The effect of the proteasome inhibition of the antiproliferative effect of anthracycline antibiotics.

Univerzita Karlova v Praze Farmaceutická fakulta v Hradci Králové Katedra biochemických věd Kandidát: Jana Kroupová Školitel: PharmDr. Anna Jirkovská, Ph.D. Název diplomové práce: Vliv inhibice proteazomu na antiproliferační účinek antracyklinových antibiotik Antracyklinová antibiotika (daunorubicin, doxorubicin) patří mezi nejúčinnější protinádorová léčiva. V současné klinické praxi jsou používány nejčastěji v kombinacích, a to jak s "klasickými", tak i novými "cílenými" protinádorovými léčivy. Mezi tato nová protinádorová léčiva patří také inhibitory proteazomu (bortezomib a karfilzomib). Proteazom je multienzymový komplex v eukaryotických buňkách, který je zodpovědný za intracelulární degradaci proteinů. Inhibitory proteazomu se doposud uplatnily převážně v terapii mnohočetného myelomu, ale jejich potenciál je studován také u jiných malignit. Jejich použití v kombinaci s antracykliny se jeví jako možná alternativa v terapii některých nádorových onemocnění, avšak účinek kombinace antracyklinů a inhibitorů proteazomu na nádorové buňky nebyl dostatečně objasněn. Terapie antracykliny je také doprovázena závažným nežádoucím účinkem - kardiotoxicitou, jejíž potenciál může být kombinací s inhibitory proteazomu ovlivněn. Cílem této diplomové práce bylo zhodnotit antiproliferační aktivitu inhibitorů...Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Jana Kroupová Supervisor: PharmDr. Anna Jirkovská, Ph.D. Title of diploma thesis: The effect of the proteasome inhibition of the antiproliferative effect of anthracycline antibiotics Anthracycline antibiotics (daunorubicin, doxorubicin) belong to the most effective antitumor drugs. In current clinical practice they are used mostly in the combinations with either "classical" or new targeted antitumor drugs. The proteasome inhibitors (bortezomib and carfilzomib) are also viewed as a part of new "targeted" antitumor drugs. The proteasome is a multienzyme complex in eukaryotic cells which is responsible for intracellular degradation of proteins. The proteasome inhibitors have been largely used in the therapy of multiple myeloma, but their potential has been also studied in the case of other malignancies. Their use in the combination with anthracyclines could be a possible alternative in the therapy of some tumor illnesses, but the effect of combination of anthracyclines and proteasome inhibitors on tumor cells have not been sufficiently explained. The anthracycline therapy is also accompanied by serious adverse side effect - the cardiotoxicity, which potential could be influenced by the...Department of Biochemical SciencesKatedra biochemických vědFarmaceutická fakulta v Hradci KrálovéFaculty of Pharmacy in Hradec Králov

Histopathological alterations of the heart in fish: proposal for a standardized assessment.

Histopathological alterations in the heart are often reported in fish as a result of exposure to a variety of chemical compounds. However, researchers presently lack a standardized method for the evaluation of histopathological alterations in the cardiovascular system of fish and the calculation of an 'organ index'. Therefore, we designed a method for a standardized assessment and evaluation of histopathological alterations in the heart of fish. As a model species, we used rainbow trout Oncorhynchus mykiss, but the protocol was also successfully applied to other fish species belonging to different taxonomic orders. To test the protocol, we re-evaluated sections of atenolol-exposed and unexposed rainbow trout obtained in a previous study. The results were in accordance with those previously published, demonstrating the applicability of the protocol. The protocol provides a universal method for the comparative evaluation of histopathological changes in the heart of fish

Vývoj kultivačních metod využívajících syntetické substráty a in vivo detekce embryonálních kmenových buněk

Angl. resum

The effect of the proteasome inhibition of the antiproliferative effect of anthracycline antibiotics.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Jana Kroupová Supervisor: PharmDr. Anna Jirkovská, Ph.D. Title of diploma thesis: The effect of the proteasome inhibition of the antiproliferative effect of anthracycline antibiotics Anthracycline antibiotics (daunorubicin, doxorubicin) belong to the most effective antitumor drugs. In current clinical practice they are used mostly in the combinations with either "classical" or new targeted antitumor drugs. The proteasome inhibitors (bortezomib and carfilzomib) are also viewed as a part of new "targeted" antitumor drugs. The proteasome is a multienzyme complex in eukaryotic cells which is responsible for intracellular degradation of proteins. The proteasome inhibitors have been largely used in the therapy of multiple myeloma, but their potential has been also studied in the case of other malignancies. Their use in the combination with anthracyclines could be a possible alternative in the therapy of some tumor illnesses, but the effect of combination of anthracyclines and proteasome inhibitors on tumor cells have not been sufficiently explained. The anthracycline therapy is also accompanied by serious adverse side effect - the cardiotoxicity, which potential could be influenced by the..

Synthetic progestin etonogestrel negatively affects mating behavior and reproduction in Endler's guppies (Poecilia wingei).

High rates of progestins consumption in the form of active ingredients in women's oral contraceptives and other hormonal preparations may lead to their increased concentrations in aquatic environments and subsequent harmful effect on fish reproduction. The objective of the present study was to assess the effect of etonogestrel, a third-generation synthetic progestin, on the reproductive behavior, fertility, gonads histology, and secondary sexual characteristics of male and female Endler's guppies (Poecilia wingei). Fish were subjected for 34 days to two concentrations of etonogestrel, including one possibly environmentally relevant (3.2 ng L-1) and one sublethal (320 ng L-1) concentration. A mating behavior study was subsequently conducted and revealed that the treatment with etonogestrel significantly reduced mating frequency in the exposed fish compared to controls. All the exposed females were unable to reproduce. In addition, female fish exposed to the highest level of etonogestrel were masculinized, as their anal fins and body coloration showed patterns similar to those of male fish. Etonogestrel-exposed females also had fewer developed oocytes. In conclusion, the low etonogestrel concentration (3.2 ng L-1) led to a reduction of mating activity in males without effect on their reproductive success, but it completely inhibited reproduction in females. Exposure to etonogestrel clearly has more severe consequences for females than males