Age-related macular degeneration (AMD) is a progressive chronic disease causing visual impairment or central vision loss in the elderly. We hypothesized that successful rheopheresis would be associated with positive changes in soluble endoglin (sENG), PSCK9, alpha-2-macroglobulin (A2M), and hs-CRP levels. 31 elderly patients with the dry form of AMD, treated with rheopheresis with a follow-up period of at least 5 years and an average age of 68 ± 4 years, were evaluated. Each treated patient received a series of 8 procedures in 10 weeks and, after the 2-year period, another 2 procedures within 1 week. Then, the patients were followed up every 6 months and divided into the successfully treated and therapeutic failure group according to best-corrected visual acuity (BCVA), size of the drusen area, and the drusenoid pigment epithelium detachment (DPED). Based on the ophthalmological assessment, rheopheresis treatment was successful in 73% of AMD patients. The therapy was associated with a significant decrease in total cholesterol, LDL-C, HDL-C, apoprotein B, lipoprotein (a) levels, and rheologically important parameters, irrespective of the therapy's success or failure. The success of rheopheresis therapy was exclusively related to a significant decrease in sENG and A2M levels. Over the long term, rheopheresis prevented the decline of BCVA, reduced the DPED and area of macular drusen, and improved the preservation of an intact photoreceptor ellipsoid zone in most patients. Moreover, we showed for the first time that sENG and A2M could be potentially sensitive biomarkers of successful rheopheresis procedure, irrespective of lipid parameters changes.

• MeSH
• biologické markery * krev   MeSH
• endoglin * krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• makulární degenerace * terapie   krev   MeSH
• senioři MeSH
• výsledek terapie MeSH
• zraková ostrost MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.

• MeSH
• Alzheimerova nemoc * metabolismus   patologie   etiologie   MeSH
• amyloidní beta-protein * metabolismus   MeSH
• buněčná membrána metabolismus   MeSH
• fosforylace MeSH
• lidé MeSH
• peptidové fragmenty metabolismus   MeSH
• protein 1 související s LDL-receptory * metabolismus   MeSH
• proteiny tau * metabolismus   MeSH
• tauopatie * metabolismus   patologie   etiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Olfactory function, orchestrated by the cells of the olfactory mucosa at the rooftop of the nasal cavity, is disturbed early in the pathogenesis of Alzheimer's disease (AD). Biometals including zinc and calcium are known to be important for sense of smell and to be altered in the brains of AD patients. Little is known about elemental homeostasis in the AD patient olfactory mucosa. Here we aimed to assess whether the disease-related alterations to biometal homeostasis observed in the brain are also reflected in the olfactory mucosa. We applied RNA sequencing to discover gene expression changes related to metals in olfactory mucosal cells of cognitively healthy controls, individuals with mild cognitive impairment and AD patients, and performed analysis of the elemental content to determine metal levels. Results demonstrate that the levels of zinc, calcium and sodium are increased in the AD olfactory mucosa concomitantly with alterations to 17 genes related to metal-ion binding or metal-related function of the protein product. A significant elevation in alpha-2-macroglobulin, a known metal-binding biomarker correlated with brain disease burden, was observed on the gene and protein levels in the olfactory mucosa cells of AD patients. These data demonstrate that the olfactory mucosa cells derived from AD patients recapitulate certain impairments of biometal homeostasis observed in the brains of patients.

• MeSH
• Alzheimerova nemoc * metabolismus   MeSH
• chelátory metabolismus   MeSH
• čichová sliznice metabolismus   MeSH
• lidé MeSH
• stopové prvky * metabolismus   MeSH
• vápník metabolismus   MeSH
• zinek metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1, including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.

• MeSH
• alfa-makroglobuliny genetika   MeSH
• fenotyp * MeSH
• genetické testování normy   MeSH
• lidé MeSH
• mutace * MeSH
• Noonanové syndrom genetika   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Stimulation with polyclonal activators is a tool to increase antibody secretion in B cells. The aim of the present study was to select the most effective common commercially available polyclonal activators of rabbit B cells. Specifically, type B oligodeoxynucleotides with unmethylated deoxycytidyl-deoxyguanosine dinucleotides (CpG-ODN), recombinant rabbit interleukin-2 (rrIL-2), lipopolysaccharide (LPS), pokeweed mitogen (PWM) and Resiquimod (R848) were tested on B cells isolated from blood and spleen by fluorescence-activated cell sorting. Based on the obtained data, stimulation with CpG-ODN induced the highest antigen-specific antibody levels detected by ELISA in supernatants when a single activator was used. In contrast, LPS, PWM and R848 showed a weak or no stimulatory effect. Stimulation with a mix of activators was more effective than CpG-ODN alone, which indicates a synergistic effect in the stimulation of antibody production.

• MeSH
• alfa-makroglobuliny aplikace a dávkování   imunologie   MeSH
• B-lymfocyty imunologie   MeSH
• králíci MeSH
• oligodeoxyribonukleotidy aplikace a dávkování   imunologie   MeSH
• tvorba protilátek účinky léků   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The present study was performed to evaluate the antibacterial activities of an antimicrobial peptide (CSpK14) and the synergies thereof with β-lactams against vancomycin-resistant Staphylococcus aureus (VRSA) and Enterococci (VRE). Our strain was isolated from fermented food (kimchi), which is 99.79 % homologous with Bacillus amyloliquefaciens subsp. plantarum FZB42(T). CSpK14 was purified to homogeneity by diammonium sulfate precipitation, concentration, dialysis, and followed by two-stage chromatographic separation, i.e., Sepharose Cl-6B and Sephadex G-25 chromatography, and had a molar mass of ~4.6 kDa via Tricine SDS-PAGE and in situ examination. It was stable at pH 6.0-11.5 and temperature up to 80 °C. In addition, it was also stable with various metal ions, solvents, and proteases. The N-terminal amino acid sequence was H-Y-D-P-G-D-D-S-G-N-T-G and did not show any significant homology with reported peptides. However, it shows some degrees of identity with alpha-2-macroglobulin and ligand-gated channel protein from different microorganisms. CSpK14 significantly reduced the minimum inhibitory concentrations (MICs) of β-lactams and had no effect on non-β-lactams against VRSA and VRE. MICs of CSpK14/oxacillin and CSpK14/ampicillin were reduced by 8- to 64-fold and 2- to 16-fold, respectively. The time killing assay between CSpK14/oxacillin (2.29-2.37 Δlog10CFU/mL at 24 h) and CSpK14/ampicillin (2.30-2.38 Δlog10CFU/mL at 24 h) being >2-fold and fractional inhibitory concentration index ˂0.5 revealed synergy. Furthermore, the biofilms formed by VRSA and VRE were reduced completely. CSpK14 was simple to purify, had low molecular mass, was stable over a wide pH range or tested chemicals, had broad inhibitory spectrum, and possessed potent synergistic antimicrobial-antibiofilm properties. CSpK14 synergistically enhanced the efficacy of β-lactams and is therefore suitable for combination therapy.

• MeSH
• ampicilin farmakologie   MeSH
• antibakteriální látky biosyntéza   izolace a purifikace   farmakologie   MeSH
• Bacillus amyloliquefaciens klasifikace   imunologie   metabolismus   MeSH
• biofilmy účinky léků   růst a vývoj   MeSH
• chromatografie iontoměničová MeSH
• enterokoky rezistentní vůči vankomycinu účinky léků   růst a vývoj   MeSH
• fylogeneze MeSH
• kationické antimikrobiální peptidy biosyntéza   izolace a purifikace   farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• mikrobiální testy citlivosti MeSH
• oxacilin farmakologie   MeSH
• rezistence na vankomycin účinky léků   MeSH
• sekvence aminokyselin MeSH
• stabilita proteinů MeSH
• Staphylococcus aureus účinky léků   růst a vývoj   MeSH
• synergismus léků MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes. Over the last decade, there has been an intensive search for novel biochemical markers for clinical diagnosis of AD and other tauopathies. In the present study, we used transgenic rat model for tauopathy expressing human truncated tau protein (aa 151-391/4R) to analyze the cerebrospinal fluid (CSF) peptidome using liquid chromatography - matrix assisted laser desorption/ionization mass spectrometry (LC-MALDI TOF/TOF). From 345 peptides, we identified a total of 175 proteins. Among them, 17 proteins were significantly altered in the CSF of transgenic rats. The following proteins were elevated in the CSF of transgenic rats when compared to the control animals: neurofilament light and medium chain, apolipoprotein E, gamma-synuclein, chromogranin A, reticulon-4, secretogranin-2, calsyntein-1 and -3, endothelin-3, neuroendocrine protein B72A, alpha-1-macroglobulin, and augurin. Interestingly most of the identified proteins were previously linked to AD and other tauopathies, indicating the significance of transgenic animals in biomarker validation.

• MeSH
• chromatografie kapalinová MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• peptidy MeSH
• potkani transgenní MeSH
• proteiny tau genetika   MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• tauopatie genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Systémová enzymoterapie je definována jako léčebná metoda, která zahrnuje perorální aplikaci kombinovaných enzymových směsí ve formě acidorezistentních tablet. Hlavní účinné látky těchto přípravků tvoří proteolytické enzymy původu živočišného (trypsin a chymotrypsin) a rostlinného (bromelain a papain). Základní podmínkou systémového účinku takto aplikovaných proteáz je jejich podávání nalačno a následné vstřebávání střevní sliznicí, při kterém zůstává zachována jejich enzymatická aktivita. Léčivé přípravky určené pro systémovou enzymoterapii jsou známy svými účinky protizánětlivými, protiotokovými, analgetickými a působí též imunomodulačně. Díky svému fibrinolytickému a antiagregačnímu účinku příznivě ovlivňují reologické vlastnosti krve. Současné podávání přípravků určených pro systémovou enzymoterapii společně s antibiotiky (ale i s dalšími léčivy) zlepšuje jejich tkáňovou dostupnost (efekt vehikula). Léčivé přípravky pro systémovou enzymoterapii Wobenzym® a Phlogenzym® jsou v České republice registrovány jako volně prodejné léky. Oborem, kde má využití systémové enzymoterapie v ČR nejdelší tradici, je patrně sportovní medicína.

Systemic enzyme therapy is defined as a therapeutic method using oral application of combined enzyme mixtures in the form of acid resistant tablets. The key active substances in these tablets are proteolytic enzymes of both animal (trypsin and chymotrypsin) and plant (bromelain and papain) origin. The systemic effect of thus applied proteases fully depends on their administration before meals and on their absorption through the intestinal mucosa, after which their enzymatic activity is preserved. Therapeutic agents for systemic enzyme therapy are known for their anti inflammatory, anti edematous, analgesic, and immunomodulatory properties. Thanks to their fibrinolytic and anti aggregation effects, they also improve the rheologic properties of the blood. Parallel application of systemic enzyme therapy and antibiotics (but also other drugs) improves their tissue availability (effect of the vehiculum). Therapeutic agents for systemic enzyme therapy Wobenzym® and Phlogenzym® are registered in the Czech Republic as over the counter drugs. The longest tradition of systemic enzyme therapy use in the Czech Republic can probably be seen in the sport medicine.

• MeSH
• alfa-makroglobuliny MeSH
• aplikace orální MeSH
• bromelainy farmakokinetika   metabolismus   MeSH
• chymotrypsin farmakokinetika   metabolismus   MeSH
• cytokiny účinky léků   MeSH
• enzymoterapie * MeSH
• imunitní systém enzymologie   MeSH
• klinické zkoušky kontrolované jako téma MeSH
• lidé MeSH
• makrofágy MeSH
• papain farmakokinetika   metabolismus   MeSH
• proteasy * farmakokinetika   metabolismus   MeSH
• střevní sliznice účinky léků   MeSH
• trypsin farmakokinetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

UNLABELLED: Crayfish spermatophores are deposited on the body surface of the female during mating and remain there for a period of time before fertilization ensues. Post-mating changes in protein expression level in the noble crayfish Astacus astacus spermatophore were quantified. In-gel digestion and high resolution mass spectrometry were used for label-free protein quantification. One hundred twelve proteins were identified in the spermatophore of noble crayfish. After 7 days of storage on the body of the female, 6 proteins were identified in the post-mating spermatophore that showed significant up-regulation and 4 significant down-regulations (p < 0.05, fold change ≥ 2). The highest rate of up-regulation was observed in sodium/hydrogen exchanger, which may indicate the importance of intracellular pH adjustment for final maturation of the crayfish spermatozoon. The highest rate of down-regulation was observed in histone H2A. This may increase chromatin flexibility and facilitate its transfer into the oocyte during fertilization. The vitellogenin protein was identified in the crayfish spermatophore and its level changed during storage on the body surface of female. Extensive proteomic modification of male gametes during storage on the body surface of the female suggests post-mating final maturation of the crayfish spermatozoon. BIOLOGICAL SIGNIFICANCE: Freshwater crayfish comprise a large and diverse group of ecologically and commercially important animals. Molecular studies of gametes in the crayfish can provide insight into the complex process of reproduction in this diverse group of animals. The results of such studies can be used for development of new techniques for artificial reproduction of these economically important species.

• MeSH
• alfa-makroglobuliny metabolismus   MeSH
• chromatografie kapalinová MeSH
• hemokyanin metabolismus   MeSH
• histony metabolismus   MeSH
• hmotnostní spektrometrie MeSH
• kapacitace spermií MeSH
• Na(+)-H(+) antiport metabolismus   MeSH
• proteomika metody   MeSH
• ryanodinový receptor vápníkového kanálu metabolismus   MeSH
• severní raci fyziologie   MeSH
• sexuální faktory MeSH
• spermatogonie fyziologie   MeSH
• spermie fyziologie   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

x

• MeSH
• alfa-makroglobuliny analýza   MeSH
• amylasy aplikace a dávkování   MeSH
• analýza přežití MeSH
• chymotrypsinogen aplikace a dávkování   MeSH
• imunosupresivní léčba MeSH
• kombinovaná farmakoterapie metody   MeSH
• melanom experimentální * farmakoterapie   patologie   MeSH
• metastázy nádorů patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádory plic epidemiologie   patologie   sekundární   MeSH
• následné studie MeSH
• prekurzory enzymů * aplikace a dávkování   MeSH
• proteasy * aplikace a dávkování   MeSH
• sarkom 180 * farmakoterapie   patologie   MeSH
• statistika jako téma MeSH
• synergismus léků MeSH
• transformující růstový faktor beta krev   MeSH
• trypsinogen aplikace a dávkování   MeSH
• tumor burden účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH