Chronic rejection represents the most common cause of transplanted graft loss in the long term. Rapamycin (sirolimus), and it's derivate RAD, are new and potent, immunosuppressive drugs. They inhibit cell proliferation driven by various growth factors. These drugs were successfully tested in some experimental models of the chronic rejection. Results of the first clinical trials have defined rapamycin pharmacokinetics and proved immunosuppressive efficacy. Rapamycin acts synergistically with cyclosporin A. The side effects are a dose-dependent thrombocytopenia and leukopenia but the most frequent is hyperlipidemia. The question, if rapamycin and RAD inhibit development of chronic rejection in man, will be solved by the prospective clinical trials over years.

• MeSH
• chronická nemoc MeSH
• imunosupresiva škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• rejekce štěpu prevence a kontrola   MeSH
• sirolimus škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• imunosupresiva MeSH
• sirolimus 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.

• Klíčová slova
• Antidepressants, Anxiety, BDNF, Bulbectomy, Cognitive deficit, Ketamine, Rapamycin, mTOR,
• 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
• Názvy látek
• antidepresiva MeSH
• ketamin MeSH
• mozkový neurotrofický faktor MeSH
• mTOR protein, rat MeSH Prohlížeč
• sirolimus MeSH
• TOR serin-threoninkinasy MeSH

A chemically defined medium was developed which satisfies the nutritional needs of the Streptomyces hygroscopicus strain producing the immunosuppressant rapamycin. More than a doubling of rapamycin biosynthesis was observed on addition of 57 mmol/L of exogenous shikimate. The previously observed inhibition of the synthesis by phenylalanine was not reversed by shikimate.

• MeSH
• fenylalanin farmakologie   MeSH
• imunosupresiva metabolismus   MeSH
• kyselina shikimová farmakologie   MeSH
• polyeny metabolismus   MeSH
• sirolimus MeSH
• Streptomyces účinky léků   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fenylalanin MeSH
• imunosupresiva MeSH
• kyselina shikimová MeSH
• polyeny MeSH
• sirolimus MeSH

Since December 2019, SARS-CoV-2 (COVID-19) has been a worldwide pandemic with enormous consequences for human health and the world economy. Remdesivir is the only drug in the world that has been approved for the treating of COVID-19. This drug, as well as vaccination, still has uncertain effectiveness. Drug repurposing could be a promising strategy how to find an appropriate molecule: rapamycin could be one of them. The authors performed a systematic literature review of available studies on the research describing rapamycin in association with COVID-19 infection. Only peer-reviewed English-written articles from the world's acknowledged databases Web of Science, PubMed, Springer and Scopus were involved. Five articles were eventually included in the final analysis. The findings indicate that rapamycin seems to be a suitable candidate for drug repurposing. In addition, it may represent a better candidate for COVID-19 therapy than commonly tested antivirals. It is also likely that its efficiency will not be reduced by the high rate of viral RNA mutation.

• Klíčová slova
• COVID-19, SARS-CoV-19, mTOR inhibitor, rapamycin, sirolimus,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Translationally controlled tumor protein (TCTP) is a multifunctional and highly conserved protein from yeast to humans. Recently, its role in non-selective autophagy has been reported with controversial results in mammalian and human cells. Herein we examine the effect of Mmi1, the yeast ortholog of TCTP, on non-selective autophagy in budding yeast Saccharomyces cerevisiae, a well-established model system to monitor autophagy. We induced autophagy by nitrogen starvation or rapamycin addition and measured autophagy by using the Pho8Δ60 and GFP-Atg8 processing assays in WT, mmi1Δ, and in autophagy-deficient strains atg8Δ or atg1Δ. Our results demonstrate that Mmi1 does not affect basal or nitrogen starvation-induced autophagy. However, an increased rapamycin-induced autophagy is detected in mmi1Δ strain when the cells enter the post-diauxic growth phase, and this phenotype can be rescued by inserted wild-type MMI1 gene. Further, the mmi1Δ cells exhibit significantly lower amounts of reactive oxygen species (ROS) in the post-diauxic growth phase compared to WT cells. In summary, our study suggests that Mmi1 negatively affects rapamycin-induced autophagy in the post-diauxic growth phase and supports the role of Mmi1/TCTP as a negative autophagy regulator in eukaryotic cells.

• Klíčová slova
• Mmi1, TCTP, autophagy, nitrogen starvation, rapamycin, reactive oxygen species, translationally controlled tumor protein,
• MeSH
• autofagie * účinky léků   MeSH
• dusík nedostatek   MeSH
• glukosa farmakologie   MeSH
• mutace genetika   MeSH
• nádorové biomarkery chemie   MeSH
• proteiny vázající vápník metabolismus   MeSH
• Saccharomyces cerevisiae - proteiny metabolismus   MeSH
• Saccharomyces cerevisiae cytologie   účinky léků   růst a vývoj   MeSH
• sirolimus farmakologie   MeSH
• superoxidy metabolismus   MeSH
• translačně kontrolovaný nádorový protein 1 MeSH
• zelené fluorescenční proteiny metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dusík MeSH
• glukosa MeSH
• nádorové biomarkery MeSH
• proteiny vázající vápník MeSH
• Saccharomyces cerevisiae - proteiny MeSH
• sirolimus MeSH
• superoxidy MeSH
• TMA19 protein, S cerevisiae MeSH Prohlížeč
• TPT1 protein, human MeSH Prohlížeč
• translačně kontrolovaný nádorový protein 1 MeSH
• zelené fluorescenční proteiny MeSH

BACKGROUND: Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations. OBJECTIVES: To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation. METHODS: This multicentre double-blind randomized placebo-controlled dose-response phase II/III study with a parallel design included participants aged 6-65 years with FAs of mild or moderate severity according to the Investigator's Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of 'clear' or 'almost clear' after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time. RESULTS: Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36-8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33-8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59-14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70-15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%). CONCLUSIONS: Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.

• MeSH
• angiofibrom * komplikace   farmakoterapie   MeSH
• dvojitá slepá metoda MeSH
• emoliencia terapeutické užití   MeSH
• imunoglobulin A MeSH
• imunosupresiva škodlivé účinky   MeSH
• lidé MeSH
• sirolimus MeSH
• tuberózní skleróza * komplikace   farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• emoliencia MeSH
• imunoglobulin A MeSH
• imunosupresiva MeSH
• sirolimus MeSH

Increased phosphorylation of the translational repressor protein 4E-BP1 was found in the cell line derived from the tumor induced in Syrian hamster by Rous sarcoma virus (RSV). This was accompanied by its dissociation from the complex with initiation factor eIF4E. The ribosomal S6 protein kinase p70S6k is supposed to be regulated by the same or a closely related rapamycin-sensitive signalling pathway to that which modulates 4E-BP1. Phosphorylation and activity of p70S6k were found to be also increased in RSV-transformed H19 cells that express significantly higher amounts of the Src protein (p60src) relative to the non-transformed hamster fibroblasts NIL-2. The increased activity and phosphorylation of p70S6k were blocked by rapamycin, indicating that the rapamycin-sensitive pathway is involved in its regulation in v-src-transformed hamster fibroblasts. In agreement with this, rapamycin reduced the expression of elongation factor eEF1alpha (whose translation is regulated by a rapamycin-sensitive mechanism thought to involve p70S6k) and did not affect the production of a housekeeping protein, alpha-tubulin, in these cells. Synthesis of Src protein was also inhibited in cells treated with rapamycin. However, treatment of cells with a concentration of rapamycin sufficient to completely inhibit the activity and phosphorylation of p70S6k resulted in only partial de-phosphorylation of 4E-BP1 and its re-association with eIF4E in the transformed cells, indicating that additional rapamycin-insensitive mechanisms/pathways are implicated in the control of 4E-BP1 phosphorylation in RSV-transformed hamster fibroblasts. Over-expression of eIF4E favours cell proliferation and can lead to a transformed phenotype, while over-expression of 4E-BP1 has the opposite effect. The altered signalling to the phosphorylation of 4E-BP1 in RSV-transformed cells, which leads to its dissociation from eIF4E and thus relief of inhibition of eIF4E function, may therefore represent an important regulatory mechanism in malignant cell growth.

• MeSH
• elongační faktor 1 MeSH
• elongační faktory biosyntéza   genetika   MeSH
• fosfoproteiny metabolismus   MeSH
• fosforylace MeSH
• geny src * MeSH
• iniciační faktory genetika   metabolismus   MeSH
• kinasy ribozomálního proteinu S6 metabolismus   MeSH
• křečci praví MeSH
• kur domácí MeSH
• nádorová transformace buněk * MeSH
• nádorové buňky kultivované MeSH
• regulace genové exprese účinky léků   MeSH
• sirolimus farmakologie   MeSH
• transformované buněčné linie MeSH
• transportní proteiny * MeSH
• viry ptačího sarkomu MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• elongační faktor 1 MeSH
• elongační faktory MeSH
• fosfoproteiny MeSH
• iniciační faktory MeSH
• kinasy ribozomálního proteinu S6 MeSH
• sirolimus MeSH
• transportní proteiny * MeSH

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

• Klíčová slova
• PIK3CD, PIK3R1, activated phosphoinositide 3-kinase δ syndrome, natural history, rapamycin, registry,
• MeSH
• dítě MeSH
• dospělí MeSH
• fosfatidylinositol-3-kinasy třídy I MeSH
• imunosupresiva terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• primární imunodeficience MeSH
• registrace * MeSH
• sirolimus terapeutické užití   MeSH
• společnosti lékařské MeSH
• syndromy imunologické nedostatečnosti farmakoterapie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• fosfatidylinositol-3-kinasy třídy I MeSH
• imunosupresiva MeSH
• sirolimus 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.

• Klíčová slova
• Dual PI3K/mTOR inhibitors, PI3K/AKT/mTOR signaling pathway, Rapalinks, Rapalogs, Rapamycin, mTOR inhibitor, mTOR kinase inhibitors,
• 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
• Názvy látek
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas MeSH
• mTOR inhibitory * MeSH
• MTOR protein, human MeSH Prohlížeč
• mTORC1 MeSH
• sirolimus MeSH
• TOR serin-threoninkinasy MeSH

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.

• Klíčová slova
• SASP phenotype, aging, anti-aging therapy, cancer, mTOR,
• Publikační typ
• časopisecké články MeSH