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Novel Pyridine-Based Thiazolyl-Hydrazone as a Promising Attenuator of Pseudomonas aeruginosa Pathogenicity by Targeting Quorum Sensing
No full textPseudomonas aeruginosa biofilm-associated infections present higher recalcitrance to antimicrobial treatments, contributing to persistent and difficult-to-treat infections. Quorum sensing (QS) regulates various cellular processes that are important for the establishment and survival of microbial communities on the host. However, QS inhibitors for the treatment of P. aeruginosa biofilms remain under-researched, partly due to the complexity of QS signalling pathways and the challenge of developing non-toxic inhibitors. Herein, the bioactivity of 2-{(2E)-2-[1-(pyridin-2-yl)ethylidene]hydrazinyl}-1,3-thiazole-4-carboxylic acid (TTNF37), a novel pyridine-based thiazolyl-hydrazone (PTH), was investigated. The compound antimicrobial activity was evaluated against a broad spectrum of microorganisms, its antioxidant potential was assessed using different assays, and its QS-inhibitory effect on P. aeruginosa was studied using bioreporter strains. The effect on P. aeruginosa biofilm formation was analysed in terms of biomass, culturability, and metabolic activity, structure, and cell membrane integrity, while virulence factors were evaluated through absorbance measurements. In addition, molecular docking studies were performed to predict the drug’s interactions with essential QS proteins and biological targets. TTNF37 exhibited potent antimicrobial activity with low to moderate minimum inhibitory concentrations against clinically relevant Gram-negative and Gram-positive bacteria, as well as fungi and yeasts. It also showed antioxidant activity, with variable effectiveness across different radicals and systems. TTNF37 inhibited the 3-oxo-C12-HSL-dependent QS system of P. aeruginosa in a dose-dependent manner, with reductions ranging from 26% to 98%. It also impaired the production and detection of 3-oxo-C12-HSL, resulting in a 56% and 65% decrease in bioluminescence, respectively. Molecular docking studies revealed strong binding interactions with LasI and LasR proteins, with affinity values exceeding those of furvina, a known potent QS inhibitor. Molecular dynamics simulations validated stable TTNF37 binding to LasR and LasI. Both experimental and docking data indicate a significant interaction with human serum albumin (HSA). TTNF37 also significantly reduced pyocyanin production and prevented biofilm set-up with a reduction of 50% in biomass with pronounced alterations in biofilm structure. These results indicate the potential of TTNF37 and related PTHs for treating biofilm-associated infections
Blood N1-methyladenosine (m1A) RNA modification and outcome after cardiac arrest
No full textAbstract:
Background: Cardiac arrest (CA) is a leading cause of mortality and
neurological disability. Prediction of post-CA outcomes is challenging.
Epitranscriptomic (RNA) modifications are emerging as potential biomarkers
due to their regulatory roles in RNA metabolism and disease progression.
However, their relevance in CA remains unexplored.
Objective: This study aimed to investigate the association between N1-
methyladenosine (m¹A) RNA modification and outcome after CA.
Methods: Total RNA was extracted from whole blood samples of 211
patients collected 48h after return of spontaneous circulation (ROSC). M¹A
and adenosine (A) blood levels were quantified using liquid chromatography
coupled to mass spectrometry (LC-MS), and the ratio m¹A/A was calculated.
Neurological outcome assessed using the cerebral performance category
(CPC) score and survival at 6 months were used as end-points.
Results: Patients with moderate to severe neurological outcome or death
within 6 months after CA (CPC 2–5) exhibited elevated m¹A/A ratio
compared to survivors without neurological sequelae (CPC 1) (p = 0.03). In
multivariable logistic regression, higher m1A/A levels were associated with
an increased risk of moderate to severe neurological outcome or death at 6
months compared to survivors without neurological sequelae (odds ratio
[95% confidence interval] 1.50 [1.04-2.19]), after adjustment for age, time
between CA and return of spontaneous circulation, lactate and neuron-
specific enolase levels. In Kaplan-Meier survival analysis, patients with
elevated m¹A/A levels showed a lower probability of survival at 6 months
(p=0.003).
