Dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA) are neurodegenerative disorders characterized by abnormal accumulation of α-synuclein. Plasmin is a serine protease with a role in various physiological processes, including tissue and synaptic remodeling, inflammation regulation, and modulation of neurotrophic factors. It has also been shown that plasmin is able to cleave extracellular α-synuclein in neuronal cell cultures. The plasminogen activator inhibitor-1 (PAI-1) and the tissue plasminogen activator (tPA) regulate the synthesis and activity of plasmin in the brain. We measured the serum levels of tPA and PAI-1 in 30 DLB, 10 PD, and 12 MSA patients and compared them to 10 adults (controls). tPA and PAI-1 serum protein concentrations were quantified by ELISA and compared across the groups. The findings demonstrated that PAI-1 serum levels were increased in DLB (p < 0.05), PD (p < 0.01), and MSA (p < 0.001) patients as compared to controls. In addition, MSA patients had higher PAI-1 serum levels (p < 0.01) as compared to DLB patients, showing the highest PAI-1 levels among all groups. No differences in tPA serum levels were found among groups. Our findings suggest an involvement of plasmin system in these synucleinopathies although there are some limitations due to the heterogeneity of our cohort of participants. Thus, these data must be seen as preliminary observations and further studies in larger and more homogenous cohorts are needed before drawing definitive conclusions.

• Publikační typ
• časopisecké články MeSH

BACKGROUND & AIMS: Exogenous recombinant fibroblast growth factor 20 (FGF20) protein has been proved to treat ulcerative colitis; however, its mechanism of action remains unclear. This study aimed to explore the role and mechanism of action of FGF20 in ulcerative colitis. METHODS: Data from patients with ulcerative colitis were analyzed using the Gene Expression Omnibus dataset. A murine colitis model was established by administering 2% dextran sodium sulfate. FGF20 knockout mice and Adenoassociated viruses (AAV)-FGF20-treated mice were used to elucidate the specific mechanisms. Proteomic analysis was conducted to identify differentially expressed genes. RESULTS: FGF20 levels were significantly elevated in the colonic tissues of subjects and mice with colitis. FGF20 deficiency exacerbated dextran sodium sulfate-induced colitis; in contrast, FGF20 replenishment alleviated colitis through 2 principal mechanisms: restoration of impaired intestinal epithelial barrier integrity, and inhibition of M1 macrophage polarization. Notably, S100A9 was identified as a pivotal downstream target of FGF20, which was further demonstrated by pharmacologic inhibition and overexpression experiments of S100A9 using paquinimod (a specific inhibitor of S100A9) and AAV-S100A9 in FGF20 knockout and AAV-FGF20 mice with colitis, respectively. Additionally, the nuclear factor-κB pathway was found to be involved in the process by which FGF20 regulates S100A9 to counteract colitis. CONCLUSIONS: These results suggest that FGF20 acts as a negative regulator of S100A9 and nuclear factor-κB, thereby inhibiting M1 macrophage polarization and restoring intestinal epithelial barrier integrity in mice with dextran sodium sulfate-induced colitis. FGF20 may serve as a potential therapeutic target for the treatment of ulcerative colitis.

• MeSH
• fibroblastové růstové faktory * metabolismus   genetika   farmakologie   MeSH
• kalgranulin B * metabolismus   genetika   MeSH
• kolitida * chemicky indukované   MeSH
• lidé MeSH
• makrofágy * imunologie   metabolismus   účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• NF-kappa B * metabolismus   MeSH
• signální transdukce MeSH
• síran dextranu toxicita   MeSH
• střevní sliznice * patologie   metabolismus   imunologie   účinky léků   MeSH
• ulcerózní kolitida * patologie   chemicky indukované   imunologie   metabolismus   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Extracellular matrix (ECM) is a network of macromolecules which has two forms-perineuronal nets (PNNs) and a diffuse ECM (dECM)-both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan (HA) synthesis, we found downregulated staining for PNNs, HA, chondroitin sulfate proteoglycans, and glial fibrillary acidic protein. These changes were enhanced after 4 and 6 months and were reversible after a normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in the somatosensory cortex by 35%, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging revealed a decrease of mean diffusivity and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum, and spinal cord. This study shows the increase in ECS volume, a loss of FA, and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell-to-cell communication, and neural plasticity.

• MeSH
• astrocyty metabolismus   MeSH
• chondroitinsulfát proteoglykany metabolismus   MeSH
• extracelulární matrix * metabolismus   MeSH
• extracelulární prostor * metabolismus   MeSH
• gliový fibrilární kyselý protein metabolismus   MeSH
• hymekromon farmakologie   MeSH
• krysa rodu rattus MeSH
• kyselina hyaluronová MeSH
• mozek metabolismus   MeSH
• nervová síť účinky léků   diagnostické zobrazování   MeSH
• potkani Sprague-Dawley MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: A critical step preceding the potential biomedical application of nanoparticles is the evaluation of their immunomodulatory effects. Such nanoparticles are expected to enter the bloodstream where they can be recognized and processed by circulating monocytes. Despite the required biocompatibility, this interaction can affect intracellular homeostasis and modulate physiological functions, particularly inflammation. This study focuses on titanium dioxide (TiO2) as an example of relatively low cytotoxic nanoparticles with potential biomedical use and aims to evaluate their possible modulatory effects on the inflammasome-based response in human primary monocytes. METHODS: Monocyte viability, phenotypic changes, and cytokine production were determined after exposure to TiO2 (diameter, 25 nm; P25) alone. In the case of the modulatory effects, we focused on NLRP3 activation. The production of IL-1β and IL-10 was evaluated after (a) simultaneous activation of monocytes with bacterial stimuli muramyl dipeptide (MDP), or lipopolysaccharide (LPS), and TiO2 (co-exposure model), (b) prior activation with TiO2 alone and subsequent exposure to bacterial stimuli MDP or LPS. The differentiation of TiO2-treated monocytes into macrophages and their polarization were also assessed. RESULTS: The selected TiO2 concentration range (30-120 μg/mL) did not induce any significant cytotoxic effects. The highest dose of TiO2 promoted monocyte survival and differentiation into macrophages, with the M2 subset being the most prevalent. Nanoparticles alone did not induce substantial production of inflammatory cytokines IL-1β, IL-6, or TNF-α. The immunomodulatory effect on NLRP3 depended on the type of costimulant used. While co-exposure of monocytes to MDP and TiO2 boosted NLRP3 activity, co-exposure to LPS and TiO2 inhibited NLRP3 by enhancing IL-10 release. The inhibitory effect of TiO2 on NLRP3 based on the promotion of IL-10 was confirmed in a post-exposure model for both costimulants. CONCLUSION: This study confirmed a non-negligible modulatory effect on primary monocytes in their inflammasome-based response and differentiation ability.

• MeSH
• acetylmuramyl-alanyl-isoglutamin farmakologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• cytokiny metabolismus   MeSH
• inflamasomy účinky léků   MeSH
• interleukin-10 metabolismus   MeSH
• interleukin-1beta metabolismus   MeSH
• kovové nanočástice chemie   toxicita   MeSH
• kultivované buňky MeSH
• lidé MeSH
• lipopolysacharidy * farmakologie   MeSH
• makrofágy účinky léků   MeSH
• monocyty * účinky léků   MeSH
• nanočástice chemie   toxicita   MeSH
• protein NLRP3 * metabolismus   MeSH
• titan * chemie   farmakologie   toxicita   MeSH
• viabilita buněk * účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Mikroorganismy si během evoluce vyvinuly širokou škálu strategií, jak uniknout vrozenému i adaptivnímu imunitnímu systému, a některým těmto strategiím se věnujeme v našem přehledu. Mikroorganismy mohou využívat podobnost svých proteinů s proteiny hostitele, produkovat protizánětlivé faktory, narušovat komplementový systém, ovlivňovat funkci a blokovat syntézu cytokinů, inhibovat rozpoznávání imunoglobulinů, snižovat expresi a modifikovat antigeny na svém povrchu, narušovat zpracování a prezentaci antigenu imunitními buňkami, vstupovat do imunitních buněk, ovlivňovat apoptózu buněk, modulovat funkce imunitních buněk nebo ovlivňovat produkci hormonů. S těmito únikovými strategiemi je nutné počítat při léčbě infekčních onemocnění.

Microorganisms have evolved a wide variety of strategies to evade both the innate and adaptive immune systems during evolution, and some of these strategies are addressed in our review. Microorganisms can use the similarity of their proteins to host proteins, produce anti-inflammatory factors, disrupt the complement system, affect the function and block the synthesis of cytokines, inhibit the recognition of immunoglobulins, reduce the expression and modify antigens on their surface, disrupt the processing and presentation of antigen by immune cells, enter immune cells , influence cell apoptosis, modulate immune cell functions or influence hormone production. These escape strategies must be taken into account when treating infectious diseases.

