Psoriasis is a chronic non-contagious autoimmune disease. Gallic acid is a natural compound with potential health benefits, including antioxidant, anticancer, antiviral and antibacterial properties. Nevertheless, the influence of gallic acid on psoriasis has not been fully determined. This investigation aimed to discover the effect of gallic acid on psoriasis. Thirty-one pairs of psoriatic skin tissues and healthy adult human skin tissues were collected. Human keratinocytes (HaCaT cells) were transfected with interleukin 17A (IL-17A) to create the psoriatic keratinocyte model. The content of bromodomain-containing protein 4 (BRD4) microRNA was assessed using qRT-PCR testing. The content of BRD4 was detected by Western blotting. Cell migration was evaluated by conducting a wound healing assay. Cell proliferation was determined using an EdU assay. Apoptosis was detected by the TUNEL assay. The contents of interferon gamma (IFN-γ), IL-6, IL-8 and IL-17 were detected by ELISA. BRD4 was up-regulated in psoriatic skin tissues and in the IL-17A group compared to the healthy adult human skin tissues and the control group. Silencing BRD4 inhibited cell migration, proliferation and inflammatory response but induced apoptosis in IL-17A-treated HaCaT cells. Conversely, BRD4 over-expression promoted cell migration, proliferation and inflammatory response but suppressed apoptosis in IL-17A-treated HaCaT cells. Gallic acid repressed cell migration, proliferation and inflammatory response but indu-ced apoptosis in HaCaT cells transfected with IL-17A by down-regulating BRD4. Gallic acid represses cell migration, proliferation and inflammatory response but induces apoptosis in IL-17A-transfected HaCaT cells by down-regulating BRD4.

• MeSH
• apoptóza * účinky léků   MeSH
• buněčné linie keratinocytů HaCaT MeSH
• buněčné linie MeSH
• dospělí MeSH
• interleukin-17 metabolismus   MeSH
• jaderné proteiny metabolismus   genetika   MeSH
• keratinocyty * účinky léků   metabolismus   MeSH
• kyselina gallová * farmakologie   MeSH
• lidé MeSH
• mikro RNA genetika   metabolismus   MeSH
• pohyb buněk * účinky léků   MeSH
• proliferace buněk * účinky léků   MeSH
• proteiny buněčného cyklu * metabolismus   genetika   MeSH
• proteiny obsahující bromodoménu MeSH
• psoriáza * metabolismus   patologie   farmakoterapie   MeSH
• regulace genové exprese účinky léků   MeSH
• transkripční faktory * metabolismus   MeSH
• zánět * patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Plasmalogens (vinyl-ether phospholipids) are an emergent class of lipid drugs against various diseases involving neuro-inflammation, oxidative stress, mitochondrial dysfunction, and altered lipid metabolism. They can activate neurotrophic and neuroprotective signaling pathways but low bioavailabilities limit their efficiency in curing neurodegeneration. Here, liquid crystalline lipid nanoparticles (LNPs) are created for the protection and non-invasive intranasal delivery of purified scallop-derived plasmalogens. The in vivo results with a transgenic mouse Parkinson's disease (PD) model (characterized by motor impairments and α-synuclein deposition) demonstrate the crucial importance of LNP composition, which determines the self-assembled nanostructure type. Vesicle and hexosome nanostructures (characterized by small-angle X-ray scattering) display different efficacy of the nanomedicine-mediated recovery of motor function, lipid balance, and transcriptional regulation (e.g., reduced neuro-inflammation and PD pathogenic gene expression). Intranasal vesicular and hexosomal plasmalogen-based LNP treatment leads to improvement of the behavioral PD symptoms and downregulation of the Il6, Il33, and Tnfa genes. Moreover, RNA-sequencing and lipidomic analyses establish a dramatic effect of hexosomal nanomedicines on PD amelioration, lipid metabolism, and the type and number of responsive transcripts that may be implicated in neuroregeneration.

• MeSH
• aplikace intranazální * MeSH
• liposomy MeSH
• metabolismus lipidů účinky léků   MeSH
• modely nemocí na zvířatech * MeSH
• myši transgenní MeSH
• myši MeSH
• nanočástice * chemie   MeSH
• nanomedicína * metody   MeSH
• Parkinsonova nemoc * metabolismus   farmakoterapie   MeSH
• plasmalogeny * chemie   farmakologie   MeSH
• regulace genové exprese účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In this study, we tested a method for long-term storage of oral mucosal epithelial cells (OMECs) so that the cells could be expanded in vitro after cryopreservation and used for the treatment of bilateral limbal stem cell deficiency. The ability of suspended primary OMECs to proliferate in vitro after cryopreservation was compared to that of OMEC cultures that had undergone the same process. Both were preserved in standard complex medium (COM) with or without cryoprotective agents (CPAs) (gly-cerol at 5 % or 10 % or dimethyl sulphoxide at 10 %). We found that after cryopreservation, primary OMECs could form a confluent cell sheet only in a few samples after 22 ± 2.9 (mean ± SD) days of cultivation with 72.4 % ± 12.9 % overall viability. Instead, all ex vivo OMEC cultures could re-expand after cryopreservation with a comparable viability of 78.6 ± 13.8 %, like primary OMECs, but with significantly faster growth rate (adj. P < 001), forming a confluent cell sheet at 13.7 ± 3.9 days. Gene expression analyses of the ex vivo expansion of OMEC cultures showed that the stemness, proliferation and differentiation-related gene expression was similar before and after cryopreservation, except for KRT13 expres-sion, which significantly decreased after the second passage (adj. P < 0.05). The addition of CPAs had no effect on these outcomes. In conclusion, the optimal strategy for OMEC preservation is to freeze the cells that have been previously cultured, in order to maintain cell viability and the capacity to create a sizable graft even without CPAs.

• MeSH
• buněčná diferenciace účinky léků   MeSH
• časové faktory MeSH
• epitelové buňky * účinky léků   cytologie   metabolismus   MeSH
• kmenové buňky * účinky léků   cytologie   metabolismus   MeSH
• kryoprezervace * metody   MeSH
• kryoprotektivní látky * farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• proliferace buněk * účinky léků   MeSH
• regulace genové exprese účinky léků   MeSH
• ústní sliznice * cytologie   účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Alisertib (MLN8237), a novel Aurora A kinase inhibitor, is currently being clinically tested in late-phase trials for the therapy of various malignancies. In the present work, we describe alisertib's potential to perpetrate pharmacokinetic drug-drug interactions (DDIs) and/or to act as an antagonist of multidrug resistance (MDR). In accumulation assays, alisertib potently inhibited ABCC1 transporter, but not ABCB1 or ABCG2. The results of molecular modeling suggested a bifunctional mechanism for interaction on ABCC1. In addition, alisertib was characterized as a low- to moderate-affinity inhibitor of recombinant CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 isoenzymes, but without potential clinical relevance. Drug combination studies revealed the capability of alisertib to synergistically antagonize ABCC1-mediated resistance to daunorubicin. Although alisertib exhibited substrate characteristics toward ABCB1 transporter in monolayer transport assays, comparative proliferation studies showed lack of its MDR-victim behavior in cells overexpressing ABCB1 as well as ABCG2 and ABCC1. Lastly, alisertib did not affect the expression of ABCC1, ABCG2, ABCB1 transporters and CYP1A2, CYP3A4, CYP2B6 isozymes on mRNA level in various systemic and tumoral models. In conclusion, our study suggests that alisertib is a drug candidate with negligible potential for perpetrating systemic pharmacokinetic DDIs on ABCB1, ABCG2 and cytochromes P450. In addition, we introduce alisertib as an effective dual-activity chemosensitizer whose MDR-antagonistic capacities are not impaired by efflux or effect on MDR phenotype. Our in vitro findings provide important pieces of information for clinicians when introducing alisertib into the clinical area.

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   metabolismus   MeSH
• azepiny farmakokinetika   farmakologie   MeSH
• buněčné linie MeSH
• katalytická doména MeSH
• konformace proteinů MeSH
• lékové interakce MeSH
• lidé MeSH
• molekulární modely MeSH
• P-glykoprotein genetika   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům antagonisté a inhibitory   MeSH
• psi MeSH
• pyrimidiny farmakokinetika   farmakologie   MeSH
• regulace genové exprese účinky léků   MeSH
• simulace molekulového dockingu MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Dabrafenib is a BRAF inhibitor used in combination treatment of malignant melanoma and non-small cell lung carcinoma. In this study, we aimed to characterize its interactions with cytochrome P450 (CYP) isoenzymes and ATP-binding cassette (ABC) efflux transporters that have critical impact on the pharmacokinetics of drugs and play a role in drug resistance development. Using accumulation assays, we showed that dabrafenib inhibited ABCG2 and, less potently, ABCB1 transporter. We also confirmed dabrafenib as a CYP2C8, CYP2C9, CYP3A4, and CYP3A5 inhibitor. Importantly, inhibition of ABCG2 and CYP3A4 by dabrafenib led to the potentiation of cytotoxic effects of mitoxantrone and docetaxel toward respective resistant cell lines in drug combination studies. On the contrary, the synergistic effect was not consistently observed in ABCB1-expressing models. We further demonstrated that mRNA levels of ABCB1, ABCG2, ABCC1, and CYP3A4 were increased after 24 h and 48 h exposure to dabrafenib. Overall, our data confirm dabrafenib as a drug frequently and potently interacting with ABC transporters and CYP isoenzymes. This feature should be addressed with caution when administering dabrafenib to patients with polypharmacy but also could be utilized advantageously when designing new dabrafenib-containing drug combinations to improve the therapeutic outcome in drug-resistant cancer.

• MeSH
• ABC transportér z rodiny G, člen 2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• antitumorózní látky aplikace a dávkování   farmakologie   MeSH
• buňky MDCK MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• daunomycin aplikace a dávkování   farmakologie   MeSH
• imidazoly aplikace a dávkování   farmakokinetika   MeSH
• inhibitory cytochromu P450 aplikace a dávkování   farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• mitoxantron aplikace a dávkování   farmakologie   MeSH
• nádorové buněčné linie MeSH
• oximy aplikace a dávkování   farmakokinetika   MeSH
• P-glykoprotein antagonisté a inhibitory   genetika   metabolismus   MeSH
• psi MeSH
• regulace genové exprese účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Zvýšené hladiny LDL-cholesterolu (LDL-C) a triglyceridů (TG) představují významné rizikové faktory aterosklerotických kardiovaskulárních onemocnění (ASKVO). Přes významné pokroky medicíny v oblasti hypolipidemik nedokážeme v současné době u řady pacientů dosáhnout cílů v léčbě dyslipidemií. Během posledních dvou dekád je intenzivně studována molekula ANGPTL3 (angiopoietin-like 3), jejíž inaktivace pomocí monoklonálních protilátek, antisense oligonukleotidů aj. představuje nový a slibný léčebný prostředek ke snížení plazmatické koncentrace LDL-C a TG. ANGPTL3 je faktor secernovaný játry, který inhibuje lipoproteinovou lipázu (LPL) a jiné lipázy cestou tvorby komplexu s příbuzným proteinem ANGPTL8. Rozsáhlé genetické studie u jedinců, kteří jsou nositelé genetických variant spojených se ztrátou funkce (LOF – loss-of-function) ANGPTL3, prokázaly vliv na snížení plazmatických koncentrací LDL-C a TG, ale i na snížení rizika ASKVO. Známy jsou již také výsledky klinických studií u pacientů s různými formami dyslipidemií, ve kterých inaktivace ANGPTL3 pomocí monoklonálních protilátek nebo antisense oligonukleotidů významně snižovala plazmatickou koncentraci LDL-C a TG. Z tohoto pohledu mají postupy využívající inhibici ANGPTL3 slibný terapeutický potenciál k redukci plazmatické koncentrace LDL-C a triglyceridů u vybraných skupin pacientů s dyslipidemií.

Elevated LDL-cholesterol (LDL-C) and triglyceride (TG) levels are significant risk factors for atherosclerotic cardiovascular diseases (ASCVD). Despite significant medical advances in the field of hypolipidemic drugs, we are currently unable to achieve our goals in treating dyslipidaemias in many patients. During the last two decades, the angiopoietin-like 3 (ANGPTL3) molecule has been intensively studied, and its inactivation by monoclonal antibodies, antisense oligonucleotides, etc. represents a new and promising therapeutic approach to reduce plasma LDL-C and TG concentrations. ANGPTL3 is a liver- secreted factor that inhibits lipoprotein lipase (LPL) and other lipases by forming a complex with the related protein ANGPTL8. Extensive genetic studies in individuals carrying ANGPTL3 loss-of-function variants have shown an effect on reducing plasma concentrations of LDL-C and TG, as well as the risk of ASCVD. Results from clinical trials in patients with various forms of dyslipidaemia, in which inactivation of ANGPTL3 with monoclonal antibodies or antisense oligonucleotides significantly reduced plasma LDL-C and TG concentrations, are also known. From this perspective, approaches using ANGPTL3 inhibition have promising therapeutic potential to reduce plasma LDL-C and triglyceride concentrations in selected groups of patients with dyslipidaemia.

• Klíčová slova
• endoteliální lipáza, evinakumab,
• MeSH
• angiopoetinu podobný protein 3 antagonisté a inhibitory   fyziologie   MeSH
• arteriální okluzní nemoci farmakoterapie   MeSH
• dyslipidemie * farmakoterapie   MeSH
• LDL-cholesterol analýza   MeSH
• lidé MeSH
• lipoproteinlipasa fyziologie   MeSH
• lipoproteiny metabolismus   MeSH
• monoklonální protilátky farmakologie   terapeutické užití   MeSH
• regulace genové exprese účinky léků   MeSH
• triglyceridy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Diamond-Blackfan anaemia (DBA) is a red blood cell aplasia that in the majority of cases is associated with ribosomal protein (RP) aberrations. However, the mechanism by which this disorder leads to such a specific phenotype remains unclear. Even more elusive is the reason why non-specific agents such as glucocorticosteroids (GCs), also known as glucocorticoids, are an effective therapy for DBA. In this review, we (1) explore why GCs are successful in DBA treatment, (2) discuss the effect of GCs on erythropoiesis, and (3) summarise the GC impact on crucial pathways deregulated in DBA. Furthermore, we show that GCs do not regulate DBA erythropoiesis via a single mechanism but more likely via several interdependent pathways.

• MeSH
• Diamondova-Blackfanova anemie farmakoterapie   metabolismus   MeSH
• erytropoéza účinky léků   MeSH
• genové regulační sítě účinky léků   MeSH
• glukokortikoidy farmakologie   terapeutické užití   MeSH
• lidé MeSH
• regulace genové exprese účinky léků   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Air pollution caused by road traffic has an unfavorable impact on the environment and also on human health. It has previously been shown, that complete gasoline emissions lead to toxic effects in cell models originating from human airways. Here we focused on extractable organic matter (EOM) from particulate matter, collected from gasoline emissions from fuels with different ethanol content. We performed cytotoxicity evaluation, quantification of mucin and extracellular reactive oxygen species (ROS) production, DNA breaks detection, and selected gene deregulation analysis, after one and five days of exposure of human bronchial epithelial model (BEAS-2B) and a 3D model of the human airway (MucilAirTM). Our data suggest that the longer exposure had more pronounced effects on the parameters of cytotoxicity and mucin production, while the impacts on ROS generation and DNA integrity were limited. In both cell models the expression of CYP1A1 was induced, regardless of the exposure period or EOM tested. Several other genes, including FMO2, IL1A, or TNF, were deregulated depending on the exposure time. In conclusion, ethanol content in the fuels did not significantly impact the toxicity of EOM. Biological effects were mostly linked to xenobiotics metabolism and inflammatory response. BEAS-2B cells were more sensitive to the treatment.

• MeSH
• benzin * MeSH
• bronchy cytologie   MeSH
• buněčné linie MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• epitelové buňky účinky léků   metabolismus   MeSH
• histony metabolismus   MeSH
• interleukin-1alfa genetika   MeSH
• látky znečišťující vzduch toxicita   MeSH
• lidé MeSH
• oxygenasy genetika   MeSH
• pevné částice toxicita   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• TNF-alfa genetika   MeSH
• výfukové emise vozidel toxicita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Perinatal exposure to Δ9-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.

• MeSH
• chování zvířat účinky léků   MeSH
• lidé MeSH
• maternofetální výměna látek MeSH
• messenger RNA metabolismus   MeSH
• metylace DNA účinky léků   MeSH
• potkani Sprague-Dawley MeSH
• prefrontální mozková kůra účinky léků   metabolismus   MeSH
• receptor kanabinoidní CB1 genetika   MeSH
• receptory dopaminu D2 genetika   MeSH
• regulace genové exprese účinky léků   MeSH
• schizofrenie genetika   MeSH
• těhotenství MeSH
• tetrahydrokanabinol farmakologie   MeSH
• zpožděný efekt prenatální expozice * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Background: Interleukin 40 (IL-40) is a newly identified B cell-associated cytokine implicated in humoral immune responses and B cell homeostasis. As B cells play a pivotal role in autoimmunity, we investigated the function of IL-40 in rheumatoid arthritis (RA). Methods: IL-40 expression was determined in the synovial tissue from RA and osteoarthritis (OA) patients. IL-40 was analysed in the serum/synovial fluid of patients with RA (n=50), systemic lupus erythematosus (SLE, n=69), OA (n=44), and healthy controls (HC, n=50). We assessed the changes of IL-40 levels in RA patients following the B cell depletion by rituximab (n=29) or after the TNF inhibition by adalimumab (n=25). We examined the relationship between IL-40, disease activity, autoantibodies, cytokines, and NETosis markers. Effect of IL-40 on synovial fibroblasts was determined. Results: IL-40 was overexpressed in RA synovial tissue, particularly by synovial lining and infiltrating immune cells. The levels of IL-40 were up-regulated in the synovial fluid of RA versus OA patients (p<0.0001). Similarly, IL-40 was increased in the serum of RA patients compared to HC, OA, or SLE (p<0.0001 for all) and decreased after 16 and 24 weeks (p<0.01 and p<0.01) following rituximab treatment. No significant effect of adalimumab on IL-40 was observed. IL-40 levels in RA patients correlated with rheumatoid factor-IgM and anti-cyclic citrullinated peptides (anti-CCP) in the serum (p<0.0001 and p<0.01), as well as in the synovial fluid (p<0.0001 and p<0.001). Synovial fluid IL-40 was also associated with disease activity score DAS28 (p<0.05), synovial fluid leukocyte count (p<0.01), neutrophil attractants IL-8 (p<0.01), MIP-1α (p<0.01), and markers of neutrophil extracellular traps externalization (NETosis) such as proteinase 3 (p<0.0001) and neutrophil elastase (p<0.0001). Synovial fibroblasts exposed to IL-40 increased the secretion of IL-8 (p<0.01), MCP-1 (p<0.05), and MMP-13 (p<0.01) compared to the unstimulated cells. Conclusions: We show the up-regulation of IL-40 in RA and its decrease following B cell depleting therapy. The association of IL-40 with autoantibodies, chemokines, and markers of NETosis may imply its potential involvement in RA development. Moreover, IL-40 up-regulates the secretion of chemokines and MMP-13 in synovial fibroblasts, indicating its role in the regulation of inflammation and tissue destruction in RA.

• MeSH
• adalimumab terapeutické užití   MeSH
• artróza kolenních kloubů imunologie   metabolismus   MeSH
• autoprotilátky krev   MeSH
• B-lymfocyty účinky léků   imunologie   MeSH
• biologické markery MeSH
• cytokiny analýza   MeSH
• dospělí MeSH
• extracelulární pasti imunologie   MeSH
• fibroblasty MeSH
• kohortové studie MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfocytární deplece MeSH
• matrixová metaloproteinasa 13 analýza   MeSH
• regulace genové exprese účinky léků   MeSH
• revmatoidní artritida genetika   imunologie   metabolismus   MeSH
• rituximab farmakologie   terapeutické užití   MeSH
• senioři MeSH
• synoviální membrána chemie   imunologie   MeSH
• synoviální tekutina chemie   imunologie   MeSH
• systémový lupus erythematodes imunologie   metabolismus   MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH