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Urinary biomarkers in prediction of subclinical acute kidney injury in pediatric oncology patients treated with nephrotoxic agents
No full textBackground: Acute kidney injury (AKI) is a common complication in pediatric oncology patients, most often caused by nephrotoxic drugs. We aimed to assess whether levels of urinary kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL), liver fatty acid binding protein (uL-FABP) and Vanin-1 (uVNN-1), individually and in combination-integrated could be early markers for cytotoxic treatment induced AKI. Methods: Children with different malignant diseases treated with cisplatin (CIS) or ifosfamide (IFO) were included. AKI was defined using pediatric KDIGO (Kidney Disease Improving Global Outcomes) criteria by comparing pretreatment serum creatinine (sCr) values with those acquired at 48 h after the first or second chemotherapy cycle. Five serum (at baseline, 2, 6, 24 and 48 h after treatment) and four urine samples (at baseline, 2, 6 and 24 h after treatment) were obtained. Urinary biomarkers (uBm) were normalized to urine creatinine. Results: Thirty-eight patients were assessed. Within 48 h following chemotherapy 6 (15.79%) patients experienced AKI. Patients with AKI were younger and tend to have lower baseline sCr values than patients without AKI, but these differences were not statistically significant. Compared to baselines, all uBm were significantly increased during the first 6 h while sCr concentrations did not change significantly during the study period. The median increases in uBm during the first 6 h after treatment were 529.8% (interquartile range – IQR, 63.9-1835.2%) – 2194.0% (IQR, 255.3-4695.5%) in AKI vs. 302.2% (IQR 114.6-561.2%) -429.8% (156.5–1467.0%) in non-AKI group depending of tested uBm. The magnitude of these changes over time didn’t differ significantly between groups. The area under receiver operator curve (AUC) for uL-FABP and uNGAL at 24 h after chemotherapy were 0.81 and 0.72, respectively. The ROC analysis revealed that the other individual biomarkers’ performance at any time-point wasn’t statistically significant (AUC < 0.7). A model of integrated-combined uBm, 2 h (AUC 0.78), 6 h (AUC 0.85) and 24 h after (AUC 0.92) treatment with CIS and/or IFO showed good utility for early AKI prediction. Conclusions: The results of this study support that the use of the uBm to improves early AKI prediction in patients receiving CIS and/or IFO containing chemotherapy. Further studies on larger comparable groups of patients are needed
Parenteral Nanoemulsion for Optimized Delivery of GL-II-73 to the Brain—Comparative In Vitro Blood–Brain Barrier and In Vivo Neuropharmacokinetic Evaluation
No full textBackground/Objectives: GL-II-73 is a positive allosteric modulator that is selective for α5GABAA receptors and has physicochemical properties that favor nanocarrier formulations when parenteral delivery to the central nervous system is desired. Our aim was to develop an optimized nanoemulsion containing GL-II-73 and subsequently test whether this would improve permeation across the blood–brain barrier (BBB) and availability in the brain. Methods: The nanoemulsions were formulated and subjected to detailed physiochemical characterization. The optimized formulation was tested in comparison to a solution of GL-II-73 in the appropriate solvent in an in vitro model of the blood–brain barrier based on human induced pluripotent stem cell-derived microvascular endothelial cells, astrocytes, and pericytes. Plasma and brain exposure to GL-II-73 and its metabolite MP-III-022 was investigated in an in vivo neuropharmacokinetic study in rats exposed to the selected nanoemulsion and the conventional solution formulation. Results: The selected biocompatible nanoemulsion exhibited satisfactory physicochemical properties for parenteral administration, with a Z-ave of 122.0 ± 1.5, PDI of 0.123 ± 0.009 and zeta potential of −40.7 ± 1.5, pH of 5.16 ± 0.04, and adequate stability after one year of storage, and allowed the localization of GL-II-73 in the stabilization layer. The permeability of GL-II-73 through the BBB was twice as high with the selected nanoemulsion as with the solution. The availability of GL-II-73 and MP-III-022 (also a positive allosteric modulator selective for α5GABAA receptors) in the brain was 24% and 61% higher, respectively, after intraperitoneal administration of the nanoemulsion compared to the solution; the former increase was statistically significant. Conclusions: The increased permeability in vitro proved to be a good predictor for the improved availability of GL-II-73 in brain tissue in vivo from the formulation obtained by encapsulation in a nanoemulsion. The putative additive effect of the parent molecule and its metabolite MP-III-022 could lead to enhanced and/or prolonged modulation of α5GABAA receptors in the brain
Behavioral characterization of a model of diabetes type 2 in middle-aged Sprague-Dawley rats of both sexes
No full textDiabetes type 2 (T2D) is a very common metabolic disease that is exacerbated by an unhealthy lifestyle. However, most preclinical studies in rats are conducted in young adult males. Therefore, we aim not only to establish T2D model based on a high-fat diet and low-dose streptozotocin in aging rats of both sexes to increase its translational potential and reduce sex-related bias in preclinical studies, but also to investigate its behavioral effects on cognition, mood and locomotor activity.
Middle-aged Sprague-Dawley rats of both sexes were fed high-fat diet or control diet, followed by administration of low dose of streptozotocin or vehicle. The behavioral battery included the sucrose preference test (SPT), the novel object recognition test (NORT), and the spontaneous locomotor activity test (SLA).
The main effect of the T2D model was significant for animal body weight and blood glucose levels, with model animals showing elevated levels compared to controls. Furthermore, in SPT test, the T2D animals had a lower sucrose intake than the control animals, regardless of sex. In NORT test, female T2D animals showed lower discrimination index than respective control animals, while in SLA test, male T2D animals traveled shorter distance compared to their respective controls.
Modeling of T2D in middle-aged rats showed robust hyperglycemia and weight gain. Interestingly, these model animals exhibited anhedonia, which was demonstrated by decreased sucrose intake. However, short-term memory and locomotor activity were impaired in female and male T2D rats, respectively, suggesting sex-dependent effects and calling for further studies focusing on the underlying molecular mechanisms
Exploring the potential of plant hydrolates in green cosmetic formulations: case study of Pannonian thyme hydrolate
No full textThe aim of this work was to investigate the potential of plant hydrolate to be used as
multifunctional ingredient in cosmetic product, emphasizing their environmental and skin-
enhancing benefits. Specifically, the work focused on the hydrolate derived from Pannonian
thyme (Thymus pannonicus All., Lamiaceae) and additionally the effect of different
manufacturing processes was evaluated. ..
Real-World Safety of Vedolizumab in Inflammatory Bowel Disease: A Retrospective Cohort Study Supported by FAERS Signal Analysis
No full textBackground/Objectives: Vedolizumab is a gut-selective anti-integrin monoclonal antibody approved for the treatment of inflammatory bowel disease (IBD). While clinical trials have demonstrated a favorable safety profile, real-world studies are essential for identifying rare adverse events (AEs) and evaluating post-marketing safety. This study assessed vedolizumab’s safety in a real-world cohort and supported the detection of potential safety signals. Methods: A retrospective chart review was conducted on adult IBD patients treated with vedolizumab at a tertiary center in the Republic of Serbia between October 2021 and August 2022. Data included demographics, AEs, and newly reported extraintestinal manifestations (EIMs). Exposure-adjusted incidence rates were calculated per 100 patient-years (PYs). Disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) was performed to identify safety signals, employing reporting odds ratios (RORs) and proportional reporting ratios (PRRs) for AEs also observed in the cohort. Prior IBD therapies and reasons for discontinuation were evaluated. Results: A total of 107 patients (42.1% Crohn’s disease, 57.9% ulcerative colitis) were included, with a median vedolizumab exposure of 605 days. There were 92 AEs (56.51/100 PYs), most frequently infections (23.95/100 PYs), gastrointestinal disorders (4.30/100 PYs), and skin disorders (4.30/100 PYs). The most frequently reported preferred terms (PTs) included COVID-19, COVID-19 pneumonia, nephrolithiasis, and nasopharyngitis. Arthralgia (12.90/100 PYs) was the most frequent newly reported EIM. No discontinuations due to vedolizumab AEs occurred. FAERS analysis revealed potential signals for events not listed in prescribing information but observed in the cohort: nephrolithiasis, abdominal pain, diarrhea, malaise, cholangitis, gastrointestinal infection, blood pressure decreased, weight decreased, female genital tract fistula, respiratory symptom, and appendicectomy. Most patients had received three prior therapies, often stopping one due to AEs. Conclusions: Vedolizumab demonstrated a favorable safety profile in the IBD cohort. However, FAERS-identified signals, such as nephrolithiasis, gastrointestinal infections, and decreased blood pressure, warrant further investigation in larger, more diverse populations
Association of Low Free T3 with Disease Presence and Activity in Ankylosing Spondylitis
No full textAnkylosing spondylitis (AS) is a chronic inflammatory disease characterized by axial skeletal involvement and systemic metabolic changes. While inflammation is central to its pathophysiology, the potential role of thyroid hormones, particularly free triiodothyronine (FT3), in disease risk and activity remains underexplored. The objective of this study is to evaluate the relationship between serum FT3 levels and both the presence and clinical activity of AS, while also examining other endocrine-metabolic parameters. In this cross-sectional study, 120 AS patients and 117 healthy controls were assessed. Demographic, anthropometric, hematologic, and biochemical parameters were recorded. Disease activity was determined using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), with BASDAI ≥ 4 indicating active disease. Logistic regression models adjusting for age, sex, BMI, and other relevant covariates were applied to identify independent predictors. FT3 levels were significantly lower in AS patients compared to controls (3.25 [3.01–3.58] vs. 3.44 [3.16–3.69] pg/mL, p = 0.037) and in patients with BASDAI ≥ 4 versus BASDAI < 4 (3.20 [2.94–3.48] vs. 3.44 [3.19–3.83] pg/mL, p = 0.004). The reduction was more evident in women, where it reflected disease presence, whereas in men it was associated with high disease activity. Low FT3 independently predicted both AS (OR 0.50, 95% CI 0.28–0.92, p = 0.026) and active disease (OR 0.48, 95% CI 0.24–0.99, p = 0.047). Lower HDL-C, BMI, and creatinine, and higher leukocyte counts were also associated with AS, but not with disease activity. Low-normal FT3 is independently associated with both the presence and activity of AS, reflecting disease presence in women and disease activity in men. This is the first study to demonstrate this sex-specific association after adjusting for metabolic parameters and multiple covariates, highlighting FT3’s potential as a marker of inflammation-driven metabolic dysregulation
Sensibilidad del índice de masa corporal como criterio actual de nutrición: nueva redefinición del índice de masa corporal para adultos jóvenes
No full textIntroduction: obesity during university studies is becoming a growing problem. In order to recognize health risks in the young population as early as possible, it is important to define objective criteria for obesity. Body mass index (BMI) and percentage of body fat (PBF) are the most common parameters for assessing obesity. Objective: the aim of this research is to determine the criteria of BMI for young university students as a young adult population based on PBF criteria. Methods: this study included 1272 university students, divided by gender (675 females and 597 males). PBF was measured using multichannel bioelectrical impedance analysis InBody 720. Results: percentile distribution was used to establish obesity criteria for PBF based in four categories: athlete, fit, normally nourished and overweight. The results for female showed that the BMI cut-off value for the athlete criterion is 21.97 kg/m2, for the fit criterion is 22.01 kg/m2, for the normally nourished 23.18 kg/m2 and for the overweight 27.29 kg/m2. The results for male showed that for the athlete criterion the cut-off value for BMI was 23.70 kg/m2, for the fit criterion 25.66 kg/m2, for the normally nourished 26.63 kg/m2 and for the overweight 29.60 kg/m2. Conclusion: the existing standard BMI criteria for young adults are not specifically accurate regarding obesity. We propose to redefine BMI nutritional status criteria based on PBF for young adult subjects.Resumen
Introducción: la obesidad durante los estudios universitarios se está convirtiendo en un problema creciente. Para reconocer los riesgos de salud
de la población joven lo antes posible, es importante definir criterios objetivos para la obesidad. El índice de masa corporal (IMC) y el porcentaje
de grasa corporal (PGC) son los parámetros más comunes para evaluar la obesidad.
Objetivo: el objetivo de esta investigación es determinar los criterios del IMC para los estudiantes universitarios jóvenes, como población de
adultos jóvenes, basados en los criterios del PGC.
Métodos: este estudio incluyó a 1272 estudiantes universitarios, divididos por género (675 mujeres y 597 hombres). El PGC se midió utilizando
el análisis de impedancia bioeléctrica multicanal InBody 720.
Resultados: se utilizó la distribución percentil para establecer los criterios de obesidad del PGC en cuatro categorías: deportista, en forma,
normalmente nutrido y con sobrepeso. Los resultados de las mujeres mostraron que el valor de corte del IMC para el criterio de deportista es de
21,97 kg/m2, para el criterio de en forma es de 22,01 kg/m2, para el de normalmente nutrido es de 23,18 kg/m2 y para el de sobrepeso es de
27,29 kg/m2. Los resultados de los hombres mostraron que, para el criterio de deportista, el valor de corte del IMC fue de 23,70 kg/m2, para el
de en forma de 25,66 kg/m2, para el de normalmente nutrido de 26,63 kg/m2 y para el de sobrepeso de 29,60 kg/m2.
Conclusión: los criterios estándar existentes del IMC para adultos jóvenes no son específicamente precisos en cuanto a la obesidad. Proponemos
redefinir los criterios del estado nutricional del IMC basándonos en el PGC de los sujetos adultos jóvenes
Polyelectrolyte complexes of chitosan as potential drug delivery systems
No full textChitosan-based polyelectrolyte complexes (CH PECs) have attracted significant attention as multifunctional carriers for advanced drug delivery. Formed through non-covalent interactions between chitosan (CH) and anionic polyelectrolytes, these systems offer advantages such as biocompatibility, biodegradability, mucoadhesion, and pH-responsive drug release. This chapter provides an in-depth overview of CH PECs, focusing on their formation mechanisms, physicochemical properties, preparation techniques, and characterization methods. The influence of critical parameters such as the degree of deacetylation, molecular weight, polymer ratios, and pH on complex stability, drug encapsulation efficiency, and release kinetics is thoroughly discussed. Applications across various administration routes, including oral, buccal, ocular, nasal, pulmonary, dermal, transdermal, vaginal, and parenteral delivery, are reviewed, highlighting the ability of CH PECs to enhance drug solubility, prolong therapeutic action, and improve bioavailability. The chapter also addresses translational challenges related to large-scale manufacturing, regulatory requirements, and in vivo performance. Overall, CH PECs represent a promising platform for the development of next-generation drug delivery systems capable of overcoming limitations of conventional formulations and facilitating clinical translation.https://link.springer.com/chapter/10.1007/978-3-032-08347-0_3#DOI
https://link.springer.com/book/10.1007/978-3-032-08347-
A pan-HDAC chemoproteomics assay to profile drugs
No full textAs some histone deacetylases (HDAC) hold key epigenetic roles, several HDAC inhibitors have already been
approved for clinical use. Indeed, dysregulation of HDACs’ activity leads to various pathological disorders (cancer,
neurodegenerative diseases). However, the substrates of the 11 zinc-dependent HDACs are not necessarily histones, not even always proteins, and act on various post-translational acylations, sometimes with poor deacetylation activity. Understanding the biological functions and substrates of each HDAC is a major focus of ongoing research, where chemical probes discovery and chemoproteomics have a central role. Chemoproteomic approaches, like affinity-based protein profiling (AfBPP), have transformed drug target identification through the combination of small-molecule affinity probes and sensitive LC-MS/MS detection. While our team’s previous efforts successfully mapped global inhibitor profiles across 9 HDACs and uncovered surprising off-targets of HDAC drugs [1,2], critical gaps remain in isoform-resolved datasets - with HDAC9 and HDAC11 remaining elusive.
Therefore, we are developing a next-generation chemoproteomic platform for pan-HDAC drug profiling. We have
synthesized and tested new hydroxamate affinity probes to address the entire zinc-dependent HDAC family.
Additionally, we are evaluating these molecules in different biological materials, including mouse brain and diverse
human cancer cell lines, which feature various HDAC expression profiles. We particularly focus on HDAC9 and
HDAC11, whose general low expression has rendered chemoproteomics analysis out of reach. With our improved
assay, this research will further our understanding of the applications of HDAC inhibitors, reveal new interaction
partners, and contribute to improving chemical probes and drug design. A pan-HDAC chemoproteomics assay
would provide two key benefits. It would allow us to re-evaluate the actual selectivity of commonly used inhibitors.
And, most importantly, it would allow us to investigate under-studied HDAC9 and HDAC11, by enhancing their
enrichment and quantification in complex samples, enabling drug repurposing. Altogether, this work advances high-
resolution chemoproteomic mapping of HDAC-inhibitor interactions.https://eebmbcongress.gr/75th-national-conference-of-the-hellenic-society-of-biochemistry-molecular-biology-hsbm
Macrophage Inhibitory Factor in Myocardial Oxidative Stress and Inflammation During Thioacetamide-Induced Liver Fibrosis: Modulation by Betaine
No full textChronic liver disease is closely associated with impaired cardiovascular function. Cardiac dysfunction is caused in part by oxidative stress and increased levels of proinflammatory and profibrogenic mediators in myocardial tissue. The present study aims to investigate the role of betaine in the modulation of MIF-mediated oxidative stress, inflammation, and fibrogenesis in heart during TAA-induced liver fibrosis in mice. The experiment is performed on wild-type and knockout MIF−/− C57BL/6 mice (MIF−/− group). They are randomly divided into groups: Control; Bet-group, received betaine (2% wt/v dissolved in drinking water); MIF−/− mice group; MIF−/−+Bet; TAA-group, treated with TAA (200 mg/kg b.w.), intraperitoneally, 3×/week/8 weeks); TAA+Bet; MIF−/−+TAA, and MIF−/−+TAA+Bet group. After eight weeks of treatment, animals are sacrificed and heart samples are taken to determine oxidative stress parameters, proinflammatory cytokines, profibrogenic factors, and histopathology of myocardial tissue. Our results suggest that MIF contributes significantly to lipid peroxidation of cardiomyocytes, as well as oxidative and nitrosative stress in myocardial tissue in mice with TAA-induced liver fibrosis compared to the control group. In addition, MIF was important for myocardial expression of the proinflammatory cytokines IL-6 and TNF as well as the profibrogenic mediators TGF-β1 and PDGF-BB in TAA-treated mice. Notably, betaine attenuated MIF effects in myocardial tissue reducing levels of MDA, AOPP, TNF, TGF-β1, PDGF-BB and increasing SOD and catalase activity in the coexistence of liver fibrosis. These results emphasize the potential of betaine as a therapeutic agent in mitigating MIF effects and demonstrate the need for further research into its optimal dosage and efficacy in preventing or slowing down cardiac dysfunction in patients with liver cirrhosis