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Peripheral metabolism of glucocorticoids in hypertensive rats
Vagnerová, Karla ; Pelouch, Václav (advisor) ; Kment, Milan (referee) ; Hampl, Richard (referee)
Klíčovým článkem periferního metabolismu glukokortikoidů Je llβ- hydroxysteroiddehydrogenasa (lI RSD), která katalyzuje přeměnu glukokortikoidů na jejich méně účinné ll-oxo deriváty a naopak a může tak ovlivnit koncentraci těchto hormonů přímo v tkáni. Existují dva isoenzymy 11HSD. llHSD2 je -schopna pouze snížit hladinu glukokortikoidů a je exprimovaná nejen v mi neralokortikoidně cílových tkáních ale i např. v p l acentě. Naproti tomu llRSDl in vivo převážně zvyšuje lokální koncentraci glukokortikoidů a je exprimovaná v nejrů znějšíc h tkáních. Přítomnost těchto isoenzymů v tkáni má obrovský význam při zprostředkování jak mineralokortikoidního tak glukokortikoidního signálu. Je známo, že mineralokortikoidy (aldosteron) glukokortikoidy (kortisol, kortikosteron) mají přibližně stejnou afinitu k mineralokortikoidnímu receptoru (MR) in vitro a navíc plazmatická hladina glukokortikodů je přibližně 1000x vyšší nežli mineralokortikoidů. In vivo dochází ovšem k specifické vazb ě aldosteronu na MR. Tato selektivní vazba je umožněna díky llHSD2, která konvertuje glukokortikoidy na méně účinné ll-oxo deriváty. Nedostatečná funkce tohoto isoenzymu vede k nadměrné aktivaci MR glukokortikoidem a tím k rozvoji hypertenze. Poslední dobou se uvažuje o tom, že v srdci a mozku, kde jsou exprimované MR a v malé míře lIRSD2,...
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"Drug Delivery" systems for nuclear medicine
Kučka, Jan ; Lešetický, Ladislav (advisor) ; Smrček, Stanislav (referee) ; Hampl, František (referee) ; Hampl, Richard (referee)
5. SummarY in Czech (Souhrn) Podařilo se stabilně vilzat skvantitativním ýěŽkem '''At na potenciálně ořímopouŽitelnýnosič,kteýdobřeodolávásilnéradio|ysevyvolanécr- ;;il; zllAt. íIavícse poáařilo částečněozřejmit chování ,''At vůči redukčněoxidačnímp.o""'ů. a stabilizovat jej v chemické formě astatidu vhodné pro značenízvoleného systému. Byly připraveny a charalÍerizovány modelové rozpustné systémy nuuizě.,e^ pio cílenímakromo1ekul do kostní tkáně a za|oŽené na statisticlcýc.h kopolymerech N-l2-(hydroxypropyl)].methakrylamidu , Ínono,n"."* obsahujítímhydroxybisfosfonátové skupiny. Byla prokázána rychlá a účinnáadsorpce cílěnýchpolymerů na in vitro model kostní tkáně hydroxyapatit (většiná polymeru je nasorbována během 1 minuty inkubace; u ruao- piípadůbylo nasorbováno za tuto dobu přes 80 % polymeru). MnoŽstvípolymeruadsorbovanéhonahydroxyapatitjesilnězávislé |r"á"usirn na.obsahu hydroxybisfosfonáj9Úch skupin v polymeru. Byly irip.uu"ny systémy ousátru.ji modelová léčívavázaná na polyrner stabilní .u,nioi"tou, nya.oíyti"ty sicpitelnou hydrazonovou vazbou. Na pol1mer uvi" """a'*ó "n".i"té kancerostatikum (doxorubicin), radiodiagnostikum |úin)u model radioterapeutika ('25|. Byl připraven, charakterizován,.. omačen a in vivo otestován termoresponsivní systémnesoucí 1311 u 90y. Byla pozorována dobrá...
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Inflammation and peripheral metabolism of glucocorticoids
Leden, Pavel ; Kment, Milan (advisor) ; Hampl, Richard (referee) ; Kršek, Michal (referee)
10 Abstract Glucocorticoids play an important role in regulation of inflammation and their immunosuppressive effect is widely used for treatment of inflammatory diseases. The biological activity of glucocorticoids depends not only on their plasma concentrations, the number of receptors and the responsiveness of the target cells but also on the local metabolism of glucocorticoids that is predominated by 11β-hydroxysteroid dehydrogenase (11HSD). Two isoforms of 11HSD are known. The isoform 11HSD1 operates in vivo predominantly as a reductase that increases the local concentrations of glucocorticoids by reduction of their 11-oxo derivatives. The isoform 11HSD2 is a pure dehydrogenase that inactivates biologically active glucocorticoids to their inactive 11-oxo derivatives. The published data concerning peripheral metabolism of glucocorticoids during inflammation were obtained mostly in in-vitro studies. The aim of the thesis therefore was: (1) to study peripheral metabolism of glucocorticoids during trinitrobenzensulfonic acid (TNBS) induced colitis in rat. (2) to study peripheral metabolism of glucocorticoids in biopsies from human ulcerative colitis (3) to examine peripheral metabolism of glucocorticoids during dextran sodium sulphate (DSS) induced colitis in rat and (4) to study peripheral metabolism of...
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Sulfation and desulfation of neuroactive steroids in normal and neoplastic primate brain tissues
Kříž, Lubomír ; Hampl, Richard (advisor) ; Lapčík, Oldřich (referee) ; Pácha, Jiří (referee)
A novel methodology for the determination of steroid sulfatase (STS) and sulfotransferase (SULT) activities in primate brain tissue have been developed and evaluated. STS activity determination was based on enzyme assay followed by liquid-liquid extraction ofthe reaction product, its subsequent derivatization and gas chromatography-mass spectrometry analysis. Indirect determination including product hydrolysis and determination by radioimmunoassay was used for assessment of SULT activity. For both, STS and SULT assays, optimal reaction conditions were found while strong structure-activity relationships for both enzyme activities were observed. Additionally, so far unidentified high-substrate inhibition for STS was revealed wíth a hypothesis suggesting its physiotogícal relevance' Determinations of STS and SULT activities in monkey brain regions revealed differences between genders and brain regions. Due to low number of samples, significance was not described. For STS kinetic characteristics were determined. In human brain tumors, STS and SULT activities showed highly significant differences according to diagnoses. Furthermore, tendency to cluster formation with respect to both enzyme activities emerged. It indicated specific metabolic characteristics especially for glioblastomas considered as the...
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Inflammation and peripheral metabolism of glucocorticoids
Leden, Pavel ; Kment, Milan (advisor) ; Hampl, Richard (referee) ; Kršek, Michal (referee)
10 Abstract Glucocorticoids play an important role in regulation of inflammation and their immunosuppressive effect is widely used for treatment of inflammatory diseases. The biological activity of glucocorticoids depends not only on their plasma concentrations, the number of receptors and the responsiveness of the target cells but also on the local metabolism of glucocorticoids that is predominated by 11β-hydroxysteroid dehydrogenase (11HSD). Two isoforms of 11HSD are known. The isoform 11HSD1 operates in vivo predominantly as a reductase that increases the local concentrations of glucocorticoids by reduction of their 11-oxo derivatives. The isoform 11HSD2 is a pure dehydrogenase that inactivates biologically active glucocorticoids to their inactive 11-oxo derivatives. The published data concerning peripheral metabolism of glucocorticoids during inflammation were obtained mostly in in-vitro studies. The aim of the thesis therefore was: (1) to study peripheral metabolism of glucocorticoids during trinitrobenzensulfonic acid (TNBS) induced colitis in rat. (2) to study peripheral metabolism of glucocorticoids in biopsies from human ulcerative colitis (3) to examine peripheral metabolism of glucocorticoids during dextran sodium sulphate (DSS) induced colitis in rat and (4) to study peripheral metabolism of...
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