Multifunctional polymers are interesting substances for the formulation of drug molecules that cannot be administered in their pure form due to their pharmacokinetic profiles or side effects. Polymer-drug formulations can enhance pharmacological properties or create tissue specificity by encapsulating the drug into nanocontainers, or stabilizing nanoparticles for drug transport. We present the synthesis of multifunctional poly(2-ethyl-2-oxazoline-co-2-glyco-2-oxazoline)s containing two reactive end groups, and an additional hydrophobic anchor at one end of the molecule. These polymers were successfully used to stabilize (solid) lipid nanoparticles ((S)LNP) consisting of tetradecan-1-ol and cholesterol with their hydrophobic anchor. While the pure polymers interacted with GLUT1-expressing cell lines mainly based on their physicochemical properties, especially via interactions of the hydrophobic anchor with membranous compartments of the cells, LNP-cell interactions hinted toward an influence of the glucosylation on particle-cell interactions. The presented LNP are therefore promising systems for the delivery of drugs into GLUT1-expressing cell lines.

• MeSH
• cholesterol chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• lipidy chemie   MeSH
• nanočástice * chemie   MeSH
• nosiče léků chemie   MeSH
• oxazoly * chemie   MeSH
• polymery chemie   MeSH
• přenašeč glukosy typ 1 metabolismus   MeSH
• systémy cílené aplikace léků metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholesterol MeSH
• lipidy MeSH
• nosiče léků MeSH
• oxazoly * MeSH
• poly(2-oxazoline) MeSH Prohlížeč
• polymery MeSH
• přenašeč glukosy typ 1 MeSH

The cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by nitric oxide (NO). During the early developmental period, rat hearts exhibit higher resistance to ischemia-reperfusion (I/R) injury, contain higher levels of serum nitrates, and their resistance cannot be further increased by IPC or IPoC. NOS blocker (L-NAME) lowers their high resistance. Wistar rat hearts (postnatal Days 1 and 10) were perfused according to Langendorff and exposed to 40 min of global ischemia followed by reperfusion with or without IPoC. NO and reactive oxygen species donors (DEA-NONO, SIN-1) and L-NAME were administered. Tolerance to ischemia decreased between Days 1 and 10. DEA-NONO (low concentrations) significantly increased tolerance to I/R injury on both Days 1 and 10. SIN-1 increased tolerance to I/R injury on Day 10, but not on Day 1. L-NAME significantly reduced resistance to I/R injury on Day 1, but actually increased resistance to I/R injury on Day 10. Cardioprotection by IPoC on Day 10 was not affected by either NO donors or L-NAME. It can be concluded that resistance of the neonatal heart to I/R injury is NO dependent, but unlike in adult hearts, cardioprotective interventions, such as IPoC, are most likely NO independent.

• Klíčová slova
• DEA‐NONO, L‐NAME, SIN‐1, ischemic postconditioning, neonatal hearts, nitric oxide,
• MeSH
• donory oxidu dusnatého farmakologie   MeSH
• ischemické přivykání metody   MeSH
• ischemický postconditioning * metody   MeSH
• krysa rodu Rattus MeSH
• molsidomin farmakologie   analogy a deriváty   MeSH
• myokard metabolismus   MeSH
• NG-nitroargininmethylester * farmakologie   MeSH
• novorozená zvířata * MeSH
• oxid dusnatý * metabolismus   MeSH
• potkani Wistar * MeSH
• reperfuzní poškození myokardu * prevence a kontrola   metabolismus   MeSH
• srdce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• donory oxidu dusnatého MeSH
• molsidomin MeSH
• NG-nitroargininmethylester * MeSH
• oxid dusnatý * MeSH

