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Exploring pulmoprotection in COVID-19: Moving toward microRNA-based theranostics
Get PDFThe relentless struggle with the aftermath of COVID-19 has driven the medical community to seek innovative methods for predicting and managing the disease’s complications. Complications such as an overactive immune response, manifesting as cytokine storms, and shifts toward a procoagulant state not only exacerbate symptoms but also elevate the risk of mortality and long-term health issues. Consequently, there is a pressing need for novel diagnostic tools and therapeutic strategies that not only track disease progression and complications but also serve as potential drug targets or can be influenced by pharmacological interventions. In the presented study by Perez-Pons et al.1 titled “MicroRNA-centered theranostics for pulmoprotection in critical COVID-19,” the authors shed light on the promising role of microRNAs (miRNAs) as dual-purpose theranostic agents. By focusing on a multicenter cohort of intensive care unit (ICU) survivors, the research elucidates the potential of miRNAs in mitigating diffusion impairment—a common but debilitating consequence of severe infection. This commentary aims to contextualize these findings within the broader spectrum of molecular and cellular therapies, underlining their significance and implications they pose for the field.
Since the outbreak of the COVID-19 pandemic, a significant number of survivors, particularly those who experienced severe illness, have continued to face post-acute pulmonary sequelae. COVID-19 survivors often experience a spectrum of long-term lung issues, with dyspnea being a common symptom reported by 42%–66% of individuals within 60–100 days post-infection.2 Individuals who experienced severe forms of COVID-19, particularly those in need of intensive respiratory support, are more likely to suffer from long-lasting lung issues.2 This includes diffusion impairment, which refers to a decreased ability of the lungs to transfer oxygen from the air into the bloodstream, as well as observable lung damage like pulmonary fibrosis on medical imaging.2 The persistence of these health issues among survivors indicates a substantial impact on their quality of life and the healthcare system, stressing the urgency in identifying effective interventions and support mechanisms for those affected
Supplementary material for: Prekrat, D., Todorović-Vasović, K. N., Vasović, N.,& Kostić, S.. (2024). Complex global dynamics of conditionally stable slopes: effect of initial conditions. in Frontiers in Earth Science Frontiers Media., 12 - 2024 https://doi.org/10.3389/feart.2024.1374942
Get PDFIn the present paper, we investigate the effect of the initial conditions on the dynamics of the spring-block landslide model. The time evolution of the studied model, which is governed by a system of stochastic delay differential equations, is analyzed in the mean-field approximation, which qualitatively exhibits the same dynamics as the initial model. The results of the numerical analysis show that changing the initial conditions has different effects in different parts of the parameter space of the model. Namely, moving away from the fixed-point initial conditions has a stabilizing effect on the dynamics when the noise, the friction parameters a (higher values) and c as well as the spring stiffness k are taken into account. The stabilization manifests itself in a complete suppression of the unstable dynamics or a partial limitation of the effect of some friction parameters. On the other hand, the destabilizing effect of changing the initial conditions occurs for the lower values of the friction parameters a and for b. The main feature of destabilization is the complete suppression of the sliding regime or a larger parameter range with a transient oscillatory regime. Our approach underlines the importance of analyzing the influence of initial conditions on landslide dynamics.Supplementary material for: [https://doi.org/10.3389/feart.2024.1374942]Related to published version: [https://farfar.pharmacy.bg.ac.rs/handle/123456789/5561
Understanding hemoglobin contribution to high-dose methotrexate disposition—population pharmacokinetics in pediatric patients with hematological malignancies
No full textPurpose: The aim of the present study was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) and to describe the influence of variability factors. Methods: The study included 50 patients of both sexes (aged 1–18 years) who received 3 or 5 g/m2 of HDMTX. A nonlinear mixed effect modeling approach was applied for data analysis. Parameter estimation was performed by first-order conditional estimation method with interaction (FOCEI), whereas stepwise covariate modeling was used to assess variability factors. Results: The final model is a two-compartment model that incorporates the effect of body surface area and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical subject were estimated at 5.75 L/h/m2 for clearance (CL), 21.3 L/m2 for volume of the central compartment (V1), 8.2 L/m2 for volume of the peripheral compartment (V2), and 0.087 L/h/m2 for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 32% in MTX CL was observed among patients’ hemoglobin values reported in the study. Conclusion: The developed population pharmacokinetic model can contribute to the therapy optimization during HDMTX in pediatric patients with ALL and NHL. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to the disposition of HDMTX
Examination of the effects of X-ray phase contrast imaging dose on DNA in mesenchymal stem cells by comet assay
Get PDFINTRODUCTION: Imaging techniques based on X-ray phase-contrast (XPC) have shown tremendous promise for applications involving biomaterials and soft tissue formation [1,2].XPC imaging can be applied at higher energy offering the potential for lower dose imaging. Essential to the development of this technique and its routine use is an understanding of the potential damage of X-ray dose on cells and tissues. EXPERIMENTAL: In this study the comet assay, a sensitive assay for DNA damage, was used to evaluate DNA damage on mesenchymal stem cells (MSCs) exposedto X-ray irradiation. We examined the effects of early (immediately following irradiation) and delayed (24h post-irradiation) X-ray effects caused by low (15mGy) and intermediate (150mGy and 1.5 Gy) exposure on MSCs during a monitoring period of 4 weeks (five irradiations, one weekly). Cells were submitted to apolychromatic X-ray source (Thermo Fisher PXS10 conditions: voltage 45 kV, source current 160A, source power 7.2 W, source spot size 9 um, photon flux on the sample 7.66106photonss-1mm-2irradiation).Statistical analysis was performedby using Two-way analysis of variance (ANOVA) with Tukey’s multiple comparisons posttest in GraphPad Prism 5.0.A difference at p< 0.05 was considered statistically significant.RESULTS AND DISCUSSION: Resultsof the DNA comet assay indicated that early effects of low-and intermediate-dose of XPC induced an increase in the number of cells with DNA damage after each irradiation, where intermediate-dose (150 mGy and 1.5 Gy) produced significantly higher damage relative to controls. DNA damage induced by low and intermediate doses returned to the control value 24h after the irradiation exposure, suggesting a strong protection of MSCs at the tested doses of XPC irradiation. CONCLUSIONS: The data presented in this studyshows that 24 h after the last of five weekly low and intermediate doses XPC irradiation, the harmful effects on DNA in MSCs were notdetected. The current study reinforces the need of investigating consequences of low and intermediate doses of X-ray PC irradiation in the field of tissue engineering and provide new basis for MSCs using in the clinics.ExcellMater Conference 2024: Innovative Biomaterials for Novel Medical Devices, Belgrade, Serbia, April 10-12, 2024
Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta
No full textHypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of “vascular” GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ 2 and α1-5 subunit proteins. To confirm the role of “vascular” GABAA receptors, we investigated the vascular effects of standard benzodiazepines, mida-zolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ 2 over other αxβ3γ 2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazo-lam, both of which at 100 μmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators
Heavy metal contamination of herbal food supplements
No full textHeavy metal contamination in herbal food supplements is one of the major public health risk factors
worldwide. Heavy metals, including lead, cadmium, mercury and arsenic, can accumulate in herbal
raw materials and dietary supplements through various sources such as soil, water, manufacturing
processes, etc. Chronic exposure to these metals is associated with a number of adverse health
effects, including neurotoxicity, nephrotoxicity, carcinogenicity, etc. In the Republic of Srpska, as
well as in EU countries, legislation prescribes maximum levels of contamination of food
supplements with lead, cadmium and mercury (3.0, 1.0 and 0.1 mg/kg, respectively). Considering
the possibility of arsenic contamination in herbal raw materials, the guidelines and standards
suggest that the arsenic content in plant-based products should also be investigated. The aim of this
study was to investigate the potential heavy metal contamination of herbal food supplements. An
atomic absorption spectrophotometer (AAS) was used to determine the lead, cadmium and arsenic
content and a direct mercury analyzer was used to determine the mercury content. 28 samples of
herbal food supplements were tested, of which 15 samples were in liquid form and 13 samples were
in the form of tablets, capsules and sachets. All samples tested showed that the lead, cadmium and
arsenic content was below the detection limits. The mercury content was below the detection limit
in most samples, while an extremely small amount of mercury was detected in some samples (0.005
to 0.016 mg/kg), which is still far below the permissible contamination limits. The tests carried out
have shown that the products tested are safe for consumption. However, continuous monitoring of
the safety this product group is necessary to protect the health of consumers
Ochratoxin A in children's food: implications on children's health
No full textOchratoxin A is a mycotoxin produced by certain molds in cereals. Its presence causes numerous
side effects, including nephrotoxicity, immunotoxicity, and carcinogenicity. Infants, with their
developing immune and renal systems, are particularly susceptible to these adverse effects.
