AIM: The reactivity of the circadian clock in the suprachiasmatic nuclei (SCN) to stressful stimuli has been controversial but most studies have confirmed the resilience of the SCN to stress. We tested the hypothesis that during a critical period shortly after birth, the developing SCN clock is affected by glucocorticoids. METHODS: Mothers of 2 rat strains with different sensitivities to stress, that is Wistar rats and spontaneously hypertensive rats (SHR), and their pups were exposed to stressful stimuli every day from delivery, and clock gene expression profiles were detected in the 4-day-old pups' SCN. Levels of glucocorticoids in plasma were measured by LC-MS/MS. The glucocorticoid receptors antagonist mifepristone was administered to pups to block the effect of the glucocorticoids. RESULTS: The glucocorticoid receptors were detected at the mRNA and protein levels in the SCN of 4-day-old pups. The exposure of mothers to stressful stimuli elevated their plasma glucocorticoid levels. In Wistar rat pups, combination of daily maternal stress with their manipulation increased the plasma glucocorticoid levels and shifted the Bmal1 rhythm in the SCN which was completely blocked by mifepristone. In contrast, in SHR pups, maternal stress on its own caused phase shift of the Bmal1 expression rhythm in the SCN but the effect was mediated via glucocorticoid-independent mechanism. The Per1 and Per2 expression profiles remained phase-locked to the light/dark cycle. CONCLUSION: The results demonstrate that the SCN is sensitive to stressful stimuli early after birth in pups maintained under light/dark conditions and the effect is mediated via glucocorticoid-dependent pathways.

• MeSH
• antagonisté hormonů farmakologie   MeSH
• cirkadiánní hodiny * účinky léků   genetika   MeSH
• druhová specificita MeSH
• fotoperioda MeSH
• glukokortikoidy krev   MeSH
• laktace MeSH
• matka - expozice noxám MeSH
• mifepriston farmakologie   MeSH
• novorozená zvířata MeSH
• nucleus suprachiasmaticus účinky léků   metabolismus   patofyziologie   MeSH
• potkani inbrední SHR MeSH
• potkani Wistar MeSH
• psychický stres genetika   metabolismus   patofyziologie   MeSH
• receptory glukokortikoidů antagonisté a inhibitory   metabolismus   MeSH
• transkripční faktory ARNTL genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Essential oils (EOs) of culinary herbs and spices are consumed on a daily basis. They are multicomponent mixtures of compounds with already demonstrated biological activities. Taking into account regular dietary intake and the chemical composition of EOs, they may be considered as candidates for endocrine-disrupting entities. Therefore, we examined the effects of 31 EOs of culinary herbs and spices on transcriptional activities of glucocorticoid receptor (GR), androgen receptor (AR) and vitamin D receptor (VDR). Using reporter gene assays in stably transfected cell lines, weak anti-androgen and anti-glucocorticoid activity was observed for EO of vanilla and nutmeg, respectively. Moderate augmentation of calcitriol-dependent VDR activity was caused by EOs of ginger, thyme, coriander and lemongrass. Mixed anti-glucocorticoid and VDR-stimulatory activities were displayed by EOs of turmeric, oregano, dill, caraway, verveine and spearmint. The remaining 19 EOs were inactive against all receptors under investigation. Analyses of GR, AR and VDR target genes by means of RT-PCR confirmed the VDR-stimulatory effects, but could not confirm the anti-glucocorticoid and anti-androgen effects of EOs. In conclusion, although we observed minor effects of several EOs on transcriptional activities of GR, AR and VDR, the toxicological significance of these effects is very low. Hence, 31 EOs of culinary herbs and spices may be considered safe, in terms of endocrine disruption involving receptors GR, AR and VDR.

• MeSH
• aktivace transkripce účinky léků   MeSH
• androgenní receptory chemie   metabolismus   MeSH
• androgeny škodlivé účinky   MeSH
• antagonisté androgenů škodlivé účinky   MeSH
• endokrinní disruptory škodlivé účinky   MeSH
• jedlé rostliny chemie   MeSH
• koření * MeSH
• léčivé rostliny chemie   MeSH
• lidé MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• oleje prchavé škodlivé účinky   MeSH
• receptory glukokortikoidů agonisté   antagonisté a inhibitory   genetika   metabolismus   MeSH
• receptory kalcitriolu agonisté   antagonisté a inhibitory   genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• rekombinantní proteiny chemie   metabolismus   MeSH
• reportérové geny účinky léků   MeSH
• reprodukovatelnost výsledků MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika MeSH

The development of biologically active molecules based on molecular recognition is an attractive and challenging task in medicinal chemistry and the molecules that can activate/deactivate certain receptors are of great medical interest. In this contribution, selected pyrimidine/piperidine derivatives were synthesized and tested for the ability to activate/deactivate Aryl hydrocarbon receptor (AhR) and Glucocorticoid receptor (GR). Tested compounds are shown to activate the receptors but to much lesser extent than positive controls, dioxin and dexamethasone for Ahr and GR, respectively. However, some of them antagonized the positive controls action. Although further in vivo studies are needed to fully characterize the bioactivities of these compounds, the reported in vitro evidences demonstrate that they might be used as the modulators of AhR and GR activities.

• MeSH
• buňky Hep G2 MeSH
• HeLa buňky MeSH
• lidé MeSH
• molekulární modely MeSH
• objevování léků MeSH
• piperidiny chemie   farmakologie   MeSH
• pyrimidiny chemie   farmakologie   MeSH
• receptory aromatických uhlovodíků agonisté   antagonisté a inhibitory   metabolismus   MeSH
• receptory glukokortikoidů agonisté   antagonisté a inhibitory   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

In the past decade, a large number of enantiopure drugs were introduced to clinical practice, since improved therapeutic effects were demonstrated for one of the enantiomers from originally racemic drug. While the therapeutic effects and safety of enantiopure drugs were tested prior to their approval, various biological enantiospecific activities of these, often "old" drugs, remain to be elucidated. In the current paper, we examined enantiospecific effects of clinically used enantiopure drugs containing one chiral center in the structure (i.e. zopiclone, tamsulosin, tolterodine, modafinil, citalopram) towards aryl hydrocarbon (AhR), glucocorticoid (GR) and pregnane X (PXR) receptors in human reporter cell lines. The cytotoxicity (IC50), agonist (EC50) and antagonist effects (IC50) of R-form, S-form and racemic mixture for each tested drugs were determined and compared in AhR-, GR- and PXR-gene reporter cell lines. Since AhR, GR and PXR are key regulators of drug metabolism, energy metabolism, immunity and play many other physiological functions, the data presented here might be of toxicological significance.

• MeSH
• azabicyklické sloučeniny chemie   farmakologie   MeSH
• benzhydrylové sloučeniny chemie   farmakologie   MeSH
• buněčné linie MeSH
• buňky Hep G2 MeSH
• citalopram chemie   farmakologie   MeSH
• fenylpropanolamin chemie   farmakologie   MeSH
• kresoly chemie   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• piperaziny chemie   farmakologie   MeSH
• receptory aromatických uhlovodíků agonisté   antagonisté a inhibitory   metabolismus   MeSH
• receptory glukokortikoidů agonisté   antagonisté a inhibitory   metabolismus   MeSH
• reportérové geny genetika   MeSH
• stereoizomerie MeSH
• steroidní receptory agonisté   antagonisté a inhibitory   metabolismus   MeSH
• sulfonamidy chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The JEG-3 choriocarcinoma cell line has been proposed as a model cell line of human placental trophoblast for induction studies via aryl hydrocarbon receptor (AHR). We examined whether glucocorticoid dexamethasone influences AHR-mediated induction of CYP1A1 enzyme in the JEG-3 cell line. We found that dexamethasone dose- and time-dependently suppresses CYP1A1 transactivation in gene reporter assays, CYP1A1 mRNA induction, and upregulation of 7-ethoxyresorufin-O-deethylase (EROD) activity by 3-methylcholanthrene (MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in JEG-3 cells. Co-transfection of JEG-3 cells with glucocorticoid receptor (GR) expression construct and treatment with dexamethasone abolished the effect of MC on CYP1A1 promoter construct in transient transfection gene reporter assays. RU486, a GR antagonist, suppressed the effect of dexamethasone on MC-induced transactivation of AHR responsive reporter constructs. We also found that dexamethasone stimulates both ligand-dependent and ligand-independent degradation of AHR but not of aryl hydrocarbon receptor nuclear translocator (ARNT) protein in JEG-3 cells. In experiments with proteasome inhibitors MG132 and bortezomib, we found that the degradation is not sensitive to proteasome inhibition in JEG-3. We can conclude that dexamethasone suppresses AHR-mediated CYP1A1 induction in JEG-3 cells through the unique mechanism of AHR-GR crosstalk, which involves accelerated degradation of AHR.

• MeSH
• aktivace transkripce MeSH
• cytochrom P-450 CYP1A1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• dexamethason farmakologie   MeSH
• glukokortikoidy farmakologie   MeSH
• interakce mezi receptory a ligandy MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• methylcholanthren toxicita   MeSH
• nádorové buněčné linie MeSH
• placenta účinky léků   metabolismus   MeSH
• polychlorované dibenzodioxiny toxicita   MeSH
• receptory aromatických uhlovodíků - jaderný translokátor genetika   metabolismus   MeSH
• receptory aromatických uhlovodíků metabolismus   MeSH
• receptory glukokortikoidů antagonisté a inhibitory   genetika   metabolismus   MeSH
• reportérové geny MeSH
• těhotenství MeSH
• upregulace MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cushingův syndrom je závažné onemocnění způsobené autonomní nadprodukcí kortizolu. Je charakterizován těžkým komplexním systémovým postižením s významně zvýšenou morbiditou a mortalitou. Proto je nezbytně nutné včasné stanovení etiologicky správné diagnózy a volba odpovídající léčby. I když léčbou první volby je u většiny příčin Cushingova syndromu chirurgické řešení, v řadě případů je nezbytné využití léčby medikamentózní. Možnosti této terapie však nejsou zcela uspokojivé ani přes určité pokroky, jichž bylo v poslední době dosaženo. V tomto článku je podán základní přehled současných možností medikamentózní léčby Cushingova syndromu.

Cushing's syndrome is a serious disease caused by the excessive autonomous production of Cortisol. It is characterized by a severe and complex systemic impairment with significantly high morbidity and mortality. This is why it is necessary to determine early on an etiologically accurate diagnosis and to select the corresponding optimal treatment. Although surgery represents the first choice treatment in most cases of Cushing's syndrome, in a number of cases medical treatment must be used. However, the options offered by the latter remain unsatisfactory despite certain advances achieved recently. In this article, we present a general overview of the current medical treatment options of Cushing's syndrome.

• Klíčová slova
• steroidogeneze, neuromodulace, léčba,
• MeSH
• Cushingův syndrom * diagnóza   etiologie   farmakoterapie   MeSH
• diferenciální diagnóza MeSH
• hydrokortison * analýza   krev   MeSH
• hypofýza MeSH
• ketokonazol škodlivé účinky   terapeutické užití   MeSH
• mitotan škodlivé účinky   terapeutické užití   MeSH
• monitorování léčiv MeSH
• nadledviny MeSH
• receptory dopaminu D1 * antagonisté a inhibitory   MeSH
• receptory glukokortikoidů * antagonisté a inhibitory   MeSH
• receptory somatostatinu * agonisté   MeSH

The human glucocorticoid receptor (hGR) plays a pivotal role in cellular processes such as development, differentiation, homeostasis, immune response and in regulation of xenobiotic metabolism. It has been demonstrated recently that colchicine inhibits hGR transcriptional activity in primary cultures of human hepatocytes by a mechanism involving impairment of hGR nucleo-cytoplasmic shuttling. In the present work, we investigated the role of the nuclear factor kappa B (NFkappaB) and c-jun-N-terminal kinase (JNK), the functional hGR antagonists, in this process. We found that microtubule disarray caused by colchicine, vincristine or nocodazole does not activate NFkappaB in human hepatocytes as revealed by p50 and p65 subunits nuclear translocation. On the other hand, we demonstrate that JNK mediates hGR transcriptional inhibition by microtubules disarray, because a specific inhibitor of JNK, 1,9-pyrazoloanthrone (SP600125), partially blocked tyrosine aminotransferase mRNA suppression due to colchicine treatment. In conclusion, JNK is at least partly involved in hGR transcriptional inhibition by colchicine in human hepatocytes, while NFkappaB involvement is doubtful.

• MeSH
• aktivace enzymů MeSH
• aktivace transkripce účinky léků   MeSH
• anthraceny farmakologie   MeSH
• hepatocyty metabolismus   ultrastruktura   MeSH
• JNK mitogenem aktivované proteinkinasy antagonisté a inhibitory   metabolismus   MeSH
• kolchicin farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mikrotubuly účinky léků   ultrastruktura   MeSH
• NF-kappa B metabolismus   farmakologie   MeSH
• receptory glukokortikoidů antagonisté a inhibitory   fyziologie   MeSH
• tyrosinaminotransferasa metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH