The hedgehog signaling pathway plays an important role in vertebrate embryonic development, tissue homeostasis, and tumorigenesis. Constitutive activation of Hh signaling in various human tumors leads to GLI-mediated transcription and tumor progression. Based on the preliminary screening of a large library of known triterpenes that exhibited interesting Hh inhibitory activity, we designed and synthesized a new series of triterpenoid analogues containing aromatic heterocyclic substituents at position C-2 to enhance their interference with Hh signaling. In this study, we evaluated the effect of 15 synthesized triterpenoids on cell proliferation and Hh pathway activity in relevant cancer cell lines. Among these compounds, two derivatives, 11a and 11b, both featuring a furan ring at position C-2, demonstrated potent inhibitory effects on proliferation and induced cell death in nonsmall cell lung cancer (NSCLC) and prostate cancer cell lines exhibiting hyper-activated Hh signaling. Moreover, these compounds significantly reduced GLI-mediated transcription in cell-based reporter assays. Detailed immunoblot analyses revealed that compounds 11a and 11b decreased the expression of endogenous GLI1 protein and its target genes associated with tumor progression and proliferation, such as Cyclin D1, N-Myc, and Bcl-2, in A549 and DU-145 cancer cells. These findings suggest that the antiproliferative effects of 11a and 11b are mediated through inhibition of the Hh signaling pathway and are promising candidates for the development of new anticancer therapies targeting Hh-dependent tumors.

• Publikační typ
• časopisecké články MeSH

Starting from benzyl 30-oxobetulinate and 30-oxobetulin diacetate, substituted dienes were synthesized and subjected to Diels-Alder reaction, yielding a variety of triterpenoid phthalates, phthalimides, and related derivatives. A total of 55 new compounds were prepared and tested for in vitro cytotoxic activity against eight cancer cell lines and two non-cancerous cell lines. Four compounds with IC50 values of 5 μM or lower were selected for further investigation. These compounds induced apoptosis in CCRF-CEM cells in a concentration-dependent manner, accompanied by mitochondrial depolarization and altered expression of key proteins involved in mitochondrial apoptosis. The compounds also disrupted DNA replication and transcriptional activity. Modulation of key proliferation pathways, including PI3K/Akt and STAT3, further supported the antiproliferative potential of these derivatives. Considering their high cytotoxicity and antiproliferative activity in CCRF-CEM cells, compounds 19, 26, 28, and 30 have been identified as promising candidates for further development.

• MeSH
• apoptóza * účinky léků   MeSH
• ftalimidy * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• mitochondrie * účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv * MeSH
• triterpeny * farmakologie   chemie   chemická syntéza   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A series of triterpenoid pyrones was synthesized and subsequently modified to introduce phthalimide or phthalate moieties into the triterpenoid skeleton. These compounds underwent in vitro cytotoxicity screening, revealing that a subset of six compounds exhibited potent activity, with IC50 values in the low micromolar range. Further biological evaluations, including Annexin V and propidium iodide staining experiment revealed, that all compounds induce selective apoptosis in cancer cells. Measurements of mitochondrial potential, cell cycle analysis, and the expression of pro- and anti-apoptotic proteins confirmed, that apoptosis was mediated via the mitochondrial pathway. These findings were further supported by cell cycle modulation and DNA/RNA synthesis studies, which indicated a significant increase in cell accumulation in the G0/G1 phase and a marked reduction in S-phase cells, alongside a substantial inhibition of DNA synthesis. The activation of caspase-3 and the cleavage of PARP, coupled with a decrease in the expression of Bcl-2 and Bcl-XL proteins, underscored the induction of apoptosis through the mitochondrial pathway. Given their high activity and pronounced effect on mitochondria function, trifluoromethyl pyrones 1f and 2f, and dihydrophthalimide 2h have been selected for further development.

• MeSH
• apoptóza MeSH
• DNA metabolismus   MeSH
• ftalimidy farmakologie   MeSH
• kyseliny ftalové * MeSH
• membránový potenciál mitochondrií MeSH
• mitochondrie metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory * farmakoterapie   MeSH
• protinádorové látky * terapeutické užití   MeSH
• pyrony farmakologie   MeSH
• triterpeny * farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH

Prevence poškození zdraví sportovce je významným medicínským i společenským tématem především z důvodu potenciální náhlé smrti. Ta bývá nejčastěji důsledkem onemocnění srdce. Diagnózy, které mohou způsobit náhlou srdeční smrt, se diametrálně liší u dětské a dospělé sportující populace. U dětí jde o diagnózy převážně vrozené, u dospělých o stavy získané. V současné době existuje většinový odborný konsenzus, jak provádět screening rizika náhlé srdeční smrti. V České republice je tento screening součástí preventivních sportovních prohlídek, které provádějí tělovýchovní lékaři, všeobecní praktičtí lékaři a praktičtí lékaři pro děti a dorost. Tyto sportovní prohlídky mají ale širší obsah, protože možná poškození zdraví u sportovce zahrnují široké spektrum stavů, z nichž některé přímo souvisejí s růstem a vývojem jedince.

Prevention of sport-related health issues is an important medical and social topic especially due to possible sudden death of athlete, which is most often caused by an adverse cardiac condition. Diagnoses that could cause sudden cardiac death differs between paediatric and adult population. Inherited conditions predominate in children and adolescents, acquired conditions are responsible for sudden cardiac death in majority of adult athletes. Nowadays there is general agreement about screening of risks of sudden cardiac death. In the Czech Republic, sports physicians, general practitioners or primary care paediatricians perform sudden cardiac death risk screening as a part of preparticipation screening. Nevertheless, many more medical conditions must be screened during preparticipation check-ups; some of them are directly related to growth and development of an individual.

• Klíčová slova
• preventivní sportovní prohlídka,
• MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• náhlá srdeční smrt * prevence a kontrola   MeSH
• primární prevence MeSH
• sportovci MeSH
• tělovýchovné lékařství MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH

AIMS: Fontan palliation is a surgical strategy for patients with complex congenital heart disease, in whom biventricular circulation cannot be achieved. Long-term survival is negatively affected by the absence of sub-pulmonary ventricle and increased systemic venous pressure. Exercise capacity is a known predictor of overall survival and quality of life in congenital heart defects. We aim to track individual trends of peak oxygen uptake (V̇O2 peak) after total cavopulmonary connection (TCPC), identify predictors of deterioration, and derive a disease-specific reference V̇O2 peak dataset. METHODS AND RESULTS: A retrospective study of serial cardiopulmonary exercise testing (CPET) data, gathered from all patients who underwent TCPC in the Czech Republic between 1992 and 2016. Of 354 consecutive patients with TCPC, 288 (81.4%) patients underwent one or more CPETs yielding 786 unique V̇O2 peak values used as a reference dataset. Longitudinal data were available in 206 (58.2%) patients, who underwent a median (inter-quartile range) of 3.0 (2.0-5.0) CPETs over a mean (standard deviation) of 8.9 (5.5) years. The decline of exercise capacity with age was linear and not faster than in healthy peers (P = 0.47), but relative values of V̇O2 peak in TCPC patients were 12.6 mL/min/kg lower. Single ventricular morphology and pulmonary artery size had no significant influence on the exercise capacity dynamics. V̇O2 peak decline correlated negatively with the trend of body mass index z-score (P = 0.006) and was faster in women than men (P = 0.008). CONCLUSIONS: Total cavopulmonary connection patients have significantly reduced exercise capacity. The age-related decline paralleled the healthy population and correlated negatively with the body mass index trend. The presented V̇O2 peak reference dataset may help the clinicians to grade the severity of exercise capacity impairment in individual TCPC patients.

• MeSH
• bypass pravého srdce metody   MeSH
• dítě MeSH
• dospělí MeSH
• Fontanova operace * metody   MeSH
• kvalita života MeSH
• lidé MeSH
• longitudinální studie MeSH
• retrospektivní studie MeSH
• spotřeba kyslíku MeSH
• tolerance zátěže * fyziologie   MeSH
• vrozené srdeční vady * patofyziologie   rehabilitace   chirurgie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinická studie MeSH
• práce podpořená grantem MeSH

A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b, 1c, 2b, 2c, and 8) were found to be preferentially and highly cytotoxic (IC50 ≈ 1 μM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c, 2b, and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26-28 gained activities of IC50 0.026-0.043 μM against K562 cells. Compounds 1b, 8, 21, 22, 23, and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF-CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b, 8, and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b, 1c, 2b, 2c, 24, and 26-28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs.

• MeSH
• chemorezistence MeSH
• fytogenní protinádorové látky * farmakologie   MeSH
• HeLa buňky MeSH
• lidé MeSH
• membránový potenciál mitochondrií MeSH
• nádorové buněčné linie MeSH
• prekurzory léčiv * farmakologie   MeSH
• protinádorové látky * farmakologie   MeSH
• pyraziny farmakologie   MeSH
• pyridiny farmakologie   MeSH
• triterpeny * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22, 4.30, 4.33, 4.39 had IC50 below 5 μmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC50 and almost complete inhibition at 5 × IC50. Interestingly, compound 4.39 at 5 × IC50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39, therefore 4.22 was the finally selected candidate for the development of anticancer drug.

• MeSH
• alkadieny chemická syntéza   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• kultivované buňky MeSH
• lidé MeSH
• molekulární struktura MeSH
• pentacyklické triterpeny chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• psi MeSH
• screeningové testy protinádorových léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Předkládaný přehled syndromů spojených s odchylkami počtu pohlavních chromozomů se na první pohled nejeví jako problematika ambulance tělovýchovného lékaře. S výjimkou Turnerova syndromu jsou vyjádřeny zpravidla velmi diskrétně, což je patrné z velmi vysokého podílu nezachycených případů. Při vysokých incidencích těchto syndromů je tak velice pravděpodobné, že pacienti s mírnějšími projevy navštěvují ambulance tělovýchovných lékařů v rámci preventivních prohlídek, a to mnohdy až dvakrát častěji než ambulance registrujících praktických lékařů. Vzhledem některým uvedeným rizikům nebo vhodnosti dispenzarizace těchto jedinců je důležité na tuto problematiku u vyšetřovaných sportovců pomýšlet.

The presented summary of the most frequent syndromes associated with sex chromosome aberations doesn't seem as a typical agenda of the sports medicine ambulance. Except for the Turner syndrome their clinical presentation is usually mild, which corresponds with the very high proportion of undetected cases. Given the high incidence of these syndromes, it is very probable that many patients with milder symptoms are visiting the sports medicine ambulances for preparticipation screening. These visits are often twice as frequent than their GP preventive care visits. It is necessary to keep the presented information in mind, as many of these sportsmen / patients may be at risk or may benefit from dispenzarization.

Na kazuistice sportovce s vysokým vzrůstem demonstrujeme diferenciálně diagnostickou rozvahu a následný složitý vyšetřovací proces vedoucí k nečekané diagnóze. Dále uvádíme užitečné vyšetřovací modality v diferenciální diagnostice poruch růstu a spektrum nejčastějších diagnóz.

We present a case report of young floorball player with tall posture, following differential diagnosis and extensive work-up with surprising results. We further discuss the most common causes of excessive growth in adolescents and applicable diagnostic modalities.

• Klíčová slova
• vizualizace výdechových kapének,
• MeSH
• diagnostické techniky dýchacího ústrojí MeSH
• dýchání ústy MeSH
• lidé MeSH
• pilotní projekty MeSH
• pozorovací studie jako téma MeSH
• vydechnutí * MeSH
• zátěžový test * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• abstrakt z konference MeSH
• práce podpořená grantem MeSH