During hypoxia, tissues are subjected to an inadequate oxygen supply, disrupting the balance needed to maintain normal function. This deficiency can occur due to reduced oxygen delivery caused by impaired blood flow or a decline in the blood's ability to carry oxygen. In tumors, hypoxia and vascularization play crucial roles, shaping their microenvironments and influencing cancer progression, response to treatment and metastatic potential. This chapter provides guidance on the use of non-invasive imaging methods including Positron Emission Tomography and Magnetic Resonance Imaging to study tumor oxygenation in pre-clinical settings. These imaging techniques offer valuable insights into tumor vascularity and oxygen levels, aiding in understanding tumor behavior and treatment effects. For example, PET imaging uses tracers such as [18F]-fluoromisonidazole (FMISO) to visualize hypoxic areas within tumors, while MRI complements this with anatomical and functional images. Although directly assessing tumor hypoxia with MRI remains challenging, techniques like Blood Oxygen Level Dependent (BOLD) and Dynamic Contrast-Enhanced MRI (DCE-MRI) provide valuable information. BOLD can track changes in oxygen levels during oxygen challenges, while DCE-MRI offers real-time access to perfusion and vessel permeability data. Integrating data from these imaging modalities can help assess oxygen supply, refine treatment strategies, enhance therapeutic effectiveness, and ultimately improve patient outcomes.
- Klíčová slova
- BOLD, DCE-MRI, FMISO, Hypoxia, Magnetic resonance imaging, Positron emission tomography, Preclinical, Tumor oxygenation, Vascularity,
- MeSH
- hypoxie diagnostické zobrazování MeSH
- kyslík metabolismus MeSH
- lidé MeSH
- magnetická rezonanční tomografie * metody MeSH
- misonidazol analogy a deriváty MeSH
- myši MeSH
- nádorová hypoxie MeSH
- nádory diagnostické zobrazování krevní zásobení patologie MeSH
- patologická angiogeneze diagnostické zobrazování patologie MeSH
- pozitronová emisní tomografie * metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fluoromisonidazole MeSH Prohlížeč
- kyslík MeSH
- misonidazol MeSH
A copper(II) tetrapyrazole-based complex of the composition of [Cu(tpyr)(H2O)(ONO2)]NO3 (1), where tpyr represents a tetradentate N-donor ligand formed by the condensation of 1H-pyrazole-5-carbaldehyde in NaOH/MeOH medium, has been prepared and characterized by elemental analysis, infrared spectroscopy, ultraviolet-visible spectroscopy, mass spectrometry, electron paramagnetic resonance and single-crystal X-ray diffraction. Spectrophotometric measurements demonstrated a remarkable peroxidase activity of the complex, which utilized hydrogen peroxide for the oxidation of phenolic compounds such as guaiacol or 3,5-dichloro-2-hydroxybenzene sulfonic acid. The optimum conditions for this reaction were found at pH 8 in ammonium bicarbonate buffer, although the activity was low but still detectable at pH 5-6 in ammonium acetate. As a peroxidase mimic, the complex exhibited enzyme-like Michaelis-Menten kinetics, showing a hyperbolic dependence of the reaction rate on hydrogen peroxide concentration. The determined Km and kcat values were 651 μmol·l-1 and 6.7 × 10-4 s-1, respectively, compared to 41 μmol·l-1 and 73 s-1 for horseradish peroxidase. EPR spectroscopy of the reaction mixture revealed no change in the copper (II) oxidation state during catalysis, suggesting that the oxidation of guaiacol may occur simultaneously with the reduction of hydrogen peroxide to water at the copper centre.
- Klíčová slova
- Copper(II), Crystal structure, MALDI-TOF, Peroxidase activity, Tetrapyrazole, XPS,
- MeSH
- biomimetické materiály * chemie MeSH
- kinetika MeSH
- komplexní sloučeniny * chemie chemická syntéza MeSH
- krystalografie rentgenová MeSH
- měď * chemie MeSH
- oxidace-redukce MeSH
- peroxid vodíku chemie MeSH
- peroxidasa * chemie MeSH
- pyrazoly * chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- komplexní sloučeniny * MeSH
- měď * MeSH
- peroxid vodíku MeSH
- peroxidasa * MeSH
- pyrazoly * MeSH
The polymerase acidic (PA) subunit of the influenza virus, an endonuclease of the RNA-dependent RNA polymerase, represents a viable target for anti-influenza therapies, as evidenced by the efficacy of the FDA-approved drug Xofluza. A characteristic feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions within the enzyme's catalytic site. Previously, our studies identified luteolin and its C-8-glucoside orientin as potent endonuclease inhibitors. This report details our subsequent investigation into the structural modifications of the phenyl moiety attached to the C-8 position of luteolin. The inhibitory potencies (IC50 values) quantified with AlphaScreen technology indicated that substituting the C-8 glucose moiety of orientin resulted in compounds with comparable inhibitory potency. From a series of eighteen compounds, acid 12 with 3-carboxylphenyl moiety at the C-8 position was the most potent inhibitor with nanomolar potency.
- Klíčová slova
- Endonuclease, Flavonoid, Influenza, Inhibitors, RNA polymerase,
- MeSH
- antivirové látky * farmakologie chemická syntéza chemie MeSH
- endonukleasy * antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů * farmakologie chemická syntéza chemie MeSH
- luteolin * farmakologie chemická syntéza chemie MeSH
- molekulární struktura MeSH
- racionální návrh léčiv * MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antivirové látky * MeSH
- endonukleasy * MeSH
- inhibitory enzymů * MeSH
- luteolin * MeSH
Vitamin B12, cobalamin, is indispensable for humans owing to its participation in two biochemical reactions: the conversion of l-methylmalonyl coenzyme A to succinyl coenzyme A, and the formation of methionine by methylation of homocysteine. Eukaryotes, encompassing plants, fungi, animals and humans, do not synthesise vitamin B12, in contrast to prokaryotes. Humans must consume it in their diet. The most important sources include meat, milk and dairy products, fish, shellfish and eggs. Due to this, vegetarians are at risk to develop a vitamin B12 deficiency and it is recommended that they consume fortified food. Vitamin B12 behaves differently to most vitamins of the B complex in several aspects, e.g. it is more stable, has a very specific mechanism of absorption and is stored in large amounts in the organism. This review summarises all its biological aspects (including its structure and natural sources as well as its stability in food, pharmacokinetics and physiological function) as well as causes, symptoms, diagnosis (with a summary of analytical methods for its measurement), prevention and treatment of its deficiency, and its pharmacological use and potential toxicity.
- Klíčová slova
- cobalamin, cobalt, megaloblastic anaemia, neuropathy, physiological function,
- MeSH
- dieta vegetariánská MeSH
- dieta MeSH
- fortifikované potraviny MeSH
- lidé MeSH
- nedostatek vitaminu B12 * diagnóza prevence a kontrola farmakoterapie etiologie MeSH
- vitamin B 12 * farmakokinetika chemie metabolismus terapeutické užití fyziologie škodlivé účinky aplikace a dávkování farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- vitamin B 12 * MeSH
BACKGROUND: Creatinine levels in different body fluids can serve as an important biomarker for kidney functioning relevant to prostate cancer and chronic kidney disease (CKD). Creatinine levels vary in concentration in different body fluids, such as blood, urine, and saliva. Unlike previously reported sensors, the developed creatinine sensor can be employed for all levels of creatinine in samples of real patients. RESULTS: In this study, an efficient voltammetric sensor for creatinine is developed by modifying a glassy carbon electrode (GCE) with poly (ethyleneimine) (PEI) capped silver nanoparticles at titanium dioxide (PEI-AgNPs)/TiO2, i.e., titanium dioxide (TiO2)/graphene oxide (GO) nanocomposites (Ag@GO/TiO2-GCE). The Ag@GO/TiO2 nanocomposite was characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), thermal gravimetric analysis (TGA), X-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential, Fourier transform infrared (FT-IR) spectroscopy, and UV-Vis spectrophotometry. Various voltammetric techniques namely cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), chronoamperometry (CA), and differential pulse voltammetry (DPV) were employed. The Ag@GO/TiO2-GCE demonstrated good selectivity, stability, and a quick response time of 1.0 s for creatinine. An extended linear dynamic range (LDR) of creatinine from 0.01 pM (DPV) to 1.0 M (CV) based on different voltammetric techniques is imperative for detecting diverse creatinine levels in various body fluids. The LOD and LOQ of the developed creatinine detection method were found to be 1.15 pM and 3.5 pM, respectively. The electrochemical sensor exhibited an exceptionally high sensitivity of 15.74 μApM-1cm-2.The body fluids from healthy volunteers were spiked with a known amount of creatinine to evaluate sensor efficiency in the context of recovery. Finally, blood serum, saliva, and urine samples of kidney patients were analyzed for creatinine levels. SIGNIFICANCE: An important merit of the developed creatinine sensor is its ability for non-invasive point-of-care diagnosis in saliva with more than 90 % recovery. The comparison of the developed method with the standard Jaffes' colorimetric method endorsed its reliability and extended ability for the samples where Jaffes' method fails. The low LOD, high sensitivity, extended LDR, and low-cost render the possibility of adopting this method for point-of-care diagnosis.
- Klíčová slova
- Biomarker, Chronic kidney disease: non-invasive diagnostics, Nanocomposite, Point-of-care diagnosis, Voltammetry,
- MeSH
- elektrochemické techniky * metody MeSH
- elektrody MeSH
- grafit chemie MeSH
- kovové nanočástice chemie MeSH
- kreatinin * analýza moč krev MeSH
- lidé MeSH
- limita detekce MeSH
- nanokompozity chemie MeSH
- polyethylenimin chemie MeSH
- stříbro chemie MeSH
- tělesné tekutiny * chemie MeSH
- titan chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- grafit MeSH
- graphene oxide MeSH Prohlížeč
- kreatinin * MeSH
- polyethylenimin MeSH
- stříbro MeSH
- titan MeSH
- titanium dioxide MeSH Prohlížeč
Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.
- Klíčová slova
- Chronic diseases, Flavonoids, Inflammation, Oxidative stress, Therapy,
- MeSH
- flavonoidy * farmakologie chemie terapeutické užití metabolismus MeSH
- lidé MeSH
- nádory farmakoterapie metabolismus patologie MeSH
- neurodegenerativní nemoci farmakoterapie metabolismus MeSH
- oxidační stres * účinky léků MeSH
- zánět * farmakoterapie metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- flavonoidy * MeSH
The design of MB327, a bispyridinium compound that ameliorates the nicotinic effects of acute organophosphorus nerve agent (NA) intoxication, followed an observation made by the German pharmacologist Klaus Schoene in the 1970s, who noted therapeutic activity in bispyridinium molecules missing the usual oxime group, CHNOH. Some of these compounds protected mice against soman. One structurally related to obidoxime called HY10 had this action. Its oxime moieties were capped by tert-butyl groups: CH=NOtBu. We modified HY10 by changing the bridge between the pyridinium units from a dimethylene ether to a trimethylene group (CH2OCH2 → CH2CH2CH2) and prepared a novel relative of trimedoxime, called LB1, whose synthesis and stereochemistry are described. Unlike obidoxime or trimedoxime, LB1 because of its capped oxime groups, cannot directly reactivate NA inhibited acetylcholinesterase. Its antidotal activity in mice is now reported. The therapeutic efficacy of LB1, atropine alone, atropine with LB1, atropine with an oxime (HI-6, obidoxime or trimedoxime), and atropine with an oxime and LB1, was studied by determining the LD50 values of the NAs soman, sarin, or tabun in mice treated with these compounds or mixtures. LB1 exceeded MB327 in toxicity and its activity was insufficient for a useful addition to the current standard antidotal treatment (protective ratio data are compared to those of MB327). Although this study produced largely negative biological results, the therapeutically beneficial mechanism of the effective bispyridinium non-oxime analogues is unclear, and has been demonstrated only in vivo. The present study points out directions in structural optimisation unlikely to yield the desired therapeutic outcomes and provides a literature review that could promote creative thinking for the design of widely-desirable non-oxime therapeutics for anticholinesterase inhibitors.
- Klíčová slova
- Bispyridinium, LB1, Mechanism, Mice, Nerve agent, Pyridinecarboxaldoxime,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota * chemická syntéza chemie farmakologie terapeutické užití MeSH
- atropin terapeutické užití farmakologie MeSH
- cholinesterasové inhibitory toxicita MeSH
- myši MeSH
- nervová bojová látka * toxicita MeSH
- organofosforové sloučeniny * toxicita MeSH
- oximy chemie MeSH
- pyridinové sloučeniny * chemická syntéza chemie terapeutické užití farmakologie MeSH
- soman toxicita MeSH
- trimedoxim chemie chemická syntéza farmakologie terapeutické užití MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- antidota * MeSH
- atropin MeSH
- cholinesterasové inhibitory MeSH
- MB327 MeSH Prohlížeč
- nervová bojová látka * MeSH
- organofosforové sloučeniny * MeSH
- oximy MeSH
- pyridinové sloučeniny * MeSH
- soman MeSH
- trimedoxim MeSH
The structure, function, and molecular mechanisms of lichen survival in harsh habitats like Antarctica and Alpine localities, where environmental extremes change frequently, are highly interesting yet largely underexplored. We used high resolution microscopy, Raman spectroscopy, and chlorophyll a fluorescence to investigate the basic structure and function, i.e., intrathalline distribution and allocation of photobionts, as well as the heat dissipation process in three Antarctic lichens: Dermatocarpon polyphyllizum (DP), Umbilicaria antarctica (UA), and Leptogium puberulum (LP). Microscopic images of their transverse slices revealed visual insights into the heterogeneous distribution of photobionts within their structurally distinct thalli. Raman spectra showed shifts in the carotenoid Raman ν1(CC) band between lichens with algal (DP and UA) and cyanobacterial (LP) photobionts, and interestingly, they revealed biosynthesis of scytonemin, a UV-screening pigment, in cyanolichen LP. We found that increasing actinic irradiance has a nearly equal effect on the shape of chlorophyll fluorescence transients also during dark relaxation in lichens with algal photobionts, but it differed greatly for cyanolichen LP. The dark relaxation kinetics of non-photochemical quenching (NPQ) in experimental lichens differed significantly between lichens with algal photobionts DP and UA; however, this parameter could not be calculated in cyanolichen LP. The components of NPQ revealed that rapidly relaxing energy dependent quenching, ΦqE, is active and protects the thallus of DP predominantly; however, in UA state transition quenching, ΦqT, predominates. The diversity in NPQ across the three examined lichens revealed intriguing aspects of heat dissipation in their photobionts as a mechanism for survival under Antarctica conditions.
- Klíčová slova
- Carotenoids, Chlorophyll a fluorescence transient, High resolution microscopy, Optical signal, Raman spectra, Scytonemin,
- MeSH
- chlorofyl a * metabolismus MeSH
- chlorofyl * metabolismus analýza MeSH
- lišejníky * metabolismus chemie fyziologie MeSH
- Ramanova spektroskopie * MeSH
- sinice metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Antarktida MeSH
- Názvy látek
- chlorofyl a * MeSH
- chlorofyl * MeSH
Human activities and climate change have significantly increased humic substances in freshwater ecosystems over the last few decades. This increase is particularly concerning during seasonal changes or after heavy rainfall, when concentrations can easily increase up to tenfold. This phenomenon, known as "browning," has unknown consequences for aquatic organisms. This study is the first to determine the effects of increasing humic substance concentrations on the transcriptomic and structural responses in the gills of rainbow trout (Oncorhynchus mykiss). Overall, 27 genes mainly involved in xenobiotic metabolism (cyp1a3, cyp1b1, pik3r6), immune response (rgs2, dll1, ccl19, acod1), and mucosal glycoprotein expression (muc2, prg4) were upregulated. No significant alterations were noted in gill morphology, although the molecular data strongly indicated a proinflammatory response. Our results highlight the risks posed by increasing humic substance concentrations for fish and aquatic ecosystems and emphasize the urgent need to implement effective monitoring and resource management strategies to address browning waters.
- Klíčová slova
- Climate change, Increasing dissolved organic carbon, Inflammation, Rainbow trout, Transcriptome analysis,
- MeSH
- benzopyrany * toxicita MeSH
- chemické látky znečišťující vodu * toxicita MeSH
- huminové látky MeSH
- Oncorhynchus mykiss * genetika metabolismus MeSH
- rybí proteiny genetika metabolismus MeSH
- sladká voda MeSH
- transkriptom * účinky léků MeSH
- žábry * účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzopyrany * MeSH
- chemické látky znečišťující vodu * MeSH
- fulvic acid MeSH Prohlížeč
- huminové látky MeSH
- rybí proteiny MeSH
INTRODUCTION: This study explored patient and clinician perspectives on a new fixed-dose combination of macitentan and tadalafil (M/T FDC) in a once-daily single tablet for treatment of pulmonary arterial hypertension (PAH). METHODS: Qualitative semi-structured interviews were conducted during the open-label period of the global, phase 3 A DUE clinical trial that evaluated M/T FDC. A subset of enrolled patients (N = 26) and site investigators (N = 18 clinicians) were interviewed. Patients received four tablets during double-blind treatment and could be in one of three arms (macitentan + placebo; tadalafil + placebo; M/T FDC + placebo) followed by M/T FDC (one tablet) during the open-label period. Patients and clinicians were asked to share their experience of pre-trial PAH medication, double-blind treatment, and open-label M/T FDC. Thematic analysis was conducted on blinded data. RESULTS: Patients preferred the M/T FDC tablet (open-label) over the four tablets during double-blind treatment. Patients were satisfied with M/T FDC, highlighting its positive impact on their psychological well-being, through reducing stress associated with managing multiple pills. All patients indicated that having a single, once-a-day pill for PAH was more convenient and associated with greater treatment adherence. Clinicians highlighted that their patients have a high daily pill burden for PAH and other comorbidities, and prefer treatments with an oral mode of administration that reduce the number of daily pills required. Clinicians felt that M/T FDC would be well received in clinical practice and potentially assist in implementing guideline-recommended combination treatment of PAH. CONCLUSIONS: In this qualitative analysis, all 26 patients and 18 clinicians provided positive feedback on M/T FDC treatment, which was consistent across countries. Reducing the number of pills needed to treat PAH, through use of single-tablet M/T FDC, is highly valued by patients and endorsed by clinicians, who both felt the single-tablet combination therapy could have a positive effect on patients' well-being and increase treatment adherence.
- Klíčová slova
- Clinician interview, Fixed-dose combination, Patient interview, Patient perspective, Polypharmacy, Pulmonary arterial hypertension, Treatment adherence,
- MeSH
- adaptivní klinické zkoušky jako téma MeSH
- antihypertenziva * aplikace a dávkování terapeutické užití MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- fixní kombinace léků MeSH
- inhibitory fosfodiesterasy 5 aplikace a dávkování terapeutické užití MeSH
- klinické zkoušky, fáze III jako téma MeSH
- kvalitativní výzkum MeSH
- lidé středního věku MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- plicní arteriální hypertenze * farmakoterapie MeSH
- plicní hypertenze * farmakoterapie MeSH
- pyrimidiny * aplikace a dávkování terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- rozhovory jako téma MeSH
- senioři MeSH
- spokojenost pacientů MeSH
- sulfonamidy * aplikace a dávkování terapeutické užití MeSH
- tablety MeSH
- tadalafil * aplikace a dávkování terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antihypertenziva * MeSH
- fixní kombinace léků MeSH
- inhibitory fosfodiesterasy 5 MeSH
- macitentan MeSH Prohlížeč
- pyrimidiny * MeSH
- sulfonamidy * MeSH
- tablety MeSH
- tadalafil * MeSH
