Transdermal drug delivery is a passive diffusion process of an active compound through the skin which is affected by drug solubility in the multilamellar lipidic matrix of the stratum corneum (SC). Widely used non-ionic surfactants (NIS) can be added into transdermal formulations to enhance the penetration of drugs by influencing the packing of the stratum corneum lipidic matrix. Objective of our study was to analyse the interaction between selected NIS and a simple SC lipidic matrix model system using a variety of surface-sensitive techniques based on the application of Langmuir monolayers. In this work, the well-known surfactant Polysorbate 80 was compared with a modern surfactant Sucrose monolaurate. Infrared reflection-absorption spectroscopy (IRRAS) and epifluorescence microscopy provide information about the effects of those surfactants on the SC model system. Monolayer isotherms of the SC model mixture indicate a very stiff and well-packed layer, however, packing defects are evidenced in epifluorescence studies. The injection of the two NIS underneath the SC monolayers proved their potential to penetrate into the SC model at the air-water interface having a maximum insertion pressure (MIP) above the assumed lateral pressure of biological membranes. The NIS adsorbed preferentially into packing defects seen in epifluorescence microscopy studies with Sucrose monolaurate being more active than Polysorbate 80 in disordering the SC monolayer.

• MeSH
• aplikace kožní MeSH
• biologické modely MeSH
• kůže * MeSH
• lipidy MeSH
• povrchově aktivní látky * MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. Implementation of high-dose cytarabine (araC) into induction therapy became standard-of-care for all newly diagnosed younger MCL patients. However, many patients relapse even after araC-based regimen. Molecular mechanisms responsible for araC resistance in MCL are unknown and optimal treatment strategy for relapsed/refractory MCL patients remains elusive. METHODS: Five araC-resistant (R) clones were derived by long-term culture of five MCL cell lines (CTRL) with increasing doses of araC up to 50 microM. Illumina BeadChip and 2-DE proteomic analysis were used to identify gene and protein expression changes associated with araC resistance in MCL. In vitro cytotoxicity assays and experimental therapy of MCL xenografts in immunodeficient mice were used to analyze their relative responsiveness to a set of clinically used anti-MCL drugs. Primary MCL samples were obtained from patients at diagnosis and after failure of araC-based therapies. RESULTS: Marked downregulation of deoxycytidine-kinase (DCK) mRNA and protein expression was identified as the single most important molecular event associated with araC-resistance in all tested MCL cell lines and in 50% primary MCL samples. All R clones were highly (20-1000x) cross-resistant to all tested nucleoside analogs including gemcitabine, fludarabine and cladribine. In vitro sensitivity of R clones to other classes of clinically used anti-MCL agents including genotoxic drugs (cisplatin, doxorubicin, bendamustine) and targeted agents (bortezomib, temsirolimus, rituximab) remained unaffected, or was even increased (ibrutinib). Experimental therapy of immunodeficient mice confirmed the anticipated loss of anti-tumor activity (as determined by overall survival) of the nucleoside analogs gemcitabine and fludarabine in mice transplanted with R clone compared to mice transplanted with CTRL cells, while the anti-tumor activity of cisplatin, temsirolimus, bortezomib, bendamustine, cyclophosphamide and rituximab remained comparable between the two cohorts. CONCLUSIONS: Acquired resistance of MCL cells to araC is associated with downregulation of DCK, enzyme of the nucleotide salvage pathway responsible for the first phosphorylation (=activation) of most nucleoside analogs used in anti-cancer therapy. The data suggest that nucleoside analogs should not be used in the therapy of MCL patients, who relapse after failure of araC-based therapies.

• MeSH
• 2D gelová elektroforéza MeSH
• buněčné klony MeSH
• chemorezistence účinky léků   MeSH
• cytarabin farmakologie   MeSH
• deoxycytidin analogy a deriváty   farmakologie   MeSH
• deoxycytidinkinasa metabolismus   MeSH
• down regulace účinky léků   MeSH
• hmotnostní spektrometrie MeSH
• kladribin farmakologie   MeSH
• lidé MeSH
• lymfom z plášťových buněk farmakoterapie   enzymologie   genetika   MeSH
• myší monoklonální protilátky farmakologie   terapeutické užití   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proteomika MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• stanovení celkové genové exprese MeSH
• vidarabin analogy a deriváty   farmakologie   MeSH
• western blotting MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• fyzikální jevy MeSH
• magnetická rezonanční tomografie MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• radiologie, nukleární medicína a zobrazovací metody
• NLK Publikační typ
• kolektivní monografie

In continuation of our search for new antimicrobial secondary metabolites from Bacillus cereus associated with rhabditid entomopathogenic nematode, a new microbial diketopiperazine, cyclo(L-Pro-D-Arg), was isolated from the ethyl acetate extract of fermented modified nutrient broth. The chemical structures of the isolated compounds were identified based on their 1D, 2D NMR and high-resolution electrospray ionisation-mass spectroscopy data. Antibacterial activity of the compound was determined by minimum inhibitory concentration and disc diffusion method against medically important bacteria, and the compound was recorded to have significant antibacterial activity against test bacteria. The highest activity was recorded against Klebsiella pneumoniae (1 μg/mL). Cyclo(L-Pro-D-Arg) was recorded to have significant antitumor activity against HeLa cells (IC50 value 50 μg/mL), and this compound was recorded to have no cytotoxicity against normal monkey kidney cells (VERO) up to 100 μg/mL). To the best of our knowledge, this is the first time that cyclo(L-Pro-D-Arg) has been isolated from a microbial natural source.

• MeSH
• antibakteriální látky chemie   izolace a purifikace   farmakologie   MeSH
• Bacillus cereus chemie   metabolismus   MeSH
• Cercopithecus aethiops MeSH
• cyklické peptidy chemie   izolace a purifikace   farmakologie   MeSH
• diketopiperaziny chemie   izolace a purifikace   farmakologie   MeSH
• HeLa buňky MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nukleární magnetická rezonance biomolekulární MeSH
• protinádorové látky chemie   izolace a purifikace   farmakologie   MeSH
• Rhabditida mikrobiologie   MeSH
• Vero buňky MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A thermoresponsive Pluronic/alginate semisynthetic hydrogel is used to bioprint 3D hepatic constructs, with the aim to investigate liver-specific metabolic activity of the 3D constructs compared to traditional 2D adherent cultures. The bioprinting method relies on a bioinert hydrogel and is characterized by high-shape fidelity, mild depositing conditions and easily controllable gelation mechanism. Furthermore, the dissolution of the sacrificial Pluronic templating agent significantly ameliorates the diffusive properties of the printed hydrogel. The present findings demonstrate high viability and liver-specific metabolic activity, as assessed by synthesis of urea, albumin, and expression levels of the detoxifying CYP1A2 enzyme of cells embedded in the 3D hydrogel system. A markedly increased sensitivity to a well-known hepatotoxic drug (acetaminophen) is observed for cells in 3D constructs compared to 2D cultures. Therefore, the 3D model developed herein may represent an in vitro alternative to animal models for investigating drug-induced hepatotoxicity.

• MeSH
• 3D tisk MeSH
• bioprinting * MeSH
• hydrogely MeSH
• lékové postižení jater * MeSH
• tkáňové inženýrství MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• diagnostické zobrazování MeSH
• monitorování fyziologických funkcí MeSH
• počítačové zpracování obrazu MeSH
• počítačové zpracování signálu MeSH
• Publikační typ
• kongresy MeSH
• sborníky MeSH

• Konspekt
• Obecná biologie
• NLK Obory
• lékařská informatika
• radiologie, nukleární medicína a zobrazovací metody