BACKGROUND: This paper details the results of an evaluation of the level of consensus amongst clinicians on the use of ataluren in both ambulatory and non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The consensus was derived using a modified Delphi methodology that involved an exploration phase and then an evaluation phase. METHODS: The exploration phase involved 90-minute virtual 1:1 interviews of 12 paediatric neurologists who cared for 30-120 DMD patients each and had patient contact every one or two weeks. The respondents managed one to ten nmDMD patients taking ataluren. The Discussion Guide for the interviews can be viewed as Appendix A. Following the exploration phase interviews, the interview transcripts were analysed by an independent party to identify common themes, views and opinions and developed 43 draft statements that the Steering Group (authors) reviewed, refined and endorsed a final list of 42 statements. Details of the recruitment of participants for the exploration and evaluation phases can be found under the Methods section. RESULTS: A consensus was agreed (> 66% of respondents agreeing) for 41 of the 42 statements using results from a consensus survey of healthcare professionals (n = 20) experienced in the treatment of nmDMD. CONCLUSIONS: The statements with a high consensus suggest that treatment with ataluren should be initiated as soon as possible to delay disease progression and allow patients to remain ambulatory for as long as possible. Ataluren is indicated for the treatment of Duchenne muscular dystrophy that results from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older (see Summary of Product Characteristics for each country).

• Klíčová slova
• Ataluren, Consensus, Disease progression, Duchenne muscular dystrophy, Dystrophin, Non-ambulatory,
• MeSH
• dítě MeSH
• Duchennova muskulární dystrofie * genetika   terapie   MeSH
• dystrofin genetika   MeSH
• konsensus MeSH
• lidé MeSH
• nesmyslný kodon MeSH
• oxadiazoly * MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Izrael MeSH
• Řecko MeSH
• Švédsko MeSH
• východní Evropa MeSH
• Názvy látek
• ataluren MeSH Prohlížeč
• dystrofin MeSH
• nesmyslný kodon MeSH
• oxadiazoly * MeSH

BACKGROUND: Monoamine oxidase (MAO) inhibitors can interact with selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs). There is clinical interest surrounding use of ozanimod with SSRIs/SNRIs because the major metabolites of ozanimod are weak inhibitors of MAO-B in vitro. OBJECTIVE: To evaluate the incidence of treatment-emergent adverse events (TEAEs) potentially related to serotonin accumulation (SA) during concomitant ozanimod and SSRI/SNRI use by performing analyses of data from an open-label, oral ozanimod 0.92 mg trial (DAYBREAK; NCT02576717). METHODS: SA narrow (serotonin syndrome, neuroleptic malignant syndrome, and hyperthermia malignant) and broad (terms potentially associated with SA) MedDRA v24.0 searches were performed using TEAE data from participants with relapsing multiple sclerosis who entered DAYBREAK from phase 3 studies (cutoff February 1, 2022). Incidences of TEAEs matching terms from each search were stratified by SSRI/SNRI use. RESULTS: Of 2257 DAYBREAK participants, 274 (12.1%) used an SSRI/SNRI. No participants had TEAEs matching the SA narrow search terms. There was no significant difference in the percentage of participants with ⩾1 TEAE matching the SA broad search for those on versus off SSRIs/SNRIs (on: 12.4%, n = 34/274; off: 15.6%, n = 310/1982, nominal p = 0.1630). CONCLUSION: MedDRA searches showed no increase in TEAEs potentially associated with SA with concomitant SSRI/SNRI and ozanimod use.

• Klíčová slova
• Multiple sclerosis, selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, sphingosine 1-phosphate receptor modulators,
• MeSH
• antidepresiva škodlivé účinky   MeSH
• indany * MeSH
• inhibitory zpětného vychytávání serotoninu a noradrenalinu * škodlivé účinky   MeSH
• lidé MeSH
• oxadiazoly * MeSH
• roztroušená skleróza * chemicky indukované   MeSH
• selektivní inhibitory zpětného vychytávání serotoninu škodlivé účinky   MeSH
• serotonin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antidepresiva MeSH
• indany * MeSH
• inhibitory zpětného vychytávání serotoninu a noradrenalinu * MeSH
• oxadiazoly * MeSH
• ozanimod MeSH Prohlížeč
• selektivní inhibitory zpětného vychytávání serotoninu MeSH
• serotonin MeSH

Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are major causes of hospital-acquired infections and sepsis. Due to increasing antibiotic resistance, new treatments are needed. Mesenchymal stem cells (MSCs) have antimicrobial effects, which can be enhanced by preconditioning with antibiotics. This study investigated using antibiotics to strengthen MSCs against MRSA and P. aeruginosa. MSCs were preconditioned with linezolid, vancomycin, meropenem, or cephalosporin. Optimal antibiotic concentrations were determined by assessing MSC survival. Antimicrobial effects were measured by minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and antimicrobial peptide (AMP) gene expression. Optimal antibiotic concentrations for preconditioning MSCs without reducing viability were 1 μg/mL for linezolid, meropenem, and cephalosporin and 2 μg/mL for vancomycin. In MIC assays, MSCs preconditioned with linezolid, vancomycin, meropenem, or cephalosporin inhibited MRSA or P. aeruginosa growth at lower concentrations than non-preconditioned MSCs (p ≤ 0.001). In MBC assays, preconditioned MSCs showed enhanced bacterial clearance compared to non-preconditioned MSCs, especially when linezolid and vancomycin were used against MRSA (p ≤ 0.05). Preconditioned MSCs showed increased expression of genes encoding the antimicrobial peptide genes hepcidin and LL-37 compared to non-preconditioned MSCs. The highest hepcidin expression was seen with linezolid and vancomycin preconditioning (p ≤ 0.001). The highest LL-37 expression was with linezolid preconditioning (p ≤ 0.001). MSCs' preconditioning with linezolid, vancomycin, meropenem, or cephalosporin at optimal concentrations enhances their antimicrobial effects against MRSA and P. aeruginosa without compromising viability. This suggests preconditioned MSCs could be an effective adjuvant treatment for antibiotic-resistant infections. The mechanism may involve upregulation of AMP genes.

• Klíčová slova
• Hepcidin, LL-37, Linezolid, Mesenchymal stem cells, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin,
• MeSH
• antibakteriální látky farmakologie   terapeutické užití   MeSH
• antimikrobiální peptidy MeSH
• cefalosporiny farmakologie   MeSH
• hepcidiny farmakologie   terapeutické užití   MeSH
• lidé MeSH
• linezolid farmakologie   terapeutické užití   MeSH
• meropenem farmakologie   terapeutické užití   MeSH
• methicilin rezistentní Staphylococcus aureus * MeSH
• mezenchymální kmenové buňky * MeSH
• mikrobiální testy citlivosti MeSH
• Pseudomonas aeruginosa genetika   MeSH
• stafylokokové infekce * mikrobiologie   MeSH
• vankomycin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• antimikrobiální peptidy MeSH
• cefalosporiny MeSH
• hepcidiny MeSH
• linezolid MeSH
• meropenem MeSH
• vankomycin MeSH

3,5-Dinitrobenzylsulfanyl tetrazoles and 1,3,4-oxadiazoles, previously identified as having high in vitro activities against both replicating and nonreplicating mycobacteria and favorable cytotoxicity and genotoxicity profiles were investigated. First we demonstrated that these compounds act in a deazaflavin-dependent nitroreduction pathway and thus require a nitro group for their activity. Second, we confirmed the necessity of both nitro groups for antimycobacterial activity through extensive structure-activity relationship studies using 32 structural types of analogues, each in a five-membered series. Only the analogues with shifted nitro groups, namely, 2,5-dinitrobenzylsulfanyl oxadiazoles and tetrazoles, maintained high antimycobacterial activity but in this case mainly as a result of DprE1 inhibition. However, these analogues also showed increased toxicity to the mammalian cell line. Thus, both nitro groups in 3,5-dinitrobenzylsulfanyl-containing antimycobacterial agents remain essential for their high efficacy, and further efforts should be directed at finding ways to address the possible toxicity and solubility issues, for example, by targeted delivery.

• MeSH
• antituberkulotika farmakologie   chemie   MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis * MeSH
• nitroreduktasy MeSH
• oxadiazoly farmakologie   chemie   MeSH
• savci MeSH
• tetrazoly farmakologie   chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antituberkulotika MeSH
• nitroreduktasy MeSH
• oxadiazoly MeSH
• tetrazoly MeSH

Poly(2-oxazoline) is a promising new class of polymeric materials due to their antibiofouling properties and good biocompatibility. Poly(2-oxazoline) coatings can be deposited on different substrates via plasma polymerization, which can be more advantageous than other coating methods. The aim of this study is to deposit poly(2-oxazoline) coatings using a surface dielectric barrier discharge burning in nitrogen at atmospheric pressure using 2-methyl-2-oxazoline and 2-ethyl-2-oxazoline vapours as monomers and compare the film properties. For the comparison, the antibacterial and cytocompatibility tests were peformed according to ISO norms. The antibacterial tests showed that all the deposited films were highly active against Staphylococcus aureus and Escherichia coli bacteria. The chemical composition of the films was studied using FTIR and XPS, and the film surface's properties were studied using AFM and surface energy measurement. The cytocompatibility tests showed good cytocompatibility of all the deposited films. However, the films deposited from 2-methyl-2-oxazoline exhibit better cytocompatibility. This difference can be explained by the different chemical compositions and surface morphologies of the films deposited from different monomers.

• Klíčová slova
• antibiofouling, plasma polymer, poly(2-oxazoline),
• MeSH
• antibakteriální látky * farmakologie   MeSH
• Escherichia coli MeSH
• oxazoly * farmakologie   chemie   MeSH
• polymerizace MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 2-ethyl-2-oxazoline MeSH Prohlížeč
• 2-methyl-2-oxazoline MeSH Prohlížeč
• antibakteriální látky * MeSH
• oxazoly * MeSH

The fungus Amanita muscaria is universally recognizable for its iconic appearance; it is also widely regarded as poisonous, inedible, and even deadly. In spite of that, there have been documented cases of use of A. muscaria-containing preparations against various diseases, including cancer, to no apparent ill effect. The search for compounds that can be used to treat cancer among various plants and fungi has been intensifying in recent years. In light of this, we describe an HPLC HILIC analytical method for the evaluation of the content of the anticancer compound ergosterol (ERG) and the neuroactive alkaloids ibotenic acid (IBO) and muscimol (MUS) that contribute significantly to the unpleasant physiological syndrome associated with A. muscaria consumption. A 'homemade' A. muscaria tincture made using 80-proof rye vodka as the solvent, an A. muscaria extract made with a standardized water-ethanol solution as the solvent, and fractions obtained from the second extract via liquid-liquid extraction with nonpolar solvents were analyzed. The study also presents the results of capillary zone electrophoresis with contactless conductivity detection and UHPLC-MS/MS analyses of the IBO and MUS content of the two native A. muscaria extracts and an evaluation of the standardized extract's cytotoxic effect against a small panel of lung cell cultures in vitro. Our results show that the standardized extract has a significant cytotoxic effect and does not contain the compounds of interest in any significant quantity.

• Klíčová slova
• Amanita muscaria, HPLC, alkaloids, cancer, capillary electrophoresis, cytotoxicity, fungi, mass spectrometry,
• MeSH
• Amanita MeSH
• antitumorózní látky * MeSH
• buněčné linie MeSH
• kyselina ibotenová analýza   MeSH
• lidé MeSH
• muscimol farmakologie   MeSH
• nádory * MeSH
• plíce chemie   MeSH
• rostlinné extrakty farmakologie   MeSH
• rozpouštědla MeSH
• tandemová hmotnostní spektrometrie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky * MeSH
• kyselina ibotenová MeSH
• muscimol MeSH
• rostlinné extrakty MeSH
• rozpouštědla MeSH

Histone deacetylase (HDAC) inhibitors used in the clinic typically contain a hydroxamate zinc-binding group (ZBG). However, more recent work has shown that the use of alternative ZBGs, and, in particular, the heterocyclic oxadiazoles, can confer higher isoenzyme selectivity and more favorable ADMET profiles. Herein, we report on the synthesis and biochemical, crystallographic, and computational characterization of a series of oxadiazole-based inhibitors selectively targeting the HDAC6 isoform. Surprisingly, but in line with a very recent finding reported in the literature, a crystal structure of the HDAC6/inhibitor complex revealed that hydrolysis of the oxadiazole ring transforms the parent oxadiazole into an acylhydrazide through a sequence of two hydrolytic steps. An identical cleavage pattern was also observed both in vitro using the purified HDAC6 enzyme as well as in cellular systems. By employing advanced quantum and molecular mechanics (QM/MM) and QM calculations, we elucidated the mechanistic details of the two hydrolytic steps to obtain a comprehensive mechanistic view of the double hydrolysis of the oxadiazole ring. This was achieved by fully characterizing the reaction coordinate, including identification of the structures of all intermediates and transition states, together with calculations of their respective activation (free) energies. In addition, we ruled out several (intuitively) competing pathways. The computed data (ΔG‡ ≈ 21 kcal·mol-1 for the rate-determining step of the overall dual hydrolysis) are in very good agreement with the experimentally determined rate constants, which a posteriori supports the proposed reaction mechanism. We also clearly (and quantitatively) explain the role of the -CF3 or -CHF2 substituent on the oxadiazole ring, which is a prerequisite for hydrolysis to occur. Overall, our data provide compelling evidence that the oxadiazole warheads can be efficiently transformed within the active sites of target metallohydrolases to afford reaction products possessing distinct selectivity and inhibition profiles.

• MeSH
• histondeacetylasa 6 chemie   MeSH
• hydrolýza MeSH
• inhibitory histondeacetylas * farmakologie   MeSH
• kyseliny hydroxamové chemie   MeSH
• oxadiazoly * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histondeacetylasa 6 MeSH
• inhibitory histondeacetylas * MeSH
• kyseliny hydroxamové MeSH
• oxadiazoly * MeSH

AIM: To investigate the epidemiology of Clostridioides difficile infection (CDI) in Slovakian hospitals after the emergence of ribotype 176 (027-like) in 2016. METHODS: Between 2018 and 2019, European Centre for Disease Control and Prevention CDI surveillance protocol v2.3 was applied to 14 hospitals, with additional data collected on recent antimicrobial use and the characterization of C. difficile isolates. RESULTS: The mean hospital incidence of CDI was 4.1 cases per 10,000 patient bed-days. One hundred and five (27.6%) in-hospital deaths were reported among the 381 cases. Antimicrobial treatment within the previous 4 weeks was recorded in 90.5% (333/368) of cases. Ribotype (RT)176 was detected in 50% (n=185/370, 14 hospitals) and RT001 was detected in 34.6% (n=128/370,13/14 hospitals) of cases with RT data. Overall, 86% (n=318/370) of isolates were resistant to moxifloxacin by Thr82Ile in GyrA (99.7%). Multi-locus variable tandem repeat analysis showed clonal relatedness of predominant RTs within and between hospitals. Seven of 14 sequenced RT176 isolates and five of 13 RT001 isolates showed between zero and three allelic differences by whole-genome multi-locus sequence typing. The majority of sequenced isolates (24/27) carried the erm(B) gene and 16/27 also carried the aac(6')-aph(2'') gene with the corresponding antimicrobial susceptibility phenotypes. Nine RT176 strains carried the cfr(E)gene and one RT001 strain carried the cfr(C) gene, but without linezolid resistance. CONCLUSIONS: The newly-predominant RT176 and endemic RT001 are driving the epidemiology of CDI in Slovakia. In addition to fluoroquinolones, the use of macrolide-lincosamide-streptogramin B antibiotics can represent another driving force for the spread of these epidemic lineages. In C. difficile, linezolid resistance should be confirmed phenotypically in strains with detected cfr gene(s).

• Klíčová slova
• 4C antibiotics, Fluoroquinolones, Mortality, Ribotyping, Surveillance, aac(6′)-aph(2′'), cfr(E), erm(B),
• MeSH
• antibakteriální látky farmakologie   terapeutické užití   MeSH
• Clostridioides difficile * genetika   MeSH
• Clostridioides genetika   MeSH
• fluorochinolony farmakologie   MeSH
• klostridiové infekce * epidemiologie   farmakoterapie   MeSH
• lidé MeSH
• linezolid MeSH
• makrolidy MeSH
• mikrobiální testy citlivosti MeSH
• multilokusová sekvenční typizace MeSH
• ribotypizace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Slovenská republika epidemiologie   MeSH
• Názvy látek
• antibakteriální látky MeSH
• fluorochinolony MeSH
• linezolid MeSH
• makrolidy MeSH