Cílem animální části navrhovaného projektu je za použití chronického mírného stresu a olfaktorické bulbektomie (model deprese) zjistit, zda aktivace (ketamin) nebo inhibice (rapamycin) mTOR signální dráhy má antidepresivní vlastnosti. Výsledky pak porovnat s SSRI. Cílem humánní/klinické části projektu je odpověď na otázku, že zda se skupina respondérů na ketamin liší od non-respondérů a) v aktivaci mTOR, b) ve anatomických a funkčních parametrech mozku (před infuzí), c) v morfologických a funkčně morfologických změnách indukovaných ketaminem (hodnocení 2 týdny po infúzi). V rámci projektu budou data publikována v recenzovaných časopisech s impakt faktorem. Měření aktivace mTOR u depresivních pacientů by mohl být prediktorem na účinnost ketaminu.; The aim of animal part of this project is to determine whether activation (ketamine) or inhibition (rapamycin) of mTOR signaling pathway have antidepressant properties, using chronic mild stress and olfactory bulbectomy as models of depression. The results will be compared to SSRI antidepressants (citalopram, sertraline).The aim of clinical part of this project is to answer the question whether the group of ketamine responders differs from ketamine non-responders a) in the activation of mTOR, b) in the anatomical and functional parameters of the brain (before infusion), c) in the morphological and functional changes induced by ketamine (evaluation 2 weeks after infusion). Obtained results will be published in peer-review journals with impact factor. The evaluation of the mTOR pathway in patients with depression could be predictor of the effectiveness of ketamine infusion.

• MeSH
• behaviorální symptomy MeSH
• bulbus olfactorius chirurgie   MeSH
• depresivní poruchy farmakoterapie   MeSH
• elektroencefalografie MeSH
• fenotyp MeSH
• inhibitory zpětného vychytávání serotoninu a noradrenalinu MeSH
• ketamin agonisté   farmakokinetika   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• magnetoencefalografie MeSH
• mozkový neurotrofický faktor analýza   MeSH
• nemoci čichového nervu MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   farmakokinetika   MeSH
• úzkost MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH

• Konspekt
• Psychiatrie
• NLK Obory
• psychiatrie
• neurologie
• biochemie
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

To date, the most studied drug in anti-aging research is the mTOR inhibitor - rapamycin. Despite its almost perfect anti-aging profile, rapamycin exerts one significant limitation - inappropriate physicochemical properties. Therefore, we have decided to utilize virtual high-throughput screening and fragment-based design in search of novel mTOR inhibiting scaffolds with suitable physicochemical parameters. Seven lead compounds were selected from the list of obtained hits that were commercially available (4, 5, and 7) or their synthesis was feasible (1, 2, 3, and 6) and evaluated in vitro and subsequently in vivo. Of all these substances, only compound 3 demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound 3 is a direct mTORC1 inhibitor. Last but not least, compound 3 was found to exhibit anti-SASP activity concurrently being relatively safe within the test of in vivo tolerability. All these outstanding results highlight compound 3 as a scaffold worthy of further investigation.

• Publikační typ
• časopisecké články MeSH

Currently, non-alcoholic fatty liver disease (NAFLD) progressing into chronic non-alcoholic steatohepatitis (NASH), liver cirrhosis, and eventually hepatocellular cancer has emerged as an epidemiological concern due to lack of proven treatment. Our review briefly comprises of the mechanism of pathogenesis and inflammation corresponding to the disease, and all the offered insights of mechanistic pathways that could be targeted in the progression of NASH. The review principally focuses on mTOR (mammalian target of rapamycin) as a promising target highlighting its immense role in lipogenesis and alleviating inflammation and fibrosis. A detailed description of signaling pathways of mTORC1 and mTORC2 that are inhibited by rapamycin and other mTOR inhibitor analogues is accentuated. The exploration of mTOR inhibitors clearly explains the exigent molecular aspects of mTOR in regulating adipocyte and lipogenic marker genes (e.g. those encoding PPARγ, SREBP1c). The literature on available mTOR inhibitors and their classification so far could be extremely useful in highlighting mTOR as a favorable drug target in the indication of NASH in the near future.

• MeSH
• hepatocelulární karcinom * patologie   MeSH
• jaterní cirhóza patologie   MeSH
• játra metabolismus   MeSH
• lidé MeSH
• nádory jater * patologie   MeSH
• nealkoholová steatóza jater * metabolismus   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Mechanistic target of rapamycin (mTOR) is a highly conserved protein kinase acting as a central regulator of cell functions. The kinase forms two distinct mTOR complexes termed as mTORC1 and mTORC2. Dysregulation of mTOR activity is associated with various pathological conditions. Inhibition of overactivated mTOR represent a rational approach in the treatment of numerous human diseases. Rapamycin is a potent natural inhibitor of mTOR exhibiting significant antitumor and immunosuppressive activity. Derivatization of rapamycin provided rapalogs, the first generation of mTOR inhibitors that selectively inhibit mTORC1 activity. Further interest of research community resulted in creation of the second generation of mTOR inhibitors involving both, mTOR kinase inhibitors and dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitors. Recently, combining advances of first and second generation of mTOR inhibitors yielded in the third generation of inhibitors termed as rapalinks. Nowadays, novel inhibitors belonging to all of the three generations are still under development. These inhibitors help us better to understand role of mTOR in mTOR signaling pathway as well as in diverse human diseases. In this review, we summarize recent reported mTOR inhibitors or methods of use thereof in the treatment of various diseases.

• MeSH
• fosfatidylinositol-3-kinasy * metabolismus   MeSH
• inhibitory fosfoinositid-3-kinasy farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• mTOR inhibitory * MeSH
• mTORC1 metabolismus   MeSH
• proliferace buněk MeSH
• sirolimus farmakologie   MeSH
• TOR serin-threoninkinasy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVE: The aim of our study was to test whether ketamine produces an antidepressant effect in animal model of olfactory bulbectomy and assess the role of mammalian target of rapamycin (mTOR) pathway in ketamine's antidepressant effect. METHODS: Bulbectomized (OBX) rats and sham controls were assigned to four subgroups according to the treatment they received (ketamine, saline, ketamine + rapamycin, and saline + rapamycin). The animals were subjected to open field (OF), elevated plus maze (EPM), passive avoidance (PA), Morris water maze (MWM), and Carousel maze (CM) tests. Blood samples were collected before and after drug administration for analysis of phosphorylated mTOR level. After behavioral testing, brains were removed for evaluation of brain-derived neurotrophic factor (BDNF) in prefrontal cortex (PFC) and hippocampus. RESULTS: Ketamine normalized hyperactivity of OBX animals in EPM and increased the time spent in open arms. Rapamycin pretreatment resulted in elimination of ketamine effect in EPM test. In CM test, ketamine + rapamycin administration led to cognitive impairment not observed in saline-, ketamine-, or saline + rapamycin-treated OBX rats. Prefrontal BDNF content was significantly decreased, and level of mTOR was significantly elevated in OBX groups. CONCLUSIONS: OBX animals significantly differed from sham controls in most of the tests used. Treatment had more profound effect on OBX phenotype than controls. Pretreatment with rapamycin eliminated the anxiolytic and antidepressant effects of ketamine in task-dependent manner. The results indicate that ketamine + rapamycin application resulted in impaired stress responses manifested by cognitive deficits in active place avoidance (CM) test. Intensity of stressor (mild vs. severe) used in the behavioral tests had opposite effect on controls and on OBX animals.

• MeSH
• antidepresiva farmakologie   MeSH
• bludiště - učení účinky léků   MeSH
• bulbus olfactorius fyziologie   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• ketamin antagonisté a inhibitory   farmakologie   MeSH
• krysa rodu rattus MeSH
• mozkový neurotrofický faktor metabolismus   MeSH
• potkani Wistar MeSH
• prefrontální mozková kůra účinky léků   metabolismus   MeSH
• sirolimus farmakologie   MeSH
• TOR serin-threoninkinasy účinky léků   metabolismus   MeSH
• učení vyhýbat se účinky léků   MeSH
• úzkost psychologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)-salt-inducible kinase 3 (SIK3)-mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.

• MeSH
• HEK293 buňky MeSH
• homozygot MeSH
• intracelulární signální peptidy a proteiny metabolismus   MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• mTORC1 metabolismus   MeSH
• mTORC2 metabolismus   MeSH
• mutantní proteiny chemie   metabolismus   MeSH
• osteogeneze * MeSH
• parathormon metabolismus   MeSH
• protein podobný parathormonu metabolismus   MeSH
• proteinkinasy chemie   nedostatek   genetika   metabolismus   MeSH
• proteolýza MeSH
• růstová ploténka metabolismus   MeSH
• sekvence aminokyselin MeSH
• signální transdukce * MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• typy dědičnosti genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

WHAT IS KNOWN AND OBJECTIVES: mTOR inhibitors possess narrow therapeutic range and substantial pharmacokinetic variability and the consequences from suboptimal dosing are serious. The aim of this review is to summarize the current knowledge about the factors influencing mTOR inhibitors pharmacokinetics and the possibility of using these relationships in order to improve its therapy individualization in solid organ transplanted patients. METHODS: Literature search from Pubmed and Web of Science databases were performed using Boolean search operators in order to identify relevant studies. RESULTS AND DISCUSSION: A total of 701 reports were identified from the initial literature search. Out of which 40 studies dealt with relationships between various factors and pharmacokinetics of mTOR inhibitors and with relevance of these associations for dosage optimization. WHAT IS NEW AND CONCLUSION: The overview of the current covariates for pharmacokinetic variability of mTOR inhibitors has been provided on the level of absorption, distribution and elimination, and consequences of these relationships for dosing optimization has been summarized.

• MeSH
• imunosupresiva MeSH
• lidé MeSH
• mTOR inhibitory MeSH
• sirolimus * farmakokinetika   terapeutické užití   MeSH
• TOR serin-threoninkinasy MeSH
• transplantace orgánů * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Everolimus je perorální inhibitor kinázy mammalian target of rapamycin (mTOR), klíčové součásti mnoha buněčných signalizačních drah. Inhibice mTOR everolimem má antiproliferační a antiangiogenní účinek. Everolimus je standardní součástí algoritmů cílené léčby metastatického renálního karcinomu (mRCC), v současnosti je indikován ve 2. a 3. linii cílené terapie. Je poměrně dobře snášen a prokazatelně prodlužuje přežití u pacientů s progresí onemocnění při léčbě tyrosinkinázovými inhibitory zaměřenými proti receptoru pro vaskulární endoteliální růstový faktor (VEGFR), což je momentálně největší skupina léků indikovaných pro mRCC.

Everolimus is an oral kinase inhibitor of mammalian target of rapamycin (mTOR), a key component of many cellular signalling pathways. Everolimus has antiproliferative and antiangiogenic activity. Currently, everolimus is a part of standard treatment algorithms for metastatic renal cell carcinoma (mRCC). It is indicated in the second- and thirdline therapy for mRCC. Everolimus is relatively well tolerated and has demonstrated prolonged survival in patients progressing on vascular endothelial growth factor receptor (VEGFR) inhibitors, which is currently the largest class of agents indicated for mRCC.

• Klíčová slova
• renální karcinom,
• MeSH
• hodnocení léčiv MeSH
• imunosupresiva MeSH
• karcinom z renálních buněk * diagnóza   farmakoterapie   terapie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory ledvin diagnóza   terapie   MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• receptory vaskulárního endoteliálního růstového faktoru účinky léků   MeSH
• sirolimus * aplikace a dávkování   farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• terapie MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   aplikace a dávkování   farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Příčinou ztráty účinku hormonální terapie u hormonálně dependentního karcinomu prsu je rezistence vůči hormonální léčbě, primární nebo získaná. Ta znemožňuje použití dosavadní hormonální léčby. Tuto rezistenci je možné překonat převedením na hormonální léčbu s jiným mechanismem účinku, nebo kombinací hormonální terapie s inhibitorem mTOR (mammalian target of rapamycin), který může obnovit citlivost nádoru k hormonální terapii, jak to prokázaly výsledky studie III. fáze BOLERO-2.

Hormonal therapy failure in hormone- -dependent breast cancer is caused by primary or acquired resistance to hormonal therapy. This renders the hormonal therapy used so far impossible. Such resistance can be overcome by switching to hormonal therapy based on a different mechanism of action, or through the combination of the hormonal therapy with an agent inhibiting mTOR (mammalian target of rapamycin). This can result in renewed sensitivity of the tumour to hormonal therapy, as shown by the results of a recent phase III trial, BOLERO-2.

• Klíčová slova
• exemestan, mTOR,
• MeSH
• androstadieny terapeutické užití   MeSH
• chemorezistence účinky léků   MeSH
• everolimus MeSH
• hodnocení léčiv statistika a číselné údaje   MeSH
• imunosupresiva terapeutické užití   MeSH
• inhibitory aromatasy terapeutické užití   MeSH
• karcinom terapie   MeSH
• klinické zkoušky jako téma statistika a číselné údaje   MeSH
• kombinovaná farmakoterapie metody   MeSH
• lidé MeSH
• metastázy nádorů terapie   MeSH
• nádory prsu terapie   MeSH
• prognóza MeSH
• protinádorové látky terapeutické užití   MeSH
• sirolimus analogy a deriváty   MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH

Preimplantation mouse embryo development involves temporal-spatial specification and segregation of three blastocyst cell lineages: trophectoderm, primitive endoderm and epiblast. Spatial separation of the outer-trophectoderm lineage from the two other inner-cell-mass (ICM) lineages starts with the 8- to 16-cell transition and concludes at the 32-cell stages. Accordingly, the ICM is derived from primary and secondary contributed cells; with debated relative EPI versus PrE potencies. We report generation of primary but not secondary ICM populations is highly dependent on temporal activation of mammalian target of Rapamycin (mTOR) during 8-cell stage M-phase entry, mediated via regulation of the 7-methylguanosine-cap (m7G-cap)-binding initiation complex (EIF4F) and linked to translation of mRNAs containing 5' UTR terminal oligopyrimidine (TOP-) sequence motifs, as knockdown of identified TOP-like motif transcripts impairs generation of primary ICM founders. However, mTOR inhibition-induced ICM cell number deficits in early blastocysts can be compensated by the late blastocyst stage, after inhibitor withdrawal; compensation likely initiated at the 32-cell stage when supernumerary outer cells exhibit molecular characteristics of inner cells. These data identify a novel mechanism specifically governing initial spatial segregation of mouse embryo blastomeres, that is distinct from those directing subsequent inner cell formation, contributing to germane segregation of late blastocyst lineages.

• MeSH
• blastocysta * MeSH
• buněčná diferenciace fyziologie   MeSH
• buněčný rodokmen MeSH
• embryo savčí * MeSH
• mTORC1 MeSH
• myši MeSH
• savci MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH