BACKGROUND: Lipopolysaccharide (LPS)-induced inflammation of lung tissues triggers irreversible alterations in the lung parenchyma, leading to fibrosis and pulmonary dysfunction. While the molecular and cellular responses of immune and connective tissue cells in the lungs are well characterized, the specific epithelial response remains unclear due to the lack of representative cell models. Recently, we introduced human embryonic stem cell-derived expandable lung epithelial (ELEP) cells as a novel model for studying lung injury and regeneration. METHODS: ELEPs were derived from the CCTL 14 human embryonic stem cell line through activin A-mediated endoderm specification, followed by further induction toward pulmonary epithelium using FGF2 and EGF. ELEPs exhibit a high proliferation rate and express key structural and molecular markers of alveolar progenitors, such as NKX2-1. The effects of Escherichia coli LPS serotype O55:B5 on the phenotype and molecular signaling of ELEPs were analyzed using viability and migration assays, mRNA and protein levels were determined by qRT-PCR, western blotting, and immunofluorescent microscopy. RESULTS: We demonstrated that purified LPS induces features of a hybrid epithelial-to-mesenchymal transition in pluripotent stem cell-derived ELEPs, triggers the unfolded protein response, and upregulates intracellular β-catenin level through retention of E-cadherin within the endoplasmic reticulum. CONCLUSIONS: Human embryonic stem cell-derived ELEPs provide a biologically relevant, non-cancerous lung cell model to investigate molecular responses to inflammatory stimuli and address epithelial plasticity. This approach offers novel insights into the fine molecular processes underlying lung injury and repair.

• MeSH
• buněčné linie MeSH
• CD antigeny metabolismus   MeSH
• endoplazmatické retikulum * metabolismus   účinky léků   MeSH
• epitelo-mezenchymální tranzice * účinky léků   MeSH
• epitelové buňky * účinky léků   metabolismus   cytologie   MeSH
• kadheriny * metabolismus   MeSH
• lidé MeSH
• lidské embryonální kmenové buňky * cytologie   MeSH
• lipopolysacharidy * farmakologie   MeSH
• plíce * cytologie   MeSH
• tyreoidální jaderný faktor 1 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Cell communication systems based on polypeptide ligands use transmembrane receptors to transmit signals across the plasma membrane. In their biogenesis, receptors depend on the endoplasmic reticulum (ER)-Golgi system for folding, maturation, transport and localization to the cell surface. ER stress, caused by protein overproduction and misfolding, is a well-known pathology in neurodegeneration, cancer and numerous other diseases. How ER stress affects cell communication via transmembrane receptors is largely unknown. In disease models of multiple myeloma, chronic lymphocytic leukemia and osteogenesis imperfecta, we show that ER stress leads to loss of the mature transmembrane receptors FGFR3, ROR1, FGFR1, LRP6, FZD5 and PTH1R at the cell surface, resulting in impaired downstream signaling. This is caused by downregulation of receptor production and increased intracellular retention of immature receptor forms. Reduction of ER stress by treatment of cells with the chemical chaperone tauroursodeoxycholic acid or by expression of the chaperone protein BiP resulted in restoration of receptor maturation and signaling. We show a previously unappreciated pathological effect of ER stress; impaired cellular communication due to altered receptor processing. Our findings have implications for disease mechanisms related to ER stress and are particularly important when receptor-based pharmacological approaches are used for treatment.

• MeSH
• chaperon endoplazmatického retikula BiP MeSH
• kyselina taurochenodeoxycholová farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• receptory buněčného povrchu * metabolismus   MeSH
• signální transdukce * účinky léků   MeSH
• stres endoplazmatického retikula * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Revision total hip arthroplasty (rTHA) is an increasingly common procedure due to the growing number of primary total hip arthroplasties (THAs) performed worldwide. This study evaluates the long-term implant survival, functional outcomes, and radiographic performance of cemented femoral stem (Beznoska s.r.o., Kladno, Czechia) in rTHA. METHODS: A retrospective analysis was conducted on 183 patients who underwent rTHA with cemented stem between March 2012 and December 2023. The mean follow-up duration was 71.26(± 39.31) months. Implant survival was analyzed using Kaplan-Meier survival estimates, and failure modes were assessed. Radiographic changes were classified using the Gruen Zones system. Functional outcomes were evaluated using the Harris Hip Score (HHS). Cox proportional hazard models were applied to identify prognostic factors influencing implant survival. RESULTS: The five-year implant survival rate was 98.1%, declining to 83.9% at twelve years. The overall failure rate was 3.83%, with periprosthetic infection (4 cases) being the most common cause, followed by aseptic loosening (2 cases). Radiographic changes were observed in 24.03% of cases, predominantly in Gruen Zones 2, 6, and 1. Functional outcomes were favorable, with a mean HHS of 81.28(± 5.74), comparable to outcomes reported for uncemented revision stems. Age, stem diameter, and stem length did not significantly impact implant survival. CONCLUSION: The cemented stem demonstrated favourable long-term survival, with high implant retention rates. Functional outcomes indicated overall satisfactory performance. Radiographic evaluation revealed localized changes around the implant, predominantly in Gruen Zones 2, 6, and 1. Implant failure was relatively rare, with periprosthetic infection being the most common cause.

• MeSH
• cementování MeSH
• dospělí MeSH
• Kaplanův-Meierův odhad MeSH
• kostní cementy MeSH
• kyčelní kloub diagnostické zobrazování   chirurgie   MeSH
• kyčelní protézy * škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada kyčelního kloubu * metody   přístrojové vybavení   škodlivé účinky   MeSH
• protézy - design MeSH
• radiografie MeSH
• reoperace * MeSH
• retrospektivní studie MeSH
• selhání protézy * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Cholestatic liver diseases are characterized by intrahepatic accumulation of bile acids (BAs), exacerbating liver inflammation, and fibrosis. Dimethyl fumarate (DMF) is a clinically approved anti-inflammatory drug that demonstrated protective effects in several experimental models of liver injury. Still, its effect on BA homeostasis and liver fibrosis has not been thoroughly studied. Herein, we hypothesized that DMF could improve BA homeostasis and mitigate the progression of cholestasis-induced liver fibrosis. The DMF was administered to mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholestasis for 4 wk. The content of individual BAs in the plasma, liver, bile, intestine, and feces was measured using the LC-MS method alongside the analysis of liver phenotype and related executive and regulatory pathways. The DMF slowed down the progression of DDC-induced liver fibrosis by suppressing hepatic stellate cell and macrophage activation and by reducing c-Jun N-terminal kinase phosphorylation. Notably, DMF reduced BA cumulation in the plasma and liver of cholestatic mice by increasing BA fecal excretion via their reduced Bacteroidetes phyla-mediated deconjugation in the intestine. In addition, DMF was identified as the antagonist of the mouse farnesoid X receptor in enterocytes. In conclusion, DMF alleviates DDC-induced cholestatic liver injury through pleiotropic action leading to significant anti-inflammatory and antifibrotic activity of the agent. In addition, DMF mitigates BA retention in the liver and plasma by increasing their fecal excretion in cholestatic mice. These findings suggest that DMF warrants further investigation as a potential therapeutic agent for human chronic fibrosing cholestatic liver disorders.NEW & NOTEWORTHY Chronic cholestatic cholangiopathies present a therapeutic challenge due to their complex pathophysiology, where the accumulation of bile acids plays a crucial role. In this study, we found that dimethyl fumarate attenuated cholestatic liver damage in a murine model through its significant anti-inflammatory and antifibrotic activity supported by reduced bile acid accumulation in the plasma and liver via their increased fecal excretion.

• MeSH
• cholestáza * farmakoterapie   metabolismus   chemicky indukované   MeSH
• dimethyl fumarát * farmakologie   terapeutické užití   MeSH
• jaterní cirhóza * metabolismus   farmakoterapie   patologie   etiologie   MeSH
• jaterní hvězdicovité buňky účinky léků   metabolismus   MeSH
• játra * metabolismus   účinky léků   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• žlučové kyseliny a soli * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Publikace se zaměřuje na ochranu osobních údajů v kontextu digitálních technologií. Určeno odborné veřejnosti.; S technickým rozvojem narůstají také možnosti zásahů do soukromí osob a přibývají i jejich nové formy. Zvláště závažnými jsou zásahy ve formě shromažďování a dalšího zpracování řady kategorií osobních údajů, často jde o zpracování hromadná, zpravidla plošného charakteru, dopadající na značná množství osob. Mnohá takováto zpracování jsou uložena obecně závaznými právními předpisy, nejde tak o zásahy samy o sobě protiprávní. Sledovaným účelem takových zpracování osobních údajů je často boj proti terorismu, mnohdy obecněji boj proti trestné činnosti, ale také např. usnadnění a kontrola výběru daní, či jiných dávek a další účely.

• MeSH
• digitální technologie MeSH
• důvěrnost informací MeSH
• informační technologie MeSH
• soukromí MeSH
• zákonodárství jako téma MeSH
• Publikační typ
• monografie MeSH
• Geografické názvy
• Česká republika MeSH
• Evropa MeSH

• Konspekt
• Ústavní právo. Správní právo
• NLK Obory
• lidská práva

BACKGROUND: The hippocampal representation of space, formed by the collective activity of populations of place cells, is considered as a substrate of spatial memory. Alzheimer's disease (AD), a widespread severe neurodegenerative condition of multifactorial origin, typically exhibits spatial memory deficits among its early clinical signs before more severe cognitive impacts develop. OBJECTIVE: To investigate mechanisms of spatial memory impairment in a double transgenic rat model of AD. METHODS: In this study, we utilized 9-12-month-old double-transgenic TgF344-AD rats and age-matched controls to analyze the spatial coding properties of CA1 place cells. We characterized the spatial memory representation, assessed cells' spatial information content and direction-specific activity, and compared their population coding in familiar and novel conditions. RESULTS: Our findings revealed that TgF344-AD animals exhibited lower precision in coding, as evidenced by reduced spatial information and larger receptive zones. This impairment was evident in maps representing novel environments. While controls instantly encoded directional context during their initial exposure to a novel environment, transgenics struggled to incorporate this information into the newly developed hippocampal spatial representation. This resulted in impairment in orthogonalization of stored activity patterns, an important feature directly related to episodic memory encoding capacity. CONCLUSIONS: Overall, the results shed light on the nature of impairment at both the single-cell and population levels in the transgenic AD model. In addition to the observed spatial coding inaccuracy, the findings reveal a significantly impaired ability to adaptively modify and refine newly stored hippocampal memory patterns.

• MeSH
• Alzheimerova nemoc * patofyziologie   MeSH
• amyloidový prekurzorový protein beta genetika   MeSH
• hipokampální oblast CA1 patofyziologie   MeSH
• hipokampus patofyziologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• poruchy paměti etiologie   patofyziologie   MeSH
• potkani inbrední F344 MeSH
• potkani transgenní * MeSH
• prostorová paměť fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Left ventricular noncompaction cardiomyopathy is associated with heart failure, arrhythmia, and sudden cardiac death. The developmental mechanism underpinning noncompaction in the adult heart is still not fully understood, with lack of trabeculae compaction, hypertrabeculation, and loss of proliferation cited as possible causes. To study this, we utilised a mouse model of aberrant Rho kinase (ROCK) signalling in cardiomyocytes, which led to a noncompaction phenotype during embryogenesis, and monitored how this progressed after birth and into adulthood. The cause of the early noncompaction at E15.5 was attributed to a decrease in proliferation in the developing ventricular wall. By E18.5, the phenotype became patchy, with regions of noncompaction interspersed with thick compacted areas of ventricular wall. To study how this altered myoarchitecture of the heart influenced impulse propagation in the developing and adult heart, we used histology with immunohistochemistry for gap junction protein expression, optical mapping, and electrocardiography. At the prenatal stages, a clear reduction in left ventricular wall thickness, accompanied by abnormal conduction of the ectopically paced beat in that area, was observed in mutant hearts. This correlated with increased expression of connexin-40 and connexin-43 in noncompacted trabeculae. In postnatal stages, left ventricular noncompaction was resolved, but the right ventricular wall remained structurally abnormal through to adulthood with cardiomyocyte hypertrophy and retention of myocardial crypts. Thus, this is a novel model of self-correcting embryonic hypertrabeculation cardiomyopathy, but it highlights that remodelling potential differs between the left and right ventricles. We conclude that disruption of ROCK signalling induces both morphological and electrophysiological changes that evolve over time, highlighting the link between myocyte proliferation and noncompaction phenotypes and electrophysiological differentiation.

• Publikační typ
• časopisecké články MeSH

• MeSH
• celkové zubní protézy MeSH
• zubní lékařství MeSH

• Konspekt
• Stomatologie
• Učební osnovy. Vyučovací předměty. Učebnice
• NLK Obory
• zubní lékařství
• technika lékařská, zdravotnický materiál a protetika
• NLK Publikační typ
• učebnice vysokých škol

Background/Objectives: For locally applied, locally acting generic drug products, comparison to an originator product based on systemic exposure is usually not feasible due to low plasma concentrations and inadequate reflection of local exposure at the site of action. Where a validated PD model exists, a comparative clinical study can be performed in healthy subjects; where no surrogate endpoint is available, patients with the relevant indication need to be enrolled, with all the associated factors which could result in lack of sensitivity. Even though the need for alternative in vitro approaches has been acknowledged by both industry and regulatory bodies, the complexity of in vivo drug delivery processes makes the development of guidance documents particularly difficult. Our objective was to present in vitro approaches less classically used and to address in vivo relevance of the selected tests. Methods: This article analyses current regulatory approaches in Europe and the U.S., and highlights the key advantages of in vitro tests in terms of their sensitivity, reliability, reproducibility and in vivo relevance using locally applied flurbiprofen in various formulations. Results: The in vitro esophageal retention (IVOR) model demonstrates that the first 6-10 min after application of different flurbiprofen formulations is important for their comparison and also offers the best correlation with in vivo data using the partial area under the concentration-time curves (pAUCs). Rheological evaluations further demonstrated that the mucoadhesive properties of the gel spray formulation are based on interaction with mucin. Conclusions: Designing a relevant in vitro test requires adequate evaluation of the complexity of the drug substance, drug product, dosing conditions and delivery processes.

• Publikační typ
• časopisecké články MeSH

Development of the craniofacies occurs in embryological intimacy with development of the brain and both show normal left-right asymmetries. While facial dysmorphology occurs to excess in psychotic illness, facial asymmetry has yet to be investigated as a putative index of brain asymmetry. Ninety-three subjects (49 controls, 22 schizophrenia, 22 bipolar disorder) received 3D laser surface imaging of the face. On geometric morphometric analysis with (x, y, z) visualisations of statistical models for facial asymmetries, in controls the upper face and periorbital region, which share embryological intimacy with the forebrain, showed marked asymmetries. Their geometry included: along the x-axis, rightward asymmetry in its dorsal-medial aspects and leftward asymmetry in its ventral-lateral aspects; along the z-axis, anterior protrusion in its right ventral-lateral aspect. In both schizophrenia and bipolar disorder these normal facial asymmetries were diminished, with residual retention of asymmetries in bipolar disorder. This geometry of normal facial asymmetries shows commonalities with that of normal frontal lobe asymmetries. These findings indicate a trans-diagnostic process that involves loss of facial asymmetries in both schizophrenia and bipolar disorder. Embryologically, they implicate loss of face-brain asymmetries across gestational weeks 7-14 in processes that involve genes previously associated with risk for schizophrenia.

• MeSH
• asymetrie obličeje * diagnostické zobrazování   patologie   MeSH
• bipolární porucha * diagnostické zobrazování   patologie   MeSH
• dospělí MeSH
• funkční lateralita fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• obličej MeSH
• psychotické poruchy diagnostické zobrazování   patologie   MeSH
• schizofrenie * diagnostické zobrazování   patologie   MeSH
• zobrazování trojrozměrné MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH