The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.

• MeSH
• Astrocytes * metabolism   pathology   MeSH
• Clusterin * metabolism   genetics   MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial * physiology   MeSH
• Mitochondria * metabolism   MeSH
• Cell Line, Tumor MeSH
• Oxidative Stress physiology   MeSH
• Oxidative Phosphorylation MeSH
• DNA Damage MeSH
• Cell Proliferation * MeSH
• Reactive Oxygen Species metabolism   MeSH
• Cellular Senescence * physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Bardet-Biedl syndrome (BBS) is a pleiotropic ciliopathy caused by dysfunction of the BBSome, a cargo adaptor essential for export of transmembrane receptors from cilia. Although actin-dependent ectocytosis has been proposed to compensate defective cargo retrieval, its molecular basis remains unclear, especially in relation to BBS pathology. In this study, we investigated how actin polymerization and ectocytosis are regulated within the cilium. Our findings reveal that ciliary CDC42, a RHO-family GTPase triggers in situ actin polymerization, ciliary ectocytosis, and cilia shortening in BBSome-deficient cells. Activation of the Sonic Hedgehog pathway further enhances CDC42 activity specifically in BBSome-deficient cilia. Inhibition of CDC42 in BBSome-deficient cells decreases the frequency and duration of ciliary actin polymerization events, causing buildup of G protein coupled receptor 161 (GPR161) in bulges along the axoneme during Sonic Hedgehog signaling. Overall, our study identifies CDC42 as a key trigger of ciliary ectocytosis. Hyperactive ciliary CDC42 and ectocytosis and the resulting loss of ciliary material might contribute to BBS disease severity.

• MeSH
• Actins * metabolism   MeSH
• Bardet-Biedl Syndrome metabolism   genetics   pathology   MeSH
• cdc42 GTP-Binding Protein * metabolism   genetics   MeSH
• Cilia * metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Hedgehog Proteins * metabolism   MeSH
• Receptors, G-Protein-Coupled metabolism   genetics   MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: This study aims to identify factors possibly contributing to complications in children with acute leukaemia. Despite diverse etiological causes, similar processes trigger the process of cell malignancy. Genomic instability has received considerable attention in this context. METHOD: We conducted chromosomal analysis of bone marrow cells and measured the micronuclei (Mn) level in buccal cells over time. Statistical reliability assessment was performed using Analysis of variance (ANOVA), and the data were analyzed and visualized using the SPSS 12 statistical analysis software package. RESULTS: On the 15th day of treatment, our findings confirmed a statistically significant correlation (χ2=3.88, P=0.04) between the number of blasts in the bone marrow and unfavourable outcome in patients with a near-tetraploid chromosome clone. Additionally, on the 33rd day of treatment, we observed a correlation between an elevated number of Mn and relapses. DISCUSSION: While it is commonly believed that a hyperdiploid clone with >50 chromosomes in childhood acute lymphoblastic leukaemia confers favorable outcome, our study revealed partially heterogeneous results and poor prognosis in patients with a near-tetraploid clone. We have also identified a correlation between the Mn level on the 33rd day of treatment and the development of complications. It is possible that the increased Mn values and the occurrence of relapses were influenced by the individual patient's sensitivity to the genotoxic effect of the medication.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics   MeSH
• Bone Marrow Cells pathology   MeSH
• Child MeSH
• Humans MeSH
• Micronucleus Tests MeSH
• Micronuclei, Chromosome-Defective * MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Tetraploidy MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3'-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.

• MeSH
• Chloride Channel Agonists therapeutic use   pharmacology   MeSH
• Aminophenols * therapeutic use   pharmacology   MeSH
• Benzodioxoles * therapeutic use   pharmacology   MeSH
• Quinolones * pharmacology   therapeutic use   MeSH
• Cystic Fibrosis * genetics   drug therapy   MeSH
• Drug Combinations MeSH
• Indoles * pharmacology   MeSH
• Humans MeSH
• Organoids * metabolism   MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator genetics   MeSH
• Pyrazoles * pharmacology   MeSH
• Pyridines pharmacology   MeSH
• Pyrrolidines pharmacology   MeSH
• Pyrroles pharmacology   MeSH
• Gene Expression Profiling methods   MeSH
• Intestines drug effects   MeSH
• Transcriptome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Foodborne diseases triggered by various infectious micro-organisms are contributing significantly to the global disease burden as well as to increasing mortality rates. Salmonella enterica belongs to the most prevalent form of bacteria accountable for significant burden of foodborne illness across the globe. The conventional therapeutic approach to cater to Salmonella enterica-based infections relies on antibiotic therapy, but the rapid emergence of the antibiotic resistance strains of Salmonella sp. necessitates the development of alternative treatment and prevention strategies. In light of this growing concern, the scientific community is rigorously exploring novel phytochemicals harnessed from medicinally important plants as a promising approach to curb Salmonella enterica infections. A variety of phytochemicals belonging to alkaloids, phenols, flavonoid, and terpene classes are reported to exhibit their inhibitory activity against bacterial cell communication, membrane proteins, efflux pumps, and biofilm formation among drug resistant Salmonella strains. The present review article delves to discuss the emergence of antibiotic resistance among Salmonella enterica strains, various plant sources, identification of phytochemicals, and the current state of research on the use of phytochemicals as antimicrobial agents against Salmonella enterica, shedding light on the promising potential of phytochemicals in the fight against this pathogen.

• MeSH
• Anti-Bacterial Agents * pharmacology   MeSH
• Drug Resistance, Bacterial MeSH
• Phytochemicals * pharmacology   chemistry   MeSH
• Humans MeSH
• Foodborne Diseases microbiology   prevention & control   drug therapy   MeSH
• Salmonella enterica * drug effects   MeSH
• Salmonella Infections * microbiology   drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Angioedémy jsou přechodné lokalizované otoky podkoží a sliznic, způsobené dočasně zvýšenou cévní permeabilitou. Při ošetření a další péči o pacienta s touto diagnózou je nutné především odlišit, zda se jedná o otoky vyvolané mediátory žírných buněk nebo způsobené bradykininem. V prvním případě zpravidla uspějeme s použitím antihistaminik a kortikosteroidů, ve druhém případě je nutné volit léčbu, která specificky ovlivňuje kaskádu kalikrein-kininy.

Angioedemas are transient localized swellings of the subcutaneous tissue and mucous membranes caused by temporarily increased vascular permeability. When treating and providing further care for a patient with this diagnosis, it is crucial to distinguish whether the swellings are triggered by mast cell mediators or caused by bradykinin. In the first case, treatment with antihistamines and corticosteroids is usually successful, while in the second case, specific treatment that specifically affects the kallikrein-kinin cascade is required.

INTRODUCTION AND OBJECTIVES: Limited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients. METHODS: We studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month. RESULTS: A total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy. CONCLUSIONS: Cardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women.

• MeSH
• Cardiomyopathy, Dilated * genetics   complications   MeSH
• Adult MeSH
• Phenotype MeSH
• Genetic Variation MeSH
• Pregnancy Complications, Cardiovascular * genetics   MeSH
• Humans MeSH
• Pregnancy MeSH
• Pregnancy Outcome * MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by excessive accumulation of surfactant components in alveolar macrophages, alveoli, and peripheral airways. The accumulation of surfactant is associated with only a minimal inflammatory response but can lead to the development of pulmonary fibrosis. Three clinical forms of PAP are distinguished - primary, secondary and congenital. In recent years, significant findings have helped to clarify the ethiology and pathogenesis of the disease. Apart from impaired surfactant protein function, a key role in the development of PAP is played by signal pathway of granulocyte and macrophage colonies stimulating growth factor (GM-CSF) which is necessary for the functioning of alveolar macrophages and for surfactant homeostasis. Surfactant is partially degraded by alveolar macrophages that are stimulated by GM-CSF. The role of GM-CSF has been shown especially in primary PAP, which is currently considered an autoimmune disease involving the development of GM-CSF neutralising autoantibodies. Clinically, the disease may be silent or manifest with dyspnoeic symptoms triggered by exertion and cough. However, there is a 10 to 15% rate of patients who develop respiratory failure. Total pulmonary lavage is regarded as the standard method of treatment. In addition, recombinant human GM-CSF has been studied as a prospective therapy for the treatment of PAP.

• MeSH
• Macrophages, Alveolar * immunology   pathology   MeSH
• Granulocyte-Macrophage Colony-Stimulating Factor * metabolism   MeSH
• Humans MeSH
• Pulmonary Alveolar Proteinosis * pathology   MeSH
• Rare Diseases * pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Respirační selhání zůstává jedním z nejčastějších důvodů vedoucích k hospitalizaci na jednotkách intenzivní a resuscitační péče. etiologie tohoto stavu je poměrně široká, nicméně infekce dolních dýchacích cest převažují jako hlavní vyvolávající faktor. součástí léčby respiračního selhání je podpora či náhrada plicních funkcí pomocí oxygenoterapie, neinvazivní a invazivní umělé plicní ventilace a dále postupy zahrnující aplikaci inhalačního oxidu dusnatého či pronační polohu. V případech, kdy tyto metody selhávají, je nezbytná mimotělní podpora životních funkcí. V následující kazuistice se věnujeme komplikovanému průběhu pneumonie u pacienta, jehož zdravotní stav vyžadoval připojení na mimotělní membránovou oxygenaci a byl komplikován rozvojem septického šoku, masivním krvácením a renálním selháním.

Respiratory failure remains one of the most common reasons leading to hospitalization in paediatric intensive care units. the aetiology of this condition is quite broad, however, lower respiratory tract infections predominate as the main triggering factor. the treatment of respiratory insufficiency includes support or replacement of lung function by oxygen therapy, non-invasive and invasive mechanical ventilation, and procedures such as inhaled nitric oxide or prone positioning. in situations where these methods fail, extracorporeal life support is necessary. in the following case report, we discuss the complicated course of pneumonia in a patient whose condition required connection to extracorporeal membrane oxygenation and was complicated by development of septic shock, massive bleeding and renal failure.

• MeSH
• Diagnostic Imaging methods   MeSH
• Disseminated Intravascular Coagulation etiology   complications   MeSH
• Child MeSH
• Humans MeSH
• Extracorporeal Membrane Oxygenation * methods   MeSH
• Pneumonia * etiology   drug therapy   complications   MeSH
• Respiratory Insufficiency etiology   complications   therapy   MeSH
• Respiratory Syncytial Viruses pathogenicity   drug effects   MeSH
• Shock, Septic etiology   complications   MeSH
• Positive-Pressure Respiration methods   instrumentation   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

Stresová kardiomyopatie je klinický syndrom, při kterém dochází k rozvoji myokardiální dysfunkce v reakci na stres. Častým spouštěčem bývá neurologické onemocnění, nejčastěji netraumatické subarachnoidální krvácení a ischemická CMP. Rozvoj stresové kardiomyopatie může být u těchto pacientů příčinou arteriální hypotenze, arytmií nebo akutního srdečního selhání. I přes reverzibilitu onemocnění je zvláště její sekundární forma nebezpečná pro riziko rozvoje závažných komplikací. Kauzální léčba se zaměřuje na eliminaci příčiny, další terapie je symptomatická, vedená echokardiografickým nálezem. Cílem tohoto přehledového článku je shrnutí dosavadních znalostí ohledně stresové kardiomyopatie se zaměřením na recentní postupy v diagnostice a terapii a zdůraznění jejich odlišností u pacientů s neurologickým onemocněním.

Stress cardiomyopathy stands for a clinical syndrome characterized by the onset of myocardial dysfunction caused by stressful event. A common trigger is neurological disease, most commonly non-traumatic subarachnoid hemorrhage and ischemic stroke. The development of stress cardiomyopathy may cause arterial hypotension, arrhythmias, or acute heart failure in these patients. Despite the reversibility of the disease, its secondary form is particularly dangerous because of the risk of developing serious complications. Causal treatment focuses on eliminating the cause; further therapy is symptomatic, guided by echocardiographic findings. The aim of this review article is to summarize the current knowledge regarding stress cardiomyopathy focusing on up- -to-date diagnostics and treatment and highlight their differences in patients with neurological disease.

• MeSH
• Acute Coronary Syndrome etiology   MeSH
• Stroke complications   MeSH
• Humans MeSH
• Risk Factors MeSH
• Subarachnoid Hemorrhage complications   MeSH
• Takotsubo Cardiomyopathy * diagnosis   etiology   complications   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH