Mixture toxicity, including agonistic and antagonistic effects, is an unrevealed environmental problem. Estrogenic endocrine disruptors are known to cause adverse effects for aquatic biota, but causative chemicals and their contributions to the total activity in sewage sludge remain unknown. Therefore, advanced analytical methods, a yeast bioassay and mixture toxicity models were concurrently applied for the characterization of 8 selected sludges with delectable estrogenic activity (and 3 sludges with no activity as blanks) out of 25 samples from wastewater treatment plants (WWTPs). The first applied full logistic model adequately explained total activity by considering the concentrations of the monitored compounds. The results showed that the activity was primarily caused by natural estrogens in municipal WWTP sludge. Nevertheless, activity in a sample originating from a car-wash facility was dominantly caused by partial agonists - nonylphenols - and only a model enabling prediction of all dose-response curve parameters of the final mixture curve explained these results. Antiestrogenic effects were negligible, and effect-directed analysis identified the causative chemicals.
- Publikační typ
- abstrakt z konference MeSH
Highly persistent, toxic and bioaccumulative per - and polyfluoroalkyl substances (PFAS) represents a serious problem for the environment and their concentrations and fate remain largely unknown. The present study consists of a PFAS screening in sludges originating from 43 wastewater treatment plants (WWTPs) in the Czech Republic. To analyze an extended group of PFAS consisting of 32 PFAS, including GenX and other new replacements of older and restricted PFAS in sludge, a new method was optimized and validated using pressurized solvent extraction, followed by the SPE clean-up step to eliminate the observed matrix effects and LC-MS/MS. The results revealed high PFAS contamination of sewage sludge, reaching values from 5.6 to 963.2 ng g-1. The results showed that in the majority of the samples (about 60%), PFOS was the most abundant among the targeted PFAS, reaching 932.9 ng g-1. Approximately 20% of the analyzed samples contained more short-chain PFAS, suggesting the replacement of long-chain PFAS (especially restricted PFOA and PFOS). GenX was detected in 9 samples, confirming the trend in the use of new PFAS. The results revealed that significantly higher contamination was detected in the samples from large WWTPs (population equivalent > 50,000; p-value <0.05). Concerning the application of sludge in agriculture, our prediction using the respective PFAS bioconcentration factors, the observed concentrations, and the legislatively permitted management of biosolids in Czech Republic agriculture revealed that PFAS can cause serious contamination of cereals and vegetables (oat, celery shoots and lettuce leaves), as well as general secondary contamination of the environment.
- MeSH
- bioakumulace MeSH
- biosolidy MeSH
- chromatografie kapalinová MeSH
- čištění vody MeSH
- fluorokarbony analýza metabolismus MeSH
- kontaminace potravin analýza MeSH
- kyseliny alkansulfonové analýza metabolismus MeSH
- látky znečišťující půdu analýza metabolismus MeSH
- odpadní voda chemie MeSH
- odpadní vody chemie MeSH
- propionáty analýza metabolismus MeSH
- průmyslová hnojiva analýza MeSH
- tandemová hmotnostní spektrometrie MeSH
- zelenina chemie růst a vývoj metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Retinoblastoma (Rb) is the most common primary malignant intraocular tumor in children which develops from the retinal stem cells. Systemic chemotherapy is the typical therapeutic treatment and though most children survive Rb, they often lose their vision, or the eye needs to be enucleated. Regarding to the pure availability of the target tumor by systemic chemotherapy, the local anticancer drug administration would be advantageous to increase the local drug concentration and minimize adverse side effects of chemotherapy. The present paper describes a new hydrogel implant enabled to deliver therapeutically active doses of low molecular weight hydrophilic antitumor drugs topotecan and vincristine. The hydrogel implant is proposed as bi-layered with an inner hydrophilic layer from 2-hydroxyethyl methacrylate (HEMA) serving as a reservoir of the chemotherapeutic agent and an outer hydrophobic layer from 2-ethoxyethyl methacrylate (EOEMA) acting as a barrier to protect the surrounding vascularized tissue against cytotoxicity of the delivered chemotherapeutics. The experiments with enucleated pig eyes demonstrated the ability of tested drugs to diffuse through sclera and reach the vitreous humor. HEMA-based hydrogels were examined in terms of sorption, release and transport properties, showing the possibility of adjusting the loading capacity and diffusion of the drugs by the degree of crosslinking. The EOEMA-based gels proved to be an inert for drug sorption and diffusion. A chorioallantoic membrane assay demonstrated excellent biocompatibility of unloaded hydrogels, and in vitro experiments confirmed significant cytotoxicity of drug-loaded hydrogels against a Rb cell line; 2 days for those topotecan-loaded and a minimum of 6 days for vincristine-loaded hydrogels. The bi-layered hydrogel implant can be considered promising for local administration of active agents to eye-globe for the treatment of Rb and also other ocular disorders.