• Klíčová slova
• únikové strategie mikroorganismů,
• MeSH
• interakce hostitele a patogenu MeSH
• lidé MeSH
• mikrobiologické jevy * MeSH
• přirozená imunita * MeSH
• trénovaná imunita MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Effort-based decision-making is particularly relevant to psychiatric conditions where motivation deficits are prominent features. Despite its clinical significance, the neurochemical mechanisms of this cognitive process remain unclarified. This study explores the impact of serotonin synthesis inhibition (PCPA) and modulation of serotonin release and 5-HT1A receptor agonism (8-OH-DPAT) on effort-based decision-making in rats. Adult male rats were trained in a modified T-maze task where they could obtain a high reward for climbing a mesh barrier or a low reward for no extra effort. Following training, rats received either acute 8-OH-DPAT treatment or subchronic PCPA treatment and were tested on their choices between high- and low-effort arms. The goal-arm choices and goal-arm entrance latencies were recorded. Next, homovanillic acid and 5-hydroxyindoleacetic acid, metabolites of dopamine and serotonin, respectively, were quantified in the rats' prefrontal cortex, striatum, and hippocampus. 8-OH-DPAT significantly increased low-effort, low-reward choices and increased goal-arm latency. In contrast, PCPA treatment did not affect these measures. Both PCPA and 8-OH-DPAT significantly decreased 5-hydroxyindoleacetic acid levels in the prefrontal cortex and the hippocampus. 8-OH-DPAT treatment was also associated with decreased homovanillic acid levels in the hippocampus. Our findings suggest that the overall reduction of serotonin levels alone does not affect effort-based decision-making and highlights the possible role of the hippocampus and the 5-HT1A receptor in this cognitive process.

• MeSH
• 8-hydroxy-2-(di-N-propylamino)tetralin * farmakologie   MeSH
• agonisté serotoninového receptoru 5-HT1 farmakologie   MeSH
• bludiště - učení účinky léků   fyziologie   MeSH
• chování zvířat účinky léků   MeSH
• krysa rodu rattus MeSH
• odměna MeSH
• potkani Sprague-Dawley MeSH
• rozhodování * fyziologie   účinky léků   MeSH
• serotonin * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) mainly afflicting young women. Various steroids can influence the onset and development of the disease or, on the contrary, mitigate its course; however, a systematic review of steroidomic changes in MS patients is lacking. Based on the gas chromatography tandem mass spectrometry (GC-MS/MS) platform and, in the case of estradiol, also using immunoassay, this study performed a comprehensive steroidomic analysis in 25 female MS patients aged 39(32, 49) years compared to 15 female age-matched controls aged 38(31, 46) years. A significant trend towards higher ratios of conjugated steroids to their unconjugated counterparts was found in patients, which is of particular interest in terms of the balance between excitatory and inhibitory steroid modulators of ionotropic receptors. Patients showed altered metabolic pathway to cortisol with decreased conversion of pregnenolone to 17-hydroxypregnenolone and 17-hydroxypregnenolone to 17-hydroxyprogesterone and increased conversion of 17-hydroxypregnenolone to dehydroepiandrosterone (DHEA), resulting in lower levels of 17-hydroxyprogesterone, as well as indications of impaired conversion of 11-deoxy-steroids to 11β-hydroxy-steroids but reduced conversion of cortisol to cortisone. Due to over-activation of hypothalamic-pituitary-adrenal axis (HPAA), however, cortisol and cortisone levels were higher in patients with indications of depleted cortisol synthesizing enzymes. Patients showed lower conversion of DHEA to androstenedione, androstenedione to testosterone, androstenedione to estradiol in the major pathway, and testosterone to estradiol in the minor pathway for estradiol synthesis at increased conversion of androstenedione to testosterone. They also showed lower conversion of immunoprotective Δ5 androstanes to their more potent 7α/β-hydroxy metabolites and had lower circulating allopregnanolone and higher ratio 3β-hydroxy-steroids to their neuroprotective 3α-hydroxy-counterparts.

• MeSH
• dospělí MeSH
• hydrokortison metabolismus   krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
• roztroušená skleróza * metabolismus   krev   MeSH
• steroidy metabolismus   MeSH
• studie případů a kontrol MeSH
• tandemová hmotnostní spektrometrie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Protein synthesis plays a major role in homeostasis and when dysregulated leads to various pathologies including cancer. To this end, imbalanced expression of eukaryotic translation initiation factors (eIFs) is not only a consequence but also a driver of neoplastic growth. eIF3 is the largest, multi-subunit translation initiation complex with a modular assembly, where aberrant expression of one subunit generates only partially functional subcomplexes. To comprehensively study the effects of eIF3 remodeling, we contrasted the impact of eIF3d, eIF3e or eIF3h depletion on the translatome of HeLa cells using Ribo-seq. Depletion of eIF3d or eIF3e, but not eIF3h reduced the levels of multiple components of the MAPK signaling pathways. Surprisingly, however, depletion of all three eIF3 subunits increased MAPK/ERK pathway activity. Depletion of eIF3e and partially eIF3d also increased translation of TOP mRNAs that encode mainly ribosomal proteins and other components of the translational machinery. Moreover, alterations in eIF3 subunit stoichiometry were often associated with changes in translation of mRNAs containing short uORFs, as in the case of the proto-oncogene MDM2 and the transcription factor ATF4. Collectively, perturbations in eIF3 subunit stoichiometry exert specific effect on the translatome comprising signaling and stress-related transcripts with complex 5' UTRs that are implicated in homeostatic adaptation to stress and cancer.

• MeSH
• eukaryotický iniciační faktor 3 * metabolismus   genetika   MeSH
• HeLa buňky MeSH
• lidé MeSH
• MAP kinasový signální systém * MeSH
• proteosyntéza MeSH
• protoonkogen Mas * MeSH
• ribozomální proteiny * metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Background/Objectives: PET imaging of bacterial infection could potentially provide added benefits for patient care through non-invasive means. [68Ga]Ga-desferrioxamine B-a radiolabelled siderophore-shows specific uptake by human-pathogenic bacteria like Staphylococcus aureus or Pseudomonas aeruginosa and sufficient serum stability for clinical application. In this report, we present data for automated production of [68Ga]Ga-desferrioxamine B on two different cassette-based synthesis modules (Modular-Lab PharmTracer and GRP 3V) utilising commercially obtainable cassettes together with a licensed 68Ge/68Ga radionuclide generator. Methods: Quality control, including the determination of radiochemical purity, as well as a system suitability test, was set up via RP-HPLC on a C18 column. The two described production processes use an acetic acid/acetate buffer system with ascorbic acid as a radical scavenger for radiolabelling, yielding ready-to-use formulations with sufficient activity yield. Results: Batch data analysis demonstrated radiochemical purity of >95% by RP-HPLC combined with ITLC and excellent stability up to 2 h after synthesis. Specifications for routine production were set up and validated with four masterbatches for each synthesis module. Conclusions: Based on this study, an academic clinical trial for imaging of bacterial infection was initiated. Both described synthesis methods enable automated production of [68Ga]Ga-desferrioxamine B in-house with high reproducibility for clinical application.

• Publikační typ
• časopisecké články MeSH

V rámci daného projektu bychom chtěli vyvinout novou skupinu léčiv cíleny ́ch na stárnutí a jeho zpomalení. Během několika posledních let náš vy ́zkum byl zaměřen na mitochondriální enzym amyloid vázající alkohol dehydrogenasu (ABAD) ve vztahu k Alzheimerově chorobě. Mezitím bylo zjištěno, že modulace ABADu může rovněž pomoci v léčbě některy ́ch typů nádorů. Navíc vy ́sledky nedávny ́ch studií poukázaly také na to, že modulátory ABADu mají imunosupresivní účinek. Na základě vy ́še uvedeny ́ch vědecky-podloženy ́ch faktů se domníváme, že modulátory ABADu mohou působit jako potenciální léčiva zpomalující stárnutí, tj. kandidátní molekuly mající schopnost zpomalit stárnutí organismu podobně jako rapamycin či jeho deriváty(rapalogy). Pro tento účel budou provedeny in silico screening, chemická syntéza, in vitro a in vivo testování nové skupiny léčiv zpomalující stárnutí na bázi simultánních modulátorů ABAD a mTOR signálních cest.; Within our project, we would like to develop a new class of anti-aging drugs - drugs intended to slow aging process. In past, we investigated mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD) in relation to Alzheimer ́s disease. In meantime, it has been found out that ABAD modulation could also help within cancer therapy. More recently, we obtained preliminary results revealing that ABAD modulators also act as immunosupressants. Due to preliminary data mentioned above, we propose ABAD modulators as possible therapeutics against aging, in particular, drug candidates able to delay aging of the organism in a similar way as rapamycine and its derivatives (rapalogs) do. For this purpose, in silico screening, chemical synthesis, in vitro and in vivo evaluation of the novel class of anti-aging drugs able to simultaneously modulate ABAD and mTOR signaling pathway will be realized.

• Klíčová slova
• věkově specifické nemoci, léky zabraňující stárnutí, ABAD, mTOR, proces stárnutí, age-associated diseases, anti-aging drugs, ABAD, mTOR, aging process, rapamycin, rapamycin,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR