Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.
- MeSH
- aplikace orální MeSH
- bolest farmakoterapie MeSH
- emulze MeSH
- kanabidiol * farmakologie chemie MeSH
- klinické křížové studie MeSH
- krysa rodu rattus MeSH
- kvalita života MeSH
- revmatoidní artritida * farmakoterapie MeSH
- voda MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In contrast to conventional diffusion magnetic resonance imaging (MRI), multi-b-value diffusion MRI methods are able to separate the signal from free water, pseudo-diffusion, and non-Gaussian components of water molecule diffusion. These approaches can then be utilised in so-called intravoxel incoherent motion imaging and diffusion kurtosis imaging. Various parameters provided by these methods can describe additional characteristics of the tissue microstructure and potentially help in the diagnosis and classification of various pathological processes. In this review, we present the basic principles and methods of analysing multi-b-value diffusion imaging data and specifically focus on the known possibilities for its use in the diagnosis of brain lesions. We also suggest possible directions for further research.
- MeSH
- difuzní magnetická rezonance * metody MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- mozek diagnostické zobrazování MeSH
- nemoci nervového systému * MeSH
- pohyb těles MeSH
- senzitivita a specificita MeSH
- voda MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Viral infection may represent a stress condition to the host cell. Cells react to it by triggering the defence programme to restore homeostasis and these events may in turn impact the viral replication. The knowledge about tick-borne encephalitis virus (TBEV) infection-associated stress is limited. Here we investigated the interplay between TBEV infection and stress pathways in PMJ2-R mouse macrophage cell line, as macrophages are the target cells in early phases of TBEV infection. First, to determine how stress influences TBEV replication, the effect of stress inducers H2O2 and tunicamycin (TM) was tested. Viral multiplication was decreased in the presence of both stress inducers suggesting that the stress and cellular stress responses restrict the virus replication. Second, we investigated the induction of oxidative stress and endoplasmic reticulum (ER) stress upon TBEV infection. The level of oxidative stress was interrogated by measuring the reactive oxygen species (ROS). ROS were intermittently increased in infected cells at 12 hpi and at 72 hpi. As mitochondrial dysfunction may result in increased ROS level, we evaluated the mitochondrial homeostasis by measuring the mitochondrial membrane potential (MMP) and found that TBEV infection induced the hyperpolarization of MMP. Moreover, a transient increase of gene expression of stress-induced antioxidative enzymes, like p62, Gclm and Hmox1, was detected. Next, we evaluated the ER stress upon TBEV infection by analysing unfolded protein responses (UPR). We found that infection induced gene expression of two general sensors BiP and CHOP and activated the IRE1 pathway of UPR. Finally, since the natural transmission route of TBEV from its tick vector to the host is mediated via tick saliva, the impact of tick saliva from Ixodes ricinus on stress pathways in TBEV-infected cells was tested. We observed only marginal potentiation of UPR pathway. In conclusion, we found that TBEV infection of PMJ2-R cells elicits the changes in redox balance and triggers cellular stress defences, including antioxidant responses and the IRE1 pathway of UPR. Importantly, our results revealed the negative effect of stress-evoked events on TBEV replication and only marginal impact of tick saliva on stress cellular pathways.
- MeSH
- buněčné linie MeSH
- klíšťová encefalitida * MeSH
- myši MeSH
- peroxid vodíku metabolismus MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- replikace viru MeSH
- viry klíšťové encefalitidy * genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Long-term peritoneal dialysis is associated with the development of peritoneal membrane alterations, both in morphology and function. Impaired ultrafiltration (UF) is the most important functional change, and peritoneal fibrosis is the major morphological alteration. Both are caused by the continuous exposure to dialysis solutions that are different from plasma water with regard to the buffer substance and the extremely high-glucose concentrations. Glucose has been incriminated as the major cause of long-term peritoneal membrane changes, but the precise mechanism has not been identified. We argue that glucose causes the membrane alterations by peritoneal pseudohypoxia and by the formation of advanced glycosylation end products (AGEs). After a summary of UF kinetics including the role of glucose transporters (GLUT), and a discussion on morphologic alterations, relationships between function and morphology and a survey of the pathogenesis of UF failure (UFF), it will be argued that impaired UF is partly caused by a reduction in small pore fluid transport as a consequence of AGE-related vasculopathy and - more importantly - in diminished free water transport due to pseudohypoxia, caused by increased peritoneal cellular expression of GLUT-1. The metabolism of intracellular glucose will be reviewed. This occurs in the glycolysis and in the polyol/sorbitol pathway, the latter is activated in case of a large supply. In both pathways the ratio between the reduced and oxidised form of nicotinamide dinucleotide (NADH/NAD+ ratio) will increase, especially because normal compensatory mechanisms may be impaired, and activate expression of hypoxia-inducible factor-1 (HIF-1). The latter gene activates various profibrotic factors and GLUT-1. Besides replacement of glucose as an osmotic agent, medical treatment/prevention is currently limited to tamoxifen and possibly Renin/angiotensis/aldosteron (RAA) inhibitors.
- MeSH
- dialyzační roztoky škodlivé účinky metabolismus MeSH
- glukosa škodlivé účinky metabolismus MeSH
- glykosylace MeSH
- lidé MeSH
- peritoneální dialýza * škodlivé účinky MeSH
- peritoneum metabolismus MeSH
- ultrafiltrace MeSH
- voda metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
V tomto článku autoři seznamují čtenáře se zajímavou kazuistikou pacienta, horníka pracujícího 18 let v hornictví, dispenzarizovaného na Klinice pracovního lékařství Fakultní nemocnice Plzeň pro dvě nemoci z povolání – pneumokonióza uhlokopa prostá byla hlášená jako nemoc z povolání v roce 1993 a onemocnění kloubů a nervů z vibrací bylo hlášeno o rok později. Pacient se od roku 2015 nedostavoval k našim pravidelným kontrolám podle dispenzárního řádu. K vyšetření se dostavil až v září 2023, kdy bylo zjištěno, že se od roku 2020 léčí pro karcinom plic. V článku je shrnuta etiopatogeneze a diagnostika pneumokonióz, problematika kritérií pro uznávání těchto nemocí z povolání, počet nově hlášených nemoci z povolání v souvislosti s hornictvím, problematika v souvislosti s prací při těžbě v černouhelných dolech a expozice oxidu křemičitého (SiO2). Krátce je zde přiblížena historie hornické činnosti v okolí Plzně, konkrétně z oblasti výkonu práce našeho pacienta před ukončením práce v dolech.
In this article, the authors introduce the reader to an interesting patient case report of a patient, a miner who worked in mining for 18 years, who was treated at our Occupational Medicine Clinic of the Pilsen University Hospital for two occupational diseases – pneumoconiosis in a miner was reported as an occupational disease in 1993 and vibration joint and nerve disease was reported a year later. Since 2015, the patient has not attended our regular check-ups according to dispensary regulations. He did not come for an examination until September 2023, when it was discovered that he was being treated for lung cancer from 2020. The article summarizes the etiopathogenesis and diagnosis of pneumoconioses, the issue of criteria for the recognition of these occupational diseases, the number of newly reported occupational diseases in connection with mining, issues related to work in coal mines and exposure to silicon dioxide (SiO2). The history of mining activity in the vicinity of Pilsen is briefly explained here, specifically from the area of our patient‘s work performance before ending his work in the mines.
- MeSH
- antrakóza diagnóza etiologie MeSH
- horníci * MeSH
- lidé MeSH
- nádory plic diagnóza etiologie terapie MeSH
- nemoci kloubů diagnóza etiologie MeSH
- nemoci z povolání * diagnóza MeSH
- oxid křemičitý toxicita MeSH
- pracovní expozice MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: Heart failure (HF) is a frequent cause of morbidity and mortality of end-stage kidney disease (ESKD) patients on hemodialysis. It is not easy to distinguish HF from water overload. The traditional HF definition has low sensitivity and specificity in this population. Moreover, many patients on hemodialysis have exercise limitations unrelated to HF. Therefore, we postulated two new HF definitions ((1) Modified definition of the Acute Dialysis Quality Improvement working group; (2) Hemodynamic definition based on the calculation of the effective cardiac output). We hypothesize that the newer definitions will better identify patients with higher number of endpoints and with more advanced structural heart disease. METHODS: Cohort, observational, longitudinal study with recording predefined endpoints. Patients (n = 300) treated by hemodialysis in six collaborating centers will be examined centrally in a tertiary cardiovascular center every 6-12 months lifelong or till kidney transplantation by detailed expert echocardiography with the calculation of cardiac output, arteriovenous dialysis fistula flow volume calculation, bio-impedance, and basic laboratory analysis including NTproBNP. Effective cardiac output will be measured as the difference between measured total cardiac output and arteriovenous fistula flow volume and systemic vascular resistance will be also assessed non-invasively. In case of water overload during examination, dry weight adjustment will be recommended, and the patient invited for another examination within 6 weeks. A composite major endpoint will consist of (1) Cardiovascular death; (2) HF worsening/new diagnosis of; (3) Non-fatal myocardial infarction or stroke. The two newer HF definitions will be compared with the traditional one in terms of time to major endpoint analysis. DISCUSSION: This trial will differ from others by: (1) detailed repeated hemodynamic assessment including arteriovenous access flow and (2) by careful assessment of adequate hydration to avoid confusion between HF and water overload.
- MeSH
- chronická renální insuficience * komplikace MeSH
- chronické selhání ledvin * diagnóza terapie komplikace MeSH
- dialýza ledvin škodlivé účinky MeSH
- lidé MeSH
- longitudinální studie MeSH
- pozorovací studie jako téma MeSH
- srdeční selhání * diagnóza etiologie terapie MeSH
- voda MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- protokol klinické studie MeSH
- Geografické názvy
- Česká republika MeSH
Cryopreservation of spheroids requires development of new improved methods. The plasma membranes permeability coefficients for water and cryoprotectants determine time characteristics of mass transfer through the cell membranes, and therefore the optimal modes of cells cryopreservation. Here we proposed an approach to cryopreservation of multicellular spheroids which considers their generalized characteristics as analogues of the membranes' permeability coefficients of the individual cells. We have determined such integral characteristics of spheroids from mesenchymal stromal cells (MSCs) as osmotically inactive volume; permeability coefficients for water and Me2SO molecules and the activation energy of their penetration. Based on these characteristics, we calculated the osmotic behavior of multicellular spheroids under cooling conditions to select the optimal cooling rate. We also determined the optimal cooling rate of spheroids using the probabilistic model developed based on the two-factor theory of cryodamage. From the calculation it follows that the optimal cooling rate of the MSC-based spheroids is 0.75°С/min. To verify the obtained theoretical estimates, we conducted experiments on freezing MSC-based spheroids under different modes. The obtained results of primary viability screening indicate that freezing at a constant linear cooling rate of 0.75-1.0°С/min gives a good result. Theoretical prediction of the spheroid osmotic behavior during cooling provided the basis for experimental verification of varying the temperature to which slow cooling should be carried out before immersion in liquid nitrogen. Slow freezing of spheroids to -40 °C followed by immersion in liquid nitrogen was shown to preserve cells better than slow freezing to -80 °C. Obtained data allow more effective use of MSC-based spheroids in drug screening and regenerative medicine.
- MeSH
- buněčné sféroidy * cytologie MeSH
- kryoprezervace * metody MeSH
- kryoprotektivní látky * farmakologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- mezenchymální kmenové buňky * cytologie MeSH
- permeabilita buněčné membrány MeSH
- viabilita buněk * MeSH
- voda chemie MeSH
- zmrazování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Flavonoids are considered as health-protecting food constituents. The testing of their biological effects is however hampered by their low oral absorption and complex metabolism. In order to investigate the direct effect(s) of unmetabolized flavonoid, a preparation in a biologically friendly solvent for intravenous administration is needed. Isorhamnetin, a natural flavonoid and a human metabolite of the most frequently tested flavonoid quercetin, has very low water solubility (<3.5 μg/mL). The aim of this study was to improve its solubility to enable intravenous administration and to test its pharmacokinetics in an animal model. By using polyvinylpyrrolidone (PVP10) and benzalkonium chloride, we were able to improve the solubility approximately 600 times to 2.1 mg/mL. This solution was then administered intravenously at a dose of 0.5 mg/kg of isorhamnetin to rats and its pharmacokinetics was analyzed. The pharmacokinetics of isorhamnetin corresponded to two compartmental model with a rapid initial distribution phase (t1/2α: 5.7 ± 4.3 min) and a slower elimination phase (t1/2β: 61 ± 47.5 min). Two sulfate metabolites were also identified. PVP10 and benzalkonium did not modify the properties of isorhamnetin (iron chelation and reduction, and cell penetration) substantially. In conclusion, the novel preparation reported in this study is suitable for future testing of isorhamnetin effects under in vivo conditions.
- MeSH
- benzalkoniové sloučeniny farmakokinetika chemie MeSH
- intravenózní podání * MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- povidon * chemie MeSH
- quercetin * farmakokinetika analogy a deriváty aplikace a dávkování chemie MeSH
- rozpustnost * MeSH
- voda * chemie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
We analyzed gene expression in THP-1 cells exposed to metal-based nanomaterials (NMs) [TiO2 (NM-100), ZnO (NM-110), SiO2 (NM-200), Ag (NM-300 K)]. A functional enrichment analysis of the significant differentially expressed genes (DEGs) identified the key modulated biological processes and pathways. DEGs were used to construct protein-protein interaction networks. NM-110 and NM-300 K induced changes in the expression of genes involved in oxidative and genotoxic stress, immune response, alterations of cell cycle, detoxification of metal ions and regulation of redox-sensitive pathways. Both NMs shared a number of highly connected protein nodes (hubs) including CXCL8, ATF3, HMOX1, and IL1B. NM-200 induced limited transcriptional changes, mostly related to the immune response; however, several hubs (CXCL8, ATF3) were identical with NM-110 and NM-300 K. No effects of NM-100 were observed. Overall, soluble nanomaterials NM-110 and NM-300 K exerted a wide variety of toxic effects, while insoluble NM-200 induced immunotoxicity; NM-100 caused no detectable changes on the gene expression level.
- MeSH
- hemoxygenasa-1 MeSH
- interleukin-8 metabolismus genetika MeSH
- kovové nanočástice toxicita MeSH
- lidé MeSH
- mapy interakcí proteinů * účinky léků MeSH
- nanostruktury toxicita MeSH
- oxid křemičitý toxicita MeSH
- oxid zinečnatý toxicita chemie MeSH
- stříbro * toxicita MeSH
- THP-1 buňky MeSH
- titan * toxicita MeSH
- transkripční faktor ATF3 genetika metabolismus MeSH
- transkriptom účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Fontány a další městské vodní prvky sice nejsou určeny přímo ke koupání, ale řada z nich svým charakterem k přímému kontaktu s vodou vybízí. Jednotlivé objekty jsou však navrhovány s různou mírou erudovanosti v problematice hygieny vody a tedy i s odlišnou technologií úpravy, recirkulací nebo návody k obsluze. V loňském roce bylo vydáno Metodické doporučení pro bezpečný provoz interaktivních městských vodních prvků, vodních hřišť a vodních parků, které je nezávazné a vzniklo jako pomůcka pro provozování a kontrolu těchto objektů za účelem zvýšení bezpečnosti a omezení možných zdravotních rizik souvisejících s jejich užíváním. Toto metodické doporučení vzniklo především na základě našich výsledků, jejichž shrnutí zde uvádíme. Hlavní hygienická rizika při kontaktu osob s vodou ve fontánách a dalších vodních prvcích souvisejí především s mikrobiálním znečištěním (střevní patogeny s fekálně orálním přenosem či mikroby, u nichž jsou potenciální rizika spojena se stykem s kůží a hlavně se sliznicemi). Z neinfekčních rizik je třeba upozornit na kluzké biofilmy u fontán s vodotrysky (nebezpečí uklouznutí a následného zranění) a na možnost výskytu vedlejších produktů dezinfekce – sliznice a dýchací cesty dráždící trichloramin či z karcinogenního účinku podezřelé trihalogenmetany u nadměrně chlorovaných vodních prvků.
Fountains and other urban water features are not designed for bathing, but many of them encourage direct contact with the water. Individual objects, however, are designed with varying degrees of erudition in water hygiene and therefore also with different modification of treatment technologies, water recirculation and operating instructions. Methodological Guidelines for the Safe Operation of Interactive Urban Water Features, Water Playgrounds and Water Parks was issued last year. It is not mandatory, but it was created as guidance to increase safety and possibly reduce health risks related to their use. The Guidelines were created primarily on the basis of our results, the assessment is summarized here. The key hygiene risks when people come into contact with water in fountains and other water features are mainly related to microbial pollution (intestinal pathogens with fecal-oral transmission or microbes with potential risks associated with contact with the skin and mainly with mucous membranes). Among the non-infectious risks, the attention should be drawn to slippery biofilms in fountains with water jets (danger of slipping and subsequent injury) and to the possibility of the occurrence of disinfection by-products - trichloramine, which irritates the mucous membranes and respiratory tract, or trihalogenmethane, suspected of having a carcinogenic effect, in excessively chlorinated water elements.
- Klíčová slova
- městské vodní prvky,
- MeSH
- kvalita vody MeSH
- lidé MeSH
- pitná voda * mikrobiologie MeSH
- znečištění vody analýza MeSH
- Check Tag
- lidé MeSH