Consequently, the assessment of ochratoxin A levels in cereal products for infants and young
children is very important in order to protect children's health. Because of the above, the legal
legislation prescribes a maximum level of ochratoxin A in cereal-based baby food, which is 0.50
mg/kg. High-performance liquid chromatography (HPLC/FLD) was used as an analytical method
for determining the content of ochratoxin A. A total of 14 samples of baby food containing cereals
were examined, of which 9 samples were fruit and vegetable porridge with cereals, and 5 were salty
porridge with cereals (porridge with vegetables, mushrooms, fish, milk). The results of the analysis
for all tested samples were below the detection limit of 0.5 mg/kg, which is in accordance with the
legislation prohibiting the presence of ochratoxin A in cereals. Assessment of ochratoxin A content
in cereal products for infants and young children is essential to preserve pediatric health and
mitigate risks associated with mycotoxin exposure. Continued research, surveillance, and regulatory
efforts are imperative to effectively save the population's public health. The conducted research
showed that products intended for infants and small children on the market of the Republic of
Srpska are safe in terms of presence of ochratoxin A
Modelling of chromatographic and electrophoretic behaviour of imidazoline and alpha adrenergic receptors ligands under different acid-base conditions
No full textBackground and Purpose: The ligands of the imidazoline and α-adrenergic receptors are mainly imidazoline and guanidine derivatives, known as centrally-acting antihypertensives and compounds with potential use in various neurological disorders. The extent of their ionisation has a major influence on their behaviour in the different analytical systems. The main objective of this work was to compare the mechanism of chromatographic retention and electrophoretic mobility under acidic, neutral and basic conditions. Experimental Approach: Multiple Linear Regression and Partial Least Squares Regression were applied for the QSRR (quantitative structure-retention relationship) and QSMR (quantitative structure-mobility relationship) modelling and to select the most important molecular parameters describing the chromatographic and electrophoretic behaviour of the investigated compounds. Key Results: The most important molecular descriptors, such as the chemical composition of the compounds, lipophilicity, polarizability and molecular branching, in the selected QSRR models showed that an important insight into the retention behaviour can be derived from the 0D-, 1D- and 2D-descriptors. The electrophoretic mobility could be explained by 2D- and 3D-descriptors, which provide information on the molecular mass, size and complexity, as well as on the influence of charge transfer and electronic properties on the migration behaviour. Conclusion: All created QSRR/QSMR models met the stringent validation criteria and showed high potential in describing the chromatographic and electrophoretic behaviour of investigated compounds
Mogućnost zamene konvencionalnih organskih rastvarača zelenim dubokim eutektičkim rastvaračima u analitici lekova
Get PDFIn recent years, Deep Eutectic Solvents (DESs) have attracted increasing attention in
various scientific disciplines. Their unique properties, such as low toxicity, biodegradability, low
cost and versatility, have made them an attractive alternative to conventional organic solvents. In
pharmaceutical analysis, where the demand for environmentally friendly methods is growing,
questions regarding whether DESs can replace organic solvents as "green solvents" have arisen.
This paper explores the potential applications of DESs in drug analysis, and highlights the benefits
and challenges they bring. Examples of the use of DESs in chromatographic techniques and in
the extraction of drugs from various samples are presented. Additionally, research on the stability
and toxicity of DESs in analytical applications is discussed. Based on the available data, it could
be concluded that DESs have the potential to become an important component of analytical
methods in pharmaceutical analysis and provide environmentally sustainable and efficient
alternatives to conventional organic solvents. However, further research is needed to better
understand their properties and optimize their application in drug analysis.Poslednjih godina, eutektički rastvarači privlače sve veću pažnju u različitim naučnim
disciplinama. Njihova jedinstvena svojstva, kao što su niska toksičnost, biorazgradivost, niska
cena i mogućnost primene u različitim oblastima, učinila su ih atraktivnom alternativom
konvencionalnim organskim rastvaračima. U farmaceutskoj analizi, gde su sve veći zahtevi za
ekološki prihvatljivim metodama, postavlja se pitanje da li eutektički rastvarači, kao „zeleni
rastvarači“, mogu da zamene organske rastvarače. Ovaj rad istražuje potencijalnu primenu
eutektičkih rastvarača u analizi lekova i ističe prednosti i izazove koje oni donose. Prikazani su
primeri upotrebe eutektičkih rastvarača u hromatografiji i u ekstrakciji lekova iz različitih
uzoraka. Pored toga, razmatrana je stabilnost i toksičnost eutektičkih rastvarača koji se koriste u
analitičkim metodama. Na osnovu dostupnih podataka, može se zaključiti da eutektički rastvarači
imaju značajan potencijal u pogledu upotrebe u analitičkim metodama u farmaceutskoj analizi i
pružanja ekološki održive i efikasne alternative konvencionalnim organskim rastvaračima.
Međutim, potrebna su dalja istraživanja kako bi se bolje razumela njihova svojstva i optimizovala
njihova primena u ispitivanju lekova
Dekodiranje molekulskog aspekta oštećenja oka prouzročenog ionizirajućim zračenjem pomoću rudarenja genomskih podataka
Get PDFEven at low levels, exposure to ionising radiation can lead to eye damage. However, the underlying molecular mechanisms are not yet fully
understood. We aimed to address this gap with a comprehensive in silico approach to the issue. For this purpose we relied on the Comparative
Toxicogenomics Database (CTD), ToppGene Suite, Cytoscape, GeneMANIA, and Metascape to identify six key regulator genes associated
with radiation-induced eye damage (ATM, CRYAB, SIRT1, TGFB1, TREX1, and YAP1), all of which have physical interactions. Some
of the identified molecular functions revolve around DNA repair mechanisms, while others are involved in protein binding, enzymatic
activities, metabolic processes, and post-translational protein modifications. The biological processes are mostly centred on response to
DNA damage, the p53 signalling pathway in particular. We identified a significant role of several miRNAs, such as hsa-miR-183 and hsamiR-589, in the mechanisms behind ionising radiation-induced eye injuries. Our study offers a valuable method for gaining deeper insights
into the adverse effects of radiation exposure.Izloženost ionizirajućem zračenju čak i pri niskim razinama može pridonijeti nastanku oštećenja oka. Međutim, osnovni molekulski
mehanizmi i dalje nisu potpuno razjašnjeni. Cilj našega istraživanja bio je ispuniti tu nedostajuću kariku primjenom sveobuhvatnog in silico
pristupa problemu. U tu svrhu, pomoću genomskih baza podataka, portala i poslužitelja (Comparative Toxicogenomics Database, ToppGene
Suite portal, Cytoscape, GeneMANIA i Metascape), identificirano je šest ključnih regulacijskih gena koji su povezani s oštećenjem oka
prouzročenog ionizirajućim zračenjem (ATM, CRYAB, SIRT1, TGFB1, TREX1 i YAP1) i koji su svi bili u fizičkoj interakciji. Neke od
identificiranih molekulskih funkcija odnosile su se na mehanizme popravka oštećenja DNA, a druge su bile uključene u vezanje proteina,
enzimsku aktivnost, metaboličke procese i posttranslacijske modifikacije proteina. Biološki procesi uglavnom su bili povezani s odgovorom
na oštećenje DNA, pogotovo sa signalnim putem p53. Uočena je i značajna uloga nekoliko miRNA, poput hsa-miR-183 i hsa-miR-589,
u mehanizmima povezanima s oštećenjem oka prouzročenog ionizirajućim zračenjem. Osim toga, u ovom je istraživanju opisana korisna
metoda za ispitivanje štetnih učinaka izloženosti zračenju