Targeting capability
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The non-specific binding of non-target species to functionalized surfaces of biosensors continues to be challenge for biosensing in real-world media. Three different low-fouling and functionalizable surface platforms were employed to study the effect of functionalization on fouling resistance from several types of undiluted media including blood plasma and food media. The surface platforms investigated in this work included two polymer brushes: hydroxy-functional poly(2-hydroxyethyl methacrylate) (pHEMA) and carboxy-functional poly(carboxybetaine acrylamide) (pCBAA), and a standard OEG-based carboxy-functional alkanethiolate self-assembled monolayer (AT-SAM). The wet and dry polymer brushes were analyzed by AFM, ellipsometry, FT-IRRAS, and surface plasmon resonance (SPR). The surfaces were functionalized by the covalent attachment of antibodies, streptavidin, and oligonucleotides and the binding and biorecognition characteristics of the coatings were compared. We found that functionalization did not substantially affect the ultra-low fouling properties of pCBAA (plasma fouling of ~20 ng/cm(2)), a finding in contrast with pHEMA that completely lost its resistance to fouling after the activation of hydroxyl groups. Blocking a functionalized AT-SAM covalently with BSA decreased fouling down to the level comparable to unblocked pCBAA. However, the biorecognition capability of blocked functionalized AT-SAM was poor in comparison with functionalized pCBAA. Limits of detection of Escherichia coli O157:H7 in undiluted milk were determined to be 6×10(4), 8×10(5), and 6×10(5) cells/ml for pCBAA, pHEMA, and AT-SAM-blocked, respectively. Effect of analyte size on biorecognition activity of functionalized coatings was investigated and it was shown that the best performance in terms of overall fouling resistance and biorecognition capability is provided by pCBAA.
- MeSH
- adsorpce MeSH
- akrylamidy chemie MeSH
- Escherichia coli izolace a purifikace MeSH
- limita detekce MeSH
- mléko mikrobiologie MeSH
- polyhydroxyethylmethakrylát chemie MeSH
- polymery chemie MeSH
- povrchová plasmonová rezonance metody MeSH
- povrchové vlastnosti MeSH
- sulfhydrylové sloučeniny chemie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Dithiocarbamates and their complexes with transition metals have been used as common pesticides, vulcanizing or analytical agents for decades. These compounds are one of the most reported inhibitors of nuclear factor-kappaB (NF-kappaB) signaling cascade. Recently, it has been found that dithiocarbamates are very potent inhibitors of proteasome. NF-kappaB plays a central role in the immune system and is described as a major actor in many of human cancers mainly because of its protective effects against apoptosis. Molecular mechanisms involved in regulation and function of NF-kappaB pathway have been elucidated recently. In particular, pivotal zinc containing proteins that alter NF-kappaB signal transduction were recognized. Additionally, proteasome system was found to be a key player in NF-kappaB pathway and is an attractive target for anticancer drug development. Collectively, the capability of dithiocarbamates to inhibit NF-kappaB and proteasome makes these compounds promising anticancer agents. This review focuses on the biological activity of dithiocarbamate coordination compounds with regard to their possible molecular targets in NF-kappaB signaling and proteasome (JAMM domain proteins). Future research should aim to find the most suitable dithiocarbamate coordination compounds for treatment of cancer and other diseases.
- MeSH
- apoptóza účinky léků MeSH
- dithiokarb farmakologie MeSH
- financování organizované MeSH
- inhibitory proteasomu MeSH
- kovy MeSH
- lidé MeSH
- NF-kappa B antagonisté a inhibitory fyziologie MeSH
- proteasomový endopeptidasový komplex fyziologie MeSH
- protinádorové látky farmakologie MeSH
- signální transdukce účinky léků MeSH
- thiokarbamáty farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Increased arterial stiffness is a degenerative vascular process, progressing with age that leads to a reduced capability of arteries to expand and contract in response to pressure changes. This progressive degeneration mainly affects the extracellular matrix of elastic arteries and causes loss of vascular elasticity. Recent studies point to significant interference of dietary polyphenols with mechanisms involved in the pathophysiology and progression of arterial stiffness. This review summarizes data from epidemiological and interventional studies on the effect of polyphenols on vascular stiffness as an illustration of current research and addresses possible etiological factors targeted by polyphenols, including pathways of vascular functionality, oxidative status, inflammation, glycation, and autophagy. Effects can either be inflicted directly by the dietary polyphenols or indirectly by metabolites originated from the host or microbial metabolic processes. The composition of the gut microbiome, therefore, determines the resulting metabolome and, as a consequence, the observed activity. On the other hand, polyphenols also influence the intestinal microbial composition, and therefore the metabolites available for interaction with relevant targets. As such, targeting the gut microbiome is another potential treatment option for arterial stiffness.
- MeSH
- analýza potravin * MeSH
- dieta * MeSH
- lidé MeSH
- polyfenoly chemie farmakologie MeSH
- střevní mikroflóra účinky léků MeSH
- tuhost cévní stěny účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Background/Objectives: Dual-modality probes, combining positron emission tomography (PET) with fluorescence imaging (FI) capabilities in a single molecule, are of high relevance for the accurate staging and guided resection of tumours. We herein present a pair of candidates targeting the cholecystokinin-2 receptor (CCK2R), namely [68Ga]Ga-CyTMG and [68Ga]Ga-CyFMG. In these probes, the SulfoCy5.5 fluorophore and two units of a CCK2R-binding motif are coupled to the chelator acting as a core scaffold, triazacyclononane-phosphinic acid (TRAP), and Fusarinine C (FSC), respectively. Using this approach, we investigated the influence of these chelators on the final properties. Methods: The synthetic strategy to both precursors was based on the stoichiometric conjugation of the components via click chemistry. The characterization in vitro included the evaluation of the CCK2R affinity and internalization in A431-CCK2R cells. Ex vivo biodistribution as well as PET and FI studies were performed in xenografted mice. Results: 68Ga labelling was accomplished with high radiochemical yield and purity for both precursors. A CCK2R affinity in the subnanomolar range of the conjugates and a receptor-specific uptake of the radioligands in cells were observed. In A431-CCK2R/A431-mock xenografted mice, the investigated compounds showed specific accumulation in the tumours and reduced off-target uptake compared to a previously developed compound. Higher accumulation and prolonged retention in the kidneys were observed for [68Ga]Ga-CyTMG when compared to [68Ga]Ga-CyFMG. Conclusions: Despite the promising targeting properties observed, further probe optimization is required to achieve enhanced imaging contrast at early timepoints. Additionally, the results indicate a distinct influence of the chelators in terms of renal accumulation and retention.
- Publikační typ
- časopisecké články MeSH
Alzheimer's disease (AD) is a neurodegenerative disease that is usually accompanied by aging, increasingly being the most common cause of dementia in the elderly. This disorder is characterized by the accumulation of beta amyloid plaques (Aβ) resulting from impaired amyloid precursor protein (APP) metabolism, together with the formation of neurofibrillary tangles and tau protein hyperphosphorylation. The exacerbated production of reactive oxygen species (ROS) triggers the process called oxidative stress, which increases neuronal cell abnormalities, most often followed by apoptosis, leading to cognitive dysfunction and dementia. In this context, the development of new therapies for the AD treatment is necessary. Antioxidants, for instance, are promising species for prevention and treatment because they are capable of disrupting the radical chain reaction, reducing the production of ROS. These species have also proven to be adjunctive to conventional treatments making them more effective. In this sense, several recently published works have focused their attention on oxidative stress and antioxidant species. Therefore, this review seeks to show the most relevant findings of these studies.
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein chemie metabolismus MeSH
- antioxidancia farmakologie terapeutické užití MeSH
- fosforylace MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- oxidační stres účinky léků MeSH
- proteiny tau chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Background Identification and elimination of nonpulmonary vein targets may improve clinical outcomes in patients with persistent atrial fibrillation (AF). We report on the use of a novel, noncontact imaging and mapping system that uses ultrasound to reconstruct atrial chamber anatomy and measures timing and density of dipolar, ionic activation (ie, charge density) across the myocardium to guide ablation of atrial arrhythmias. Methods The prospective, nonrandomized UNCOVER AF trial (Utilizing Novel Dipole Density Capabilities to Objectively Visualize the Etiology of Rhythms in Atrial Fibrillation) was conducted at 13 centers across Europe and Canada. Patients with persistent AF (>7 days, <1 year) aged 18 to 80 years, scheduled for de novo catheter ablation, were eligible. Before pulmonary vein isolation, AF was mapped and then iteratively remapped to guide each subsequent ablation of charge density-identified targets. AF recurrence was evaluated at 3, 6, 9, and 12 months using continuous 24-hour ECG monitors. The primary effectiveness outcome was freedom from AF >30 seconds at 12 months for a single procedure with a secondary outcome being acute procedural efficacy. The primary safety outcome was freedom from device/procedure-related major adverse events. Results Between October 2016 and April 2017, 129 patients were enrolled, and 127 underwent mapping and catheter ablation. Acute procedural efficacy was demonstrated in 125 patients (98%). At 12 months, single procedure freedom from AF on or off antiarrhythmic drugs was 72.5% (95% CI, 63.9%-80.3%). After 1 or 2 procedures, freedom from AF was 93.2% (95% CI, 87.1%-97.0%). A total of 29 (23%) retreatments because of arrhythmia recurrence were performed with average time from index procedure to first retreatment being 7 months. The primary safety outcome was 98% with no device-related major adverse events reported. Conclusions This novel ultrasound imaging and charge density mapping system safely guided ablation of nonpulmonary vein targets in persistent AF patients with 73% single procedure and 93% second procedure freedom from AF at 12 months. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02825992 EU/NCT02462980 CN.
- MeSH
- akční potenciály * MeSH
- časové faktory MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- elektrofyziologické techniky kardiologické * MeSH
- elektrokardiografie ambulantní MeSH
- fibrilace síní diagnostické zobrazování patofyziologie chirurgie MeSH
- katetrizační ablace MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nerandomizované kontrolované studie jako téma MeSH
- prediktivní hodnota testů MeSH
- převodní systém srdeční diagnostické zobrazování patofyziologie chirurgie MeSH
- prospektivní studie MeSH
- recidiva MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- srdeční frekvence * MeSH
- ultrasonografie * MeSH
- venae pulmonales patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- klinické zkoušky MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
- Kanada MeSH
Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-β (A-β) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7-hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e-g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu-5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-β1-40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease.
- MeSH
- acetylcholinesterasa chemie MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein chemie MeSH
- butyrylcholinesterasa chemie MeSH
- cholinesterasové inhibitory * chemická syntéza chemie MeSH
- GPI-vázané proteiny chemie MeSH
- kumariny * chemická syntéza chemie MeSH
- lidé MeSH
- měď chemie MeSH
- oxidační stres * MeSH
- peptidové fragmenty chemie MeSH
- takrin * chemická syntéza chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The inverse electron-demand Diels-Alder reaction between 1,2,4,5-tetrazine (Tz) and trans-cyclooct-2-ene (TCO) has gained increasing attraction among extensive studies on click chemistry due to its exceptionally fast reaction kinetics and high selectivity for in vivo pretargeting applications including PET imaging. The facile two-step approach utilizing TCO-modified antibodies as targeting structures has not made it into clinics yet. An increase in the blood volume of humans in comparison to mice seems to be the major limitation. This study aims to show if the design of multimeric Tz-ligands by chelator scaffolding can improve the binding capacity and may lead to enhanced PET imaging with gallium-68. We utilized for this purpose the macrocyclic siderophore Fusarinine C (FSC) which allows conjugation of up to three Tz-residues due to three primary amines available for site specific modification. The resulting mono- di- and trimeric conjugates were radiolabelled with gallium-68 and characterized in vitro (logD, protein binding, stability, binding towards TCO modified rituximab (RTX)) and in vivo (biodistribution- and imaging studies in normal BALB/c mice using a simplified RTX-TCO tumour surrogate). The 68Ga-labelled FSC-based Tz-ligands showed suitable hydrophilicity, high stability and high targeting specificity. The binding capacity to RTX-TCO was increased according to the grade of multimerization. Corresponding in vivo studies showed a multimerization typical profile but generally suitable pharmacokinetics with low accumulation in non-targeted tissue. Imaging studies in RTX-TCO tumour surrogate bearing BALB/c mice confirmed this trend and revealed improved targeting by multimerization as increased accumulation in RTX-TCO positive tissue was observed.
- Publikační typ
- časopisecké články MeSH
MicroRNAs (miRNAs) are short, 18-25-nucleotide long, non-coding single-stranded RNAs, which are capable to regulate gene expression on post-transcriptional level through binding to their target protein-encoding mRNAs. miRNAs regulate individual components of multiple oncogenic pathways. One of them is epidermal growth factor receptor (EGFR) signalling pathway that regulates cell proliferation, differentiation, migration, angiogenesis and apoptosis. All these processes are deregulated in colorectal cancer (CRC). Moreover, EGFR has been validated as the therapeutic target in CRC, and monoclonal antibodies cetuximab and panitumumab are used in the therapy of patients with metastatic CRC. Because of the extensive involvement of miRNAs in the regulation of EGFR signalling, it seems they could also serve as promising predictive biomarkers to anti-EGFR therapy. In this review, we summarize current knowledge about miRNAs targeting EGFR signalling pathway, their functioning in CRC pathogenesis and potential usage as biomarkers.
- MeSH
- erbB receptory genetika metabolismus MeSH
- kolorektální nádory genetika metabolismus MeSH
- lidé MeSH
- mikro RNA genetika MeSH
- nádorové biomarkery genetika MeSH
- proteinkinasy genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- RNA interference MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The mitochondrial contact site and cristae organization system (MICOS) is a multiprotein complex responsible for cristae formation. Even though cristae are found in all mitochondria capable of oxidative phosphorylation, only Mic10 and Mic60 appear to be conserved throughout eukaryotes. The remaining 4 or 5 known MICOS subunits are specific to the supergroup Opisthokonta, which includes yeast and mammals that are the only organisms in which this complex has been analyzed experimentally. We have isolated the MICOS from Trypanosoma brucei, a member of the supergroup Excavata that is profoundly diverged from opisthokonts. We show that it is required for the maintenance of the unique discoidal cristae that typify excavates, such as euglenids and kinetoplastids, the latter of which include trypanosomes. The trypanosome MICOS consists of 9 subunits, most of which are essential for normal growth. Unlike in opisthokonts, it contains two distinct Mic10 orthologs and an unconventional putative Mic60 that lacks a mitofilin domain. Interestingly, one of the essential trypanosomatid-specific MICOS subunits called TbMic20 is a thioredoxin-like protein that appears to be involved in import of intermembrane space proteins, including respiratory chain complex assembly factors. This result points to trypanosome MICOS coordinating cristae shaping and population of its membrane with proteins involved in respiration, the latter via the catalytic activity of TbMic20. Thus, trypanosome MICOS allows us to define which of its features are conserved in all eukaryotes and decipher those that represent lineage-specific adaptations.
