac muscle (lusitropy). Cardiomyopathy-linked mutations primarily affect Ca2+ regulation or the PKA-dependent modulatory system, such that Ca2+-sensitivity becomes independent of phosphorylation level (uncoupling) and this could be sufficient to induce cardiomyopathy. A drug that could restore the phosphorylation-dependent modulation of Ca2+-sensitivity could have potential for treatment of these pathologies. We have found that a number of small molecules, including silybin B, resveratrol and EGCG, can restore coupling in single filament assays. METHODS: We did molecular dynamics simulations (5x1500ns for each condition) of the unphosphorylated and phosphorylated cardiac troponin core with the G159D DCM mutation in the presence of the 5 ligands and analysed the effects on several dynamic parameters. We also studied the effect of the ligands on the contractility of cardiac muscle myocytes with ACTC E99K and TNNT2 R92Q mutations in response to dobutamine. RESULTS: Silybin B, EGCG and resveratrol restored the phosphorylation-induced change in molecular dynamics to wild-type values, whilst silybin A, an inactive isomer of silybin B, and Epicatechin gallate, an EGCG analogue that does not recouple, did not. We analysed the atomic-level changes induced by ligand binding to explain recoupling. Mutations ACTC E99K and TNNT2 R92Q blunt the increased relaxation speed response to β1 adrenergic stimulation of cardiac myocytes and we found that resveratrol, EGCG and silybin B could restore the β1 adrenergic response, whereas silybin A did not. DISCUSSION: The uncoupling phenomenon caused by cardiomyopathy-related mutations and the ability of small molecules to restore coupling in vitro and lusitropy in myocytes is observed at the cellular, molecular and atomistic levels therefore, restoring lusitropy is a suitable target for treatment. Further research on compounds that restore lusitropy is thus indicated as treatments for genetic cardiomyopathies. Further molecular dynamics simulations could define the specific properties needed for recoupling and allow for the prediction and design of potential new drugs.
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Active recovery (AR) is used during exercise training; however, it is unclear whether the AR should involve the whole body, only the upper extremities, or only the lower extremities when aiming to maintain localized upper body performance. Therefore, this study aimed to evaluate the impact of different AR strategies on repeated intermittent finger flexor performance leading to exhaustion. METHODS: A crossover trial involving a familiarization session and three laboratory visits, each including three exhaustive intermittent isometric tests at 60% of finger flexor maximal voluntary contraction separated by 22 min of randomly assigned AR: walking, intermittent hanging, and climbing. RESULTS: The impulse (Nꞏs) significantly decreased from the first to third trials after walking (-18.4%, P = 0.002, d = 0.78), climbing (-29.5%, P < 0.001, d = 1.48), and hanging (-27.2%, P < 0.001, d = 1.22). In the third trial, the impulse from the intermittent test was significantly higher after walking (21,253 ± 5,650 Nꞏs) than after hanging (18,618 ± 5,174 Nꞏs, P = 0.013, d = 0.49) and after climbing (18,508 ± 4,435 Nꞏs, P = 0.009, d = 0.54). CONCLUSIONS: The results show that easy climbing or intermittent isolated forearm contractions should not be used as AR strategies to maintain subsequent performance in comparison to walking, indicating that using the same muscle group for AR should be avoided between exhaustive isometric contractions.
- Publikační typ
- časopisecké články MeSH
The increasing contamination of cereals by micromycetes and mycotoxins during malting still poses an unresolved food safety problem. This study characterises the potential of the novel, rapidly developing food production technology of Pulsed Electric Field (PEF) to reduce the viability of Fusarium fungi and the production of mycotoxins during malting. Barley, artificially inoculated with four Fusarium species, was treated by PEF with two different intensities and then malted using a standard Pilsner-type technology. Concentrations of fungi were quantified by RT-PCR, expression of fungal growth-related genes was assessed using mRNA sequencing, and mycotoxin levels were analysed by U-HPLC-HRMS/MS. Despite the different trends for micromycetes and mycotoxins after application of variously intense PEF conditions, significant reductions were generally observed. The greatest decrease was for F. sporotrichioides and F. poae, where up to six fold lower levels were achieved for malts produced from the PEF-treated barley when compared to the control. For F. culmorum and F. graminearum, up to a two-fold reduction in the PEF-generated malts was observed. These reductions mostly correlated with a decrease in relevant mycotoxins, specifically type A trichothecenes.
- MeSH
- elektřina MeSH
- Fusarium * metabolismus genetika růst a vývoj MeSH
- ječmen (rod) * mikrobiologie MeSH
- jedlá semena * mikrobiologie MeSH
- kontaminace potravin prevence a kontrola MeSH
- manipulace s potravinami metody MeSH
- mykotoxiny * biosyntéza metabolismus MeSH
- potravinářská mikrobiologie MeSH
- Publikační typ
- časopisecké články MeSH
Olfactory sensitivity to odorant molecules is a complex biological function influenced by both endogenous factors, such as genetic background and physiological state, and exogenous factors, such as environmental conditions. In animals, this vital ability is mediated by olfactory sensory neurons (OSNs), which are distributed across several specialized olfactory subsystems depending on the species. Using the phosphorylation of the ribosomal protein S6 (rpS6) in OSNs following sensory stimulation, we developed an ex vivo assay allowing the simultaneous conditioning and odorant stimulation of different mouse olfactory subsystems, including the main olfactory epithelium, the vomeronasal organ, and the Grueneberg ganglion. This approach enabled us to observe odorant-induced neuronal activity within the different olfactory subsystems and to demonstrate the impact of environmental conditioning, such as temperature variations, on olfactory sensitivity, specifically in the Grueneberg ganglion. We further applied our rpS6-based assay to the human olfactory system and demonstrated its feasibility. Our findings show that analyzing rpS6 signal intensity is a robust and highly reproducible indicator of neuronal activity across various olfactory systems, while avoiding stress and some experimental limitations associated with in vivo exposure. The potential extension of this assay to other conditioning paradigms and olfactory systems, as well as its application to other animal species, including human olfactory diagnostics, is also discussed.
- MeSH
- čich fyziologie MeSH
- čichová sliznice metabolismus MeSH
- čichové buňky * metabolismus fyziologie MeSH
- fosforylace MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- odoranty analýza MeSH
- ribozomální protein S6 * metabolismus MeSH
- vomeronazální orgán metabolismus fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The viscoelastic properties of biological membranes are crucial in controlling cellular functions and are determined primarily by the lipids' composition and structure. This work studies these properties by varying the structure of the constituting lipids in order to influence their interaction with high-density lipoprotein (HDL) particles. Various fluorescence-based techniques were applied to study lipid domains, membrane order, and the overall lateral as well as the molecule-internal glycerol region mobility in HDL-membrane interactions (i.e., binding and/or cargo transfer). The analysis of interactions with HDL particles and various lipid phases revealed that both fully fluid and some gel-phase lipids preferentially interact with HDL particles, although differences were observed in protein binding and cargo exchange. Both interactions were reduced with ordered lipid mixtures containing cholesterol. To investigate the mechanism, membranes were prepared from single-lipid components, enabling step-by-step modification of the lipid building blocks. On a biophysical level, the different mixtures displayed varying stiffness, fluidity, and hydrogen bond network changes. Increased glycerol mobility and a strengthened hydrogen bond network enhanced anchoring interactions, while fluid membranes with a reduced water network facilitated cargo transfer. In summary, the data indicate that different lipid classes are involved depending on the type of interaction, whether anchoring or cargo transfer.
- Publikační typ
- časopisecké články MeSH