Conclusion: This study provides the first evidence that m1A RNA
methylation, reflected by the m1A/A ratio, is associated with neurological
outcome and death at 6 months after CA. Although these findings require
validation, they raise the possibility that m¹A RNA methylation could help to
improve prognostication after CA
Editorial: Pharmacological and nutritional approaches to metabolic associated fatty liver disease: a step towards achieving SDG 3
No full textMetabolic-Associated Fatty Liver Disease (MAFLD) has rapidly become a leading global
health challenge of the 21st century, currently affecting around a quarter of the adult population
worldwide (Younossi et al., 2025). As a systemic metabolic disorder, MAFLD is strongly
associated with obesity and type 2 diabetes mellitus (T2DM), as well as an increased risk of
cardiovascular mortality (Zhou et al., 2023). Addressing the MAFLD epidemic is not only a
clinical necessity, but also a critical step towards achieving United Nations Sustainable
Development Goal 3 (SDG 3), which aims to ensure healthy lives and promote wellbeing
at all ages (United Nations, 2015). In this context, the present Research Topic, titled
“Pharmacological and Nutritional Approaches to Metabolic-Associated Fatty Liver Disease”,
brings together five studies that collectively highlight emerging therapeutic perspectives
Novel N-doped carbon/Co/Co3O4 ternary composites derived by direct carbonization of ZIF-67: Efficient electrocatalysts for oxygen reduction reaction
No full textCobalt-containing zeolitic imidazole framework ZIF-67 was synthesized in high yield, and directly carbonized by different heating routes at 800 and 900 °C. The products of carbonization, C(ZIF-67)s, were comprehensively characterized in terms of elemental composition (FAAS, EDX, XPS), crystalline (XRD) and molecular structure (FTIR and Raman spectroscopies), morphology (SEM), electrical conductivity, textural (N2 physisorption), and electrochemical properties. It was found that C(ZIF-67)s represent novel meso/microporous ternary composites of the type N-doped carbon/Co/Co3O4, containing metallic Co nanoparticles (NPs) with cubic body-centred crystalline structure, and predominately amorphous Co3O4. They exhibited high electrical conductivity (up to 4.2 S cm−1), notable BET specific surface area (197–265 cm2 g−1), and almost doubled mesopore volume compared to the parent ZIF-67. The effects of carbonization conditions on the structure, physico-chemical properties, and performance of C(ZIF-67)s as electrode materials in electrocatalysis of oxygen reduction reaction (ORR) and charge storage were studied. All C(ZIF-67) composites showed excellent ORR electrocatalytic activity in 0.1 M KOH, with four-electron reduction pathway. The highest ORR activity (the onset potential of −0.13 V vs. SCE) showed the composite produced by gradual heating up to 800 °C followed by holding at that temperature for 3 h. This is attributed to its highest mesopore volume, appropriate meso/micropore structure, high surface content of heteroatom-containing active sites (C–O–C, Co–N, Co–O), high surface Co2+/Co3+ ratio and the presence of Co NPs. The applied direct carbonization of ZIF-67, without additives and post-synthetic modifications, was shown as a simple way to produce meso/microporous electroconducting composites with high potential in energy related applications
Highly Efficient Electrochemical Degradation of Dyes via Oxygen Reduction Reaction Intermediates on N-Doped Carbon-Based Composites Derived from ZIF-67
No full textA cobalt-containing zeolitic imidazolate framework (ZIF-67) was carbonized by different routes to composite materials (cZIFs) composed of metallic Co, Co3O4, and N-doped carbonaceous phase. The effect of the carbonization procedure on the water pollutant removal properties of cZIFs was studied. Higher temperature and prolonged thermal treatment resulted in more uniform particle size distribution (as determined by nanoparticle tracking analysis, NTA) and surface charge lowering (as determined by zeta potential measurements). Surface-governed environmental applications of prepared cZIFs were tested using physical (adsorption) and electrochemical methods for dye degradation. Targeted dyes were methylene blue (MB) and methyl orange (MO), chosen as model compounds to establish the specificity of selected remediation procedures. Electrodegradation was initiated via an intermediate reactive oxygen species formed during oxygen reduction reaction (ORR) on cZIFs serving as electrocatalysts. The adsorption test showed relatively uniform adsorption sites at the surface of cZIFs, reaching a removal of over 70 mg/g for both dyes while governed by pseudo-first-order kinetics favored by higher mesoporosity. In the electro-assisted degradation process, cZIF samples demonstrated impressive efficiency, achieving almost complete degradation of MB and MO within 4.5 h. Detailed analysis of energy consumption in the degradation process enabled the calculation of the current conversion efficiency index and the amount of charge associated with O2•−/•OH generation, normalized by the quantity of removed dye, for tested materials. Here, the proposed method will assist similar research studies on the removal of organic water pollutants to discriminate among electrode materials and procedures based on energy efficiency
Pinpointing triple point of noncommutative matrix model with curvature
No full textWe study a Hermitian matrix model with a quartic potential, modified by a curvature term
tr(RΦ2), where R is a fixed external matrix. Inspired by the truncated Heisenberg algebra formu-
lation of the Grosse–Wulkenhaar model, this term breaks unitary invariance and, through per-
turbative expansion, induces an effective multitrace matrix model. We analyze the resulting action
both analytically and numerically, including Hamiltonian Monte Carlo simulations, focusing on
two features closely tied to renormalizability: the shift of the triple point and the suppression of the
noncommutative striped phase. Our findings show that the curvature term drives the phase struc-
ture toward renormalizable behavior by removing the striped phase in the large-N limit, while also
unexpectedly revealing a possible novel multi-cut phase observed at the level of finite matrix size
Population Pharmacokinetics Model of Cyclosporin A in Children and Young Adult Renal Transplant Patients: Focus on Haemoglobin Contribution to Exposure Variability
No full textBackground/Objectives: Cyclosporine A (CsA) is a key immunosuppressant in post-
transplantation therapy protocol characterized by large interindividual and intraindividual
pharmacokinetic (PK) variability and a narrow therapeutic range necessitating therapeu-
tic drug monitoring (TDM) to prevent graft rejection and minimize side effects. TDM
data can be used for developing PK models with the objective of identification and quan-
tification of variability factors that contribute to the differences in CsA concentrations.
Methods: Retrospectively collected data from medical records of 58 patients (children and
young adults) regarding CsA blood concentrations, concomitant medications, and labo-
ratory findings of significance were used for the population PK model development in
NONMEM® (version 7.5) with first-order conditional estimation method with interaction
(FOCE-I). Simulation of the concentrations and area under the curve (AUC) was performed
in the web application e-campsis®. RStudio (version 4.5.0) was used for the purpose of
descriptive statistics analysis and graphs plotting. Results: A one-compartment model
with first-order absorption and elimination best described the data. Value of clearance
(CL/F) was estimated to be 15 L/h, and volume of distribution (V/F) was 71.1 L for a
typical patient weighing 40 kg. Interindividual variability (IIV) on CL/F and V/F was
34.91% and 43.05%, respectively. Interoccasional variability (IOV) was 12.25%. Body weight
(WT) was introduced allometrically on CL/F and V/F, with the estimated exponent of
0.89 for CL/F and 1 (fixed) for V/F. According to the final model, CL/F decreases with
increasing haemoglobin (HGB) value. A difference of almost 22.5% in CL/F was observed
among patients’ HGB values reported in the study. Conclusions: Our findings indicate that
HGB levels significantly influence CsA PK, particularly minimum concentration (Cmin),
highlighting the importance of regular HGB levels monitoring together with CsA levels
Knowledge and Attitudes Regarding Pharmacogenetics of Pharmacists in the Netherlands: A National Online Survey Study
No full textRationale, Aims and Objectives: Pharmacogenetics is considered a promising method to improve pharmacotherapy, yet its implementation in clinical practice is hampered, limiting its potential benefits to the public. Previously, its uptake has been investigated within a variety of healthcare professional groups. Commonly cited barriers by prescribing physicians are lack of knowledge and insurance coverage. An important occupational group who may support physicians due to their expert knowledge are pharmacists. However, they have been understudied in research on pharmacogenetics implementation thus far. Therefore, we investigated the experience and attitudes of pharmacists regarding pharmacogenetics using an online questionnaire. Method: Using Qualtrics software, an online survey was distributed nationally from April 1st to December 1st 2024. Respondents were recruited during a national conference organized by the Dutch pharmacy residents, through email-invites, and via newsletters of national pharmacist-associations. Results: In total, data of n = 281 respondents were analyzed in the study, the majority of which were working professionals (±15.8 years of experience). Although only 44.4% had ever requested a pharmacogenetic test, 88.6% of respondents had experience with test result interpretation. Cost, lack of reimbursement through insurance, and lack of availability of pharmacogenetic guidelines including clinical evidence, were found as key barriers. Importantly, respondents generally felt confident regarding their own pharmacogenetics-related knowledge and skills, while maintaining caution in situations where pharmacogenetic evidence is limited. Conclusion: Successful adoption of pharmacogenetics in practice may benefit from interprofessional collaboration, expanding the pharmacogenetics evidence base, and prioritizing pharmacogenetics in updated health policy
Growing Nutrition on Waste: Exploring Pleurotus columbinus as a Sustainable Functional Food
No full textThe present study investigated the cultivation of Pleurotus columbinus on alternative substrates derived from spent mushroom substrate combined with spent coffee grounds or wheat straw, with or without supplementation with wheat bran and soybean flour, in comparison to conventional wheat straw. All substrates were evaluated for their effects on the nutritional composition, amino acid profile, lipid, carbohydrate contents and bioactive compounds of the harvested carposomes. Protein content ranged from 15.6 to 21.4% w/w. Methionine was identified as the first limiting amino acid and the essential amino acid index was up to 60.9%. Carbohydrate content exceeded 63.3% w/w in all samples, with glucose identified as the major monosaccharide. Lipid content was low (1.7–3.4% w/w), with polyunsaturated fatty acids predominating. Ash content ranged from 5.7 to 6.3% w/w and the energy value varied between 36.2 and 37.1 kcal/100 g f.w. Bioactive compounds, including β-glucans (35.9–44.4% w/w) and ergosterol (3.3–4.7 mg/g d.w.), along with their metabolites, were successfully quantified. Non-supplemented substrates enhanced β-glucan levels; most of them were further isolated, whereas lovastatin was not detected in any sample. Overall, P. columbinus cultivated on alternative substrates exhibited improved nutritional quality and higher bioactive compound content compared to conventional cultivation, demonstrating the potential of agro-industrial by-products as sustainable substrates for high-value mushroom production
Cytopenias as Adverse Drug Reactions: A 10-Year Analysis of Reporting Structure, Rate, and Trend
No full textBackground/Objectives: Underreporting is very common in drug-induced cytopenias
(DICs) due to the late onset of symptoms and the need for laboratory confirmation and
monitoring. This research aimed to analyze spontaneously reported adverse drug reaction
(ADR) cases of leucopenia, anemia, thrombocytopenia, and total cytopenia, including their
reporting structure, rate, and trend, globally (World) and in Serbia. Methods: Based on
real-world data from VigiBase, analyses of the DIC reporting structure, rate, and trend
over 10 years (2014–2023) were performed. The reporting rate was calculated and ex-
pressed as the number of reports per 1,000,000 inhabitants per year (ADR/million/year).
Statistics included descriptions, a chi-square test, joinpoint analysis, and measures
of variability. Results: Leucopenia was reported more often in Serbia compared to
World (1.26 versus 0.96 reports/million/year, respectively), anemia more often in World
(2.09 versus 1.75 reports/million/year), while thrombocytopenia reporting was comparable
(1.83 reports/million/year globally versus 1.82 reports/million/year in Serbia). In Serbia,
there was a constant increase in reporting throughout the observed period, regardless of the
cytopenia type, while globally, anemia reports decreased over time. Most of the reported
DICs were serious and occurred in females aged 45–64 years. In Serbia, 76.34% of DICs
were reported by physicians compared to 31.72% globally. Conclusions: Although upward
trends in DIC reporting are observed, variability in reporting between years was greater
in Serbia than in World. Many measures are needed to promote the early detection of
DICs, with the priority of increasing access to blood count results for all healthcare workers,
including pharmacists