- MeSH
- hydrogely chemie MeSH
- kinetika MeSH
- lidé MeSH
- methakryláty chemie MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemie MeSH
- oči účinky léků metabolismus MeSH
- prasata MeSH
- protézy a implantáty MeSH
- retinoblastom metabolismus patologie MeSH
- stabilita léku MeSH
- topotekan chemie metabolismus farmakologie MeSH
- viabilita buněk účinky léků MeSH
- vinkristin chemie metabolismus farmakologie MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Although ellipticine (Elli) is an efficient anticancer agent, it exerts several adverse effects. One approach to decrease the adverse effects of drugs is their encapsulation inside a suitable nanocarrier, allowing targeted delivery to tumour tissue whereas avoiding healthy cells. We constructed a nanocarrier from apoferritin (Apo) bearing ellipticine, ApoElli, and subsequently characterized. The nanocarrier exhibits a narrow size distribution suggesting its suitability for entrapping the hydrophobic ellipticine molecule. Ellipticine was released from ApoElli into the water environment under pH 6.5, but only less than 20% was released at pH 7.4. The interaction of ApoElli with microsomal membrane particles containing cytochrome P450 (CYP) biotransformation enzymes accelerated the release of ellipticine from this nanocarrier making it possible to be transferred into this membrane system even at pH 7.4 and facilitating CYP-mediated metabolism. Reactive metabolites were formed not only from free ellipticine, but also from ApoElli, and both generated covalent DNA adducts. ApoElli was toxic in UKF-NB-4 neuroblastoma cells, but showed significantly lower cytotoxicity in non-malignant fibroblast HDFn cells. Ellipticine either free or released from ApoElli was concentrated in the nuclei of neuroblastoma cells, concentrations of which being significantly higher in nuclei of UKF-NB-4 than in HDFn cells. In HDFn the higher amounts of ellipticine were sequestrated in lysosomes. The extent of ApoElli entering the nuclei in UKF-NB-4 cells was lower than that of free ellipticine and correlated with the formation of ellipticine-derived DNA adducts. Our study indicates that the ApoElli form of ellipticine seems to be a promising tool for neuroblastoma treatment.
- MeSH
- adukty DNA genetika metabolismus MeSH
- antitumorózní látky chemie farmakologie MeSH
- apoferritiny chemie farmakologie MeSH
- cytochrom P-450 CYP3A metabolismus MeSH
- elipticiny chemie farmakologie MeSH
- fosforylace MeSH
- histony metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nanočástice * MeSH
- neuroblastom farmakoterapie enzymologie genetika patologie MeSH
- nosiče léků * MeSH
- příprava léků MeSH
- uvolňování léčiv MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Poly(d,l-lactide)/polyethylene glycol (PLA/PEG) micro/nanofibers loaded with paclitaxel (PTX, 10 wt%) were prepared by needless electrospinning technology, which allows large scale production for real medicinal practice. The fiber structure and properties were investigated by several methods including scanning electron microscopy, nitrogen adsorption/desorption isotherm measurements, differential scanning calorimetry, and X-ray diffraction measurements to examine their morphology (fiber diameter distribution, specific surface area, and total pore volume), composition, drug-loading efficiency, and physical state. An HPLC-UV method was optimized and validated to quantify in vitro PTX release into PBS. The results showed that the addition of PEG into PLA fibers promoted the release of higher amounts of hydrophobic PTX over prolonged time periods compared to fibers without PEG. An in vitro cell assay demonstrated the biocompatibility of PLA/PEG fibrous materials and showed significant cytotoxicity of PTX-loaded PLA/PEG fibers against a human fibrosarcoma HT1080 cell line. The chick chorioallantoic membrane assay proved that PTX-loaded fibers exhibited antiangiogenic activity, with a pronounced effect in the case of the PEG-containing fibers. In vivo evaluation of PTX-loaded PLA/PEG fibers in a human fibrosarcoma recurrence model showed statistically significant inhibition in tumor incidence and growth after primary tumor resection compared to other treatment groups.
- MeSH
- buněčná smrt účinky léků MeSH
- difrakce rentgenového záření MeSH
- inhibitory angiogeneze farmakologie MeSH
- kur domácí MeSH
- lidé MeSH
- lokální recidiva nádoru patologie prevence a kontrola MeSH
- myši nahé MeSH
- nádorové buněčné linie MeSH
- nanovlákna chemie ultrastruktura MeSH
- nosiče léků chemie MeSH
- paclitaxel farmakologie MeSH
- polyestery chemie MeSH
- polyethylenglykoly chemie MeSH
- tělesná hmotnost MeSH
- teplota MeSH
- tumor burden účinky léků MeSH
- uvolňování léčiv * MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
Neuroblastoma (NBL) originates from undifferentiated cells of the sympathetic nervous system. Chemotherapy is judged to be suitable for successful treatment of this disease. Here, the influence of histone deacetylase (HDAC) inhibitor valproate (VPA) combined with DNA-damaging chemotherapeutic, ellipticine, on UKF-NB-4 and SH-SY5Y neuroblastoma cells was investigated. Treatment of these cells with ellipticine in combination with VPA led to the synergism of their anticancer efficacy. The effect is more pronounced in the UKF-NB-4 cell line, the line with N-myc amplification, than in SH-SY5Y cells. This was associated with caspase-3-dependent induction of apoptosis in UKF-NB-4 cells. The increase in cytotoxicity of ellipticine in UKF-NB-4 by VPA is dictated by the sequence of drug administration; the increased cytotoxicity was seen only after either simultaneous exposure to these drugs or after pretreatment of cells with ellipticine before their treatment with VPA. The synergism of treatment of cells with VPA and ellipticine seems to be connected with increased acetylation of histones H3 and H4. Further, co-treatment of cells with ellipticine and VPA increased the formation of ellipticine-derived DNA adducts, which indicates an easier accessibility of ellipticine to DNA in cells by its co-treatment with VPA and also resulted in higher ellipticine cytotoxicity. The results are promising for in vivo studies and perhaps later for clinical studies of combined treatment of children suffering from high-risk NBL.
- MeSH
- apoptóza MeSH
- elipticiny toxicita MeSH
- inhibitory histondeacetylas toxicita MeSH
- kyselina valproová toxicita MeSH
- lidé MeSH
- mutageny toxicita MeSH
- nádorové buněčné linie MeSH
- neuroblastom metabolismus MeSH
- neurony účinky léků metabolismus MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- bezmléčná dieta, školní stravování,
- MeSH
- dietoterapie * metody MeSH
- dítě MeSH
- fyziologie výživy dětí MeSH
- jídelníček MeSH
- lidé MeSH
- mléčné výrobky škodlivé účinky MeSH
- mléko škodlivé účinky MeSH
- předškolní dítě MeSH
- školy MeSH
- stravovací služby * MeSH
- vitamin D MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- předškolní dítě MeSH
