Glucocorticoids are potent anti-inflammatory drugs, although their use is associated with severe side effects. Loading glucocorticoids into suitable nanocarriers can significantly reduce these undesirable effects. Macrophages play a crucial role in inflammation, making them strategic targets for glucocorticoid-loaded nanocarriers. The main objective of this study is to develop a glucocorticoid-loaded PLGA nanocarrier specifically targeting liver macrophages, thereby enabling the localized release of glucocorticoids at the site of inflammation. Dexamethasone acetate (DA)-loaded PLGA nanospheres designed for passive macrophage targeting are synthesized using the nanoprecipitation method. Two types of PLGA NSs in the size range of 100-300 nm are prepared, achieving a DA-loading efficiency of 19 %. Sustained DA release from nanospheres over 3 days is demonstrated. Flow cytometry analysis using murine bone marrow-derived macrophages demonstrates the efficient internalization of fluorescent dye-labeled PLGA nanospheres, particularly into pro-inflammatory macrophages. Significant down-regulation in pro-inflammatory cytokine genes mRNA is observed without apparent cytotoxicity after treatment with DA-loaded PLGA nanospheres. Subsequent experiments in mice confirm liver macrophage-specific nanospheres accumulation following intravenous administration using in vivo imaging, flow cytometry, and fluorescence microscopy. Taken together, the data show that the DA-loaded PLGA nanospheres are a promising drug-delivery system for the treatment of inflammatory liver diseases.
- MeSH
- antiflogistika farmakologie chemie MeSH
- dexamethason * farmakologie chemie analogy a deriváty MeSH
- játra * účinky léků metabolismus MeSH
- kopolymer kyseliny glykolové a mléčné * chemie MeSH
- makrofágy * účinky léků metabolismus MeSH
- myši MeSH
- nanokuličky * chemie MeSH
- nosiče léků chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
During development, tooth germs undergo various morphological changes resulting from interactions between the oral epithelium and ectomesenchyme. These processes are influenced by the extracellular matrix, the composition of which, along with cell adhesion and signaling, is regulated by metalloproteinases. Notably, these include matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs). Our analysis of previously published scRNAseq datasets highlight that these metalloproteinases show dynamic expression patterns during tooth development, with expression in a wide range of cell types, suggesting multiple roles in tooth morphogenesis. To investigate this, Marimastat, a broad-spectrum inhibitor of MMPs, ADAMs, and ADAMTSs, was applied to ex vivo cultures of mouse molar tooth germs. The treated samples exhibited significant changes in tooth germ size and morphology, including an overall reduction in size and an inversion of the typical bell shape. The cervical loop failed to extend, and the central area of the inner enamel epithelium protruded. Marimastat treatment also disrupted proliferation, cell polarization, and organization compared with control tooth germs. In addition, a decrease in laminin expression was observed, leading to a disruption in continuity of the basement membrane at the epithelial-mesenchymal junction. Elevated hypoxia-inducible factor 1-alpha gene (Hif-1α) expression correlated with a disruption to blood vessel development around the tooth germs. These results reveal the crucial role of metalloproteinases in tooth growth, shape, cervical loop elongation, and the regulation of blood vessel formation during prenatal tooth development.NEW & NOTEWORTHY Inhibition of metalloproteinases during tooth development had a wide-ranging impact on molar growth affecting proliferation, cell migration, and vascularization, highlighting the diverse role of these proteins in controlling development.
- MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus genetika MeSH
- inhibitory matrixových metaloproteinas farmakologie MeSH
- kyseliny hydroxamové farmakologie MeSH
- metaloproteasy metabolismus genetika MeSH
- moláry embryologie růst a vývoj metabolismus enzymologie MeSH
- morfogeneze MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- odontogeneze * MeSH
- proliferace buněk * MeSH
- vývojová regulace genové exprese MeSH
- zubní zárodek embryologie metabolismus enzymologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Twenty-eight endurance-trained males aged 31.1 ± 10.2 years (body mass [BM] 81.9 ± 9.0 kg) completed this randomized double-blind placebo (PLA)-controlled crossover study investigating the effect of 12-week Colostrum Bovinum (COL) supplementation (25gCOL·day-1) on aerobic fitness and capacity, time to exhaustion, BM and body composition (BC), and blood lactate concentration. There were four main-before/after supplementation study visits (COLPRE and COLPOST; PLAPRE, and PLAPOST). During study visits, BM and BC evaluation, incremental rowing test (IRT) to exhaustion, and evaluation of resting (REST) and post-exercise (POST-IRT) blood lactate concentration were performed. COL, but not PLA supplementation, significantly increased (p < 0.05) time to ventilatory threshold (TVT). Moreover, the implemented treatments had large (mL·min-1) and moderate (mL·min-1·kg-1) effects on oxygen uptake at VT (VO2VT), as well as moderate effect on power output at VT (PVT; W·kg-1) with the highest values observed at COLPOST visit. Neither significant influence of COL supplementation on time to exhaustion (TEXH) in IRT, BM, and BC on blood lactate was observed. Importantly, there were significantly (p < 0.05) higher increases in VO2VT (mL·min-1 and mL·min-1·kg-1) after COL compared to PLA supplementation. In summary, COL supplementation resulted in a favorable increase in TVT, and tended to improve some of the evaluated threshold indicators, namely VO2VT and PVT in endurance-trained male athletes during IRT. Therefore, COL supplementation may be considered as a support to improve aerobic fitness and capacity in endurance-trained males; however, supplementation strategy must be personalized and properly incorporated into the individual training. TRIAL REGISTRATION: The study protocol was registered at ClinicalTrials.gov (NCT06390670).
- MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- fyzická vytrvalost * MeSH
- klinické křížové studie MeSH
- kolostrum * MeSH
- kyselina mléčná krev MeSH
- lidé MeSH
- mladý dospělý MeSH
- potravní doplňky * MeSH
- složení těla * MeSH
- spotřeba kyslíku MeSH
- vytrvalostní trénink * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.
- MeSH
- apoptóza * účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- histondeacetylasy metabolismus MeSH
- inhibitory histondeacetylas * farmakologie chemická syntéza chemie MeSH
- kyseliny hydroxamové * farmakologie chemická syntéza chemie MeSH
- kyseliny kumarové * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemická syntéza chemie MeSH
- screeningové testy protinádorových léčiv MeSH
- simulace molekulového dockingu MeSH
- THP-1 buňky MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia are considered emerging pathogens classified as a public health problem due to extensive antimicrobial resistance. Therefore, the discovery of new therapeutic strategies has become crucial. This study aimed to evaluate the antimicrobial activity of gallic acid and methyl gallate against non-fermenting bacteria. The study included five clinical isolates of Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia. The minimum inhibitory concentrations of gallic acid and methyl gallate were determined by the broth microdilution method. Growth curves, metabolic activity, and biofilm formation of each bacterial strain in the presence or absence of phenolic compounds were performed. Finally, the therapeutic efficacy of the compounds was evaluated using an in vivo model. Gallic acid and methyl gallate showed antibacterial activity against bacterial strains in a concentration range of 64 to 256 μg/mL, both compounds reduced bacterial growth and metabolic activity of the strains, even at subinhibitory concentrations. Only, methyl gallate exhibited activity to inhibit the formation of bacterial biofilms. Moreover, gallic acid and methyl gallate increased larval survival by up to 60% compared to 30% survival of untreated larvae in a bacterial infection model in Galleria mellonella. Our results highlight the potential of gallic acid and methyl gallate as therapeutic alternatives for infections by emerging non-fermentative bacteria.
The study focuses on the effects of fluvastatin on immunomarkers of the M1 and M2 macrophages and its direct role in macrophage (M0) polarization. Moreover, it investigates the dependency of immunomodulatory properties of fluvastatin on the mevalonate pathway. Macrophages (M0, M1, M2), differentiated from human blood monocytes, were treated with fluvastatin. Mevalonate and geranylgeranyl pyrophosphate intermediates were introduced to assess the mevalonate pathway dependence. The immunomarkers were evaluated with qPCR, ELISA, Griess assay, and flow cytometry. Fluvastatin significantly reduces the pro-inflammatory gene expression (NFκB, IL-1β, IL-6, iNOS) in M1 while enhancing the anti-inflammatory markers (Arg-1, TGFβ) in M2 macrophages. The production of the TNFα, IL-1β, and IL-6 cytokines is reduced in M1, and IL-10 production increased in M2 macrophages. Fluvastatin decreases the iNOS activity in M1 macrophages. The intermediates reverse the fluvastatin's effects on anti-inflammatory gene expression by M2 macrophages, cytokine production (by M1 and M2 macrophages), and iNOS activity (by M1 macrophages). Their impact on surface marker expression was somewhat limited. These findings demonstrate that fluvastatin exerts anti-inflammatory effects on polarized macrophages without affecting polarization per se and also highlight the dependency on the mevalonate pathway. This study deepens the understanding of statins' immunomodulatory mechanisms, suggesting potential applications in treating inflammatory diseases.
- MeSH
- antiflogistika * farmakologie MeSH
- cytokiny metabolismus MeSH
- fluvastatin * farmakologie MeSH
- kyselina mevalonová * metabolismus MeSH
- lidé MeSH
- makrofágy * účinky léků metabolismus imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
V České republice je zneužívání γ-hydroxybutyrátu (GHB) či jeho prekurzoru 1,4-butanediolu (1,4-BD) pro jejich euforizačně sedativní efekt nejspíše okrajovou záležitostí. V dostupné literatuře není evidován počet intoxikací GHB či počet hospitalizací nebo úmrtí po požití GHB. Práce podává základní údaje o farmakokinetických a farmakodynamických vlastnostech GHB a 1,4-BD a klinickém dopadu užívání těchto látek. Připojena je kazuistika mladého muže, který byl dvakrát hospitalizován pro poruchy chování v rámci intoxikace GHB.
In the Czech Republic, the abuse of γ-hydroxybutyrate (GHB), or its precursor 1,4-butanediol (1,4-BD), for euphoric and sedative effects is presumably uncommon. Among existing literature there are no statistics on intoxication, hospitalization, or fatality after ingestion of GHB. This report concerns the pharmacokinetic and pharmacodynamic background of GHB and 1,4-BD, as well as the clinical impact of their abu- se. Also included is a case report documenting a young man who was hospitalized twice for behavioural anomalies due to GHB intoxication.
- MeSH
- analýza vlasů metody MeSH
- benzodiazepinony aplikace a dávkování MeSH
- butylenglykoly * aplikace a dávkování farmakologie otrava škodlivé účinky MeSH
- hypnotika a sedativa aplikace a dávkování farmakologie otrava škodlivé účinky MeSH
- lidé MeSH
- mladiství MeSH
- otrava alkoholem etiologie farmakoterapie patologie MeSH
- otrava etiologie farmakoterapie patologie MeSH
- oxybát sodný analýza farmakologie metabolismus otrava MeSH
- poruchy spojené s užíváním psychoaktivních látek * etiologie farmakoterapie patologie MeSH
- poruchy způsobené alkoholem etiologie farmakoterapie patologie MeSH
- toxikologické jevy MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- přehledy MeSH
Numerous studies have reported that increased interleukin 6 (IL-6) and soluble IL-6 receptor (sIL-6) levels induce inflammatory conditions. However, the exact mechanisms by which IL-6 drives inflammatory conditions remain unclear. Therefore, we investigated the potential role of IL-6/sIL-6R in inducing energy metabolism, including glycolysis, oxidative phosphorylation, lactate secretion and Akt/mTOR phosphorylation, in Jurkat cells, and whether IL-6 would increase the risk of developing inflammatory conditions due to the high metabolic profile of the T cells. Jurkat CD4 T-cell lines were stimulated with IL-6/sIL-6R for 24 h prior to 48-h stimulation with anti-CD3/CD28. Lactate secretion, glycolysis and oxidative phosphorylation levels were characterized using the Seahorse XF analyser. The Akt and mTOR phosphorylation status was detected using Western blotting. IL-6/sIL-6R significantly induced glycolysis and oxidative phosphorylation and their related parameters, including glycolytic capacity and maximal respiration, followed by significantly increased lactate secretion. Akt and mTOR phosphorylation were increased, which could have resulted from energy metabolism. Here we show that IL-6 enhanced the metabolic profile of Jurkat cells. This effect could have consequences for the metabolism-related signalling pathways, including Akt and mTOR, suggesting that IL-6 might promote T-cell energy metabolism, where T-cell hyperactivity might increase the inflammatory disease risk. The findings should be validated using studies on primary cells isolated from humans.
- MeSH
- energetický metabolismus * účinky léků MeSH
- fosforylace účinky léků MeSH
- glykolýza účinky léků MeSH
- interleukin-6 * metabolismus MeSH
- Jurkat buňky MeSH
- kyselina mléčná metabolismus MeSH
- lidé MeSH
- oxidativní fosforylace účinky léků MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- signální transdukce * účinky léků MeSH
- TOR serin-threoninkinasy * metabolismus MeSH
- zánět * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Prokinetika jsou skupinou léčiv, které díky schopnosti stimulace hladké svaloviny zvyšují motilitu trávicího traktu, a to především v jeho proximální části. V současnosti se prokinetika využívají primárně pro léčbu funkční dyspepsie, ale uplatnění mohou nalézt i u jiných indikací. Pozitivního účinku na motilitu dosahují prostřednictvím mechanismů, které jsou v rámci skupiny prokinetik do značné míry heterogenní. Článek poskytuje čtenářům základní přehled informací vztahujícím se k jednotlivým prokinetikům aktuálně registrovaných na trhu v České republice, blíže popisuje jejich farmakologické účinky a diskutuje užití prokinetik v léčbě funkční dyspepsie a refluxní nemoci jícnu, což jsou nejčastější indikace k užití prokinetik v klinické praxi.
Prokinetics are a group of drugs that, due to their ability to stimulate smooth muscle contraction, enhance the motility of the digestive tract, particularly in its proximal part. Currently, prokinetics are primarily used to treat functional dyspepsia, though they may also be prescribed for other indications. They exert their positive effects on motility through mechanisms that vary within this drug class. This article provides readers with a basic overview of the prokinetic agents currently registered on the market in the Czech Republic, describes their pharmacological effects in more detail, and discusses the use of prokinetics in the treatment of functional dyspepsia and gastroesophageal reflux disease, which are the most common indications for the use of prokinetics in clinical practice.
- Klíčová slova
- prokinetika, cinitaprid, itoprid,
- MeSH
- benzamidy aplikace a dávkování farmakologie MeSH
- dyspepsie farmakoterapie MeSH
- gastroezofageální reflux farmakoterapie MeSH
- gastrointestinální látky * aplikace a dávkování klasifikace MeSH
- gastrointestinální motilita * účinky léků MeSH
- gastrointestinální nemoci farmakoterapie MeSH
- lidé MeSH
- metoklopramid farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Virové bradavice jsou celosvětově časté onemocnění způsobené lidským papilomavirem, který má řadu genotypů. Mnoho z těchto virů je komenzálních a u imunokompetentních hostitelů nevyvolávají žádné projevy. Za vhodných podmínek některé způsobují klinické změny na kůži nebo na sliznicích v anogenitální či orofaryngeální oblasti. U dětí se nejčastěji setkáváme s verruca vulgaris, verruca plantaris a verruca plana. Řada těchto projevů samovolně vymizí, problémem jsou perzistentní či úporně recidivující bradavice. Léčbou se snažíme nejen zlikvidovat viditelné změny za minimalizace bolesti a bez jizvení, ale také o prevenci recidivy ať již v místě původní bradavice nebo kdekoli jinde na těle.
Viral warts are a common disease worldwide caused by the human papillomavirus, which has a number of genotypes. Many of these viruses are commensal and do not cause any symptoms in immunocompetent hosts. Under appropriate conditions, however, some cause clinical changes on the skin or mucous membranes in the anogenital or oropharyngeal part. Verruca vulgaris, verruca plantaris and verruca plana are most often encountered in children. Many of these manifestations disappear on their own, the problem is persistent or stubbornly recurring warts. With the treatment, we try not only to eliminate visible changes while minimizing pain and without scarring, but also to prevent recurrence, whether at the site of the original wart or anywhere else on the body.
- MeSH
- bradavice * farmakoterapie terapie MeSH
- dítě * MeSH
- fluoruracil farmakologie terapeutické užití MeSH
- infekce papilomavirem přenos terapie MeSH
- keratinocyty patologie MeSH
- kryoterapie metody MeSH
- kyselina salicylová terapeutické užití MeSH
- kyselina trichloroctová terapeutické užití MeSH
- lasery MeSH
- lidé MeSH
- podofylin farmakologie terapeutické užití MeSH
- Check Tag
- dítě * MeSH
- lidé MeSH
