Medicine and Pharmacology

Abstract: Objective. The present study aimed to elucidate if the metabolic effects of probiotic bacterium Hafnia alvei 4597 depend on the melanocortin receptors (MCRs) signaling. Methods. The response to a 3-week intragastric treatment with the H. alvei bacterial suspension or total protein extract was compared between genetically similar mouse sub-strains but with different sensitivity of MCRs, KK and KK.Cg-Ay/a (KK-Ay), the latter overproducing agouti protein. Results. Treatment of KK mice with H. alvei protein extract stimulated energy expenditure and carbohydrate oxidation but reduced lipid oxidation, leptin level, pancreatic weight, and hypothalamic insulin and leptin receptor mRNA expression. Live bacteria in KK mice reduced food intake and stimulated hypothalamic mRNA expression of proopiomelanocortin, agouti-related peptide, and insulin receptors. In the sub-strain KK-Ay, probiotics had no effect on the aforementioned metabolic parameters. H. alvei-based probiotics improved glucose tolerance and deceased body fat and liver glycogen in both mouse sub-strains. Activation of MC4R by H. alvei protein extract was revealed by in vitro study showing of β-arrestin recruitment. Conclusion. These findings confirm beneficial effects of the H. alvei bacteria and show that, for several parameters, the bacterial protein extract may be a more efficacious than bacterial suspension. Differential responses to the treatment between the mouse sub-strains, particularly in energy metabolism, as well as in vitro data, indicate that the effects of H. alvei are mediated by MCRs signaling.

Abstract: Severe metabolic acidosis is a frequent finding in the intensive care unit (ICU) and a critical marker of clinical severity and organ dysfunction, closely linked to acute kidney injury (AKI) due to shared physiological mechanisms and the loss of the kidney's ability to maintain acid-base homeostasis. Therefore, it represents the biochemical expression of heterogeneous pathophysiological mechanisms related to acid-base balance. These include tissue hypoperfusion, sepsis, mitochondrial dysfunction, accumulation of unmeasured anions, bicarbonate loss, and reduced renal excretion of the acid load. Its presence is associated with increased mortality, greater vasopressor and mechanical ventilation requirements, prolonged ICU stay, and a higher likelihood of renal replacement therapy (RRT). However, pH correction alone does not guarantee clinical improvement. Therefore, contemporary management prioritizes the etiology, severity of the acidemia, and hemodynamic status. In this context, sodium bicarbonate plays a limited and selective role, particularly in severe acidemia with advanced AKI or hyperkalemia, or as temporary supportive therapy while the underlying cause is corrected or extracorporeal support is arranged. Similarly, RRT should be reserved for refractory cases and should not be initiated based solely on isolated pH thresholds. This review analyzes the definition, epidemiology, clinical implications, pathophysiology, and therapeutic strategies for severe metabolic acidosis in critically ill patients, with emphasis on its interaction with AKI, the rational use of bicarbonate, and the timing of RRT initiation.

Abstract: Background: Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R) activation exert anti-diabetic and anti-obesity effects. Tirzepatide, a dual GIPR/GLP-1R agonist, has demonstrated cardiovascular benefits in clinical studies. However, the direct vascular actions of tirzepatide and their potential advantages over selective GLP-1 receptor agonists (GLP-1RA) remain unclear. We investigated the vasoprotective effects of tirzepatide and compared them with those of GLP-1 receptor agonists in vivo and in vitro. Methods: Non-diabetic C57BL/6 and diabetic KK-Ay mice received tirzepatide, semaglutide, or vehicle. Arterial remodeling was induced by femoral artery wire injury. A subset of mice was co-treated with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). After 4 weeks, biochemical, morphometric, and immunofluorescence analyses were performed. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with tirzepatide or liraglutide to assess nitric oxide (NO) production. Results: In non-diabetic mice, tirzepatide suppressed intimal hyperplasia without affecting metabolic parameters, whereas semaglutide had no significant effect on intimal hyperplasia at the same molar dose. The protective effects of tirzepatide were abolished by L-NAME. In diabetic mice, tirzepatide and semaglutide similarly improved metabolic parameters and attenuated intimal hyperplasia. In HUVECs, tirzepatide increased NO production in a dose-dependent manner, and this effect was preserved under hyperglycemic conditions. Tirzepatide and liraglutide induced comparable NO production at equivalent molar concentrations. Conclusions: Tirzepatide exerted greater vasoprotective effects than selective GLP-1RA under non-diabetic conditions in an NO-dependent manner, whereas both agents exhibited comparable vasoprotective effects under diabetic conditions.

Abstract: Background: Interindividual variability in response to anti-inflammatory therapies remains a major challenge in clinical practice. Nonsteroidal anti-inflammatory drugs, corticosteroids, and biologic agents are widely used in adult and pediatric inflammatory diseases, but their efficacy and safety are influenced by pharmacokinetic, pharmacodynamic, developmental, and genetic factors. Methods: A structured literature review was conducted in PubMed and Embase for English-language publica-tions from January 2000 to January 2026. Clinical studies, trials, observational studies, systematic reviews, meta-analyses, guidelines, and relevant reviews were analyzed, with emphasis on phar-macogenomic determinants of response and toxicity. Results: The strongest actionable evidence concerns CYP2C9 variants affecting the metabolism of several nonsteroidal anti-inflammatory drugs, including ibuprofen, celecoxib, meloxicam, and related agents. Reduced-function alleles are associated with decreased clearance, increased drug exposure, and higher risk of dose-related ad-verse events. For corticosteroids, variants in NR3C1, FKBP5, STIP1, GLCCI1, and pharmacokinetic genes may contribute to variability in responsiveness and toxicity, although clinical implementation remains limited. For biologics, HLA-DQA1*05 is a reproducible predictor of anti-drug antibody formation and secondary non-response to anti-TNF therapy. Conclusion: Pharmacogenomics offers a promising strategy to personalize anti-inflammatory therapy. While CYP2C9-guided nonsteroidal anti-inflammatory drug prescribing is currently the most clinically actionable application, further prospective and pediatric-specific studies are needed to support broader implementation.

Abstract: Background/Objectives: Advanced maternal age (≥35 years) significantly increases the risk of fetal chromosomal abnormalities, particularly trisomies 21, 18, and 13. Non-invasive prenatal testing (NIPT) based on cell-free fetal DNA (cffDNA) in maternal plasma has substantially improved the accuracy and safety of prenatal screening. Methods: We previously developed and clinically validated a multiplex droplet digital PCR (ddPCR)-based NIPT assay for detecting fetal trisomies 21, 18, and 13 in Mongolia. The assay targeted specific loci on chromosomes 21, 18, and 13, using chromosome 1 as an internal reference. A Z-score threshold >3 indicated high risk, and all positive results were confirmed by invasive karyotyping. Results: In this study we collected 74 pregnant women of advanced maternal age and samples were successfully analyzed, with high technical performance (mean >100,000 accepted droplets per reaction and clear signal separation). Ten high-risk pregnancy cases were identified (8 trisomy 21 and 2 trisomy 18), all of which showed complete concordance with confirmatory karyotyping. Complete concordance with available reference standard results were observed in this limited cohort. No trisomy 13 cases were detected. Conclusions: This ddPCR-based NIPT assay exhibited excellent diagnostic accuracy and reproducibility in a Mongolian cohort of advanced maternal age pregnancies. Its technical simplicity, relatively low cost, and minimal infrastructure requirements make it a promising tool for implementation in resource-limited settings. However, the small sample size limits generalizability, and larger multicenter studies are needed to confirm clinical utility across broader populations, including low-risk pregnancies.

Abstract: Background/Objectives: Oxidative stress is a well-established driver of neuronal dysfunction and a shared pathological mechanism across neurodegenerative diseases. Pharmacological activation of the Nrf2/ARE pathway is a validated strategy to counteract oxidative damage, as demonstrated by the clinical approval of dimethyl fumarate (DMF) and monomethyl fumarate (MMF) for relapsing forms of multiple sclerosis. These electrophilic compounds activate Nrf2 via covalent Keap1 modification. Cynara scolymus L. structurally related electrophilic metabolites; however, their contribution to Nrf2 activation remains undefined. This study aimed to identify and characterize the constituents responsible for Nrf2 activation and benchmark their potency against DMF and MMF. Methods: Bioactivity-guided fractionation combining Soxhlet extraction, Nrf2/ARE luciferase reporter screening, semi-preparative HPLC, and spectroscopic identification was employed. Functional validation included extracellular thiol quantification, H₂O₂ cytoprotection assays, and western blot analysis of heme oxygenase-1 (HO-1). Results: The dichloromethane extract exhibited the highest Nrf2-inducing activity (54.4 - fold). Fractionation yielded five guaianolide sesquiterpene lactones (1-5), four of which were active. The α-methylene-γ-lactone moiety was essential for activity. Aguerin B (3) exhibited the highest activity (39.14 ± 11.13-fold), while TBA analysis identified cynaropicrin (2) as the dominant extract-level contributor (62.9% of total activity). Notably, aguerin B and cynaropicrin (2) induced greater activation than DMF and MMF in Nrf2/ARE reporter assay. Downstream pathway activation was confirmed by concentration- and time-dependent HO-1 upregulation, elevated extracellular glutathione and CysGly levels, and significant protection against H₂O₂-induced cytotoxicity without intrinsic toxicity. Conclusions: Guaianolide sesquiterpene lactones are the primary mediators of Nrf2 activation in C. scolymus. Cynaropicrin (2) exhibited superior in vitro potency over fumarates, supporting its relevance for further pharmacological investigation.

Abstract: Peritoneal metastasis (PM) is the most frequent and lethal pattern of dissemination in gastrointestinal malignancies. Despite advances in systemic chemotherapy, outcomes remain poor because the unique biology of PM, characterized by poor vascularization and the peritoneal–plasma barrier (PPB), limits drug penetration and contributes to treatment resistance. To address these challenges, several locoregional treatment strategies have been developed, including cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). However, their widespread adoption is constrained by invasiveness, strict patient selection, and inconsistent survival benefits. Catheter-based normothermic intraperitoneal chemotherapy (CBIP) has emerged as a practical and less invasive alternative, particularly in East Asia. Through an implanted intraperitoneal port, CBIP enables repeated drug administration, providing sustained regional exposure while imposing minimal procedural burden. Importantly, it can be readily integrated with systemic chemotherapy, making it suitable for long-term multimodal treatment. Among available agents, paclitaxel (PTX) is particularly well suited for intraperitoneal administration because of its prolonged retention within the peritoneal cavity and limited systemic absorption. These pharmacokinetic properties allow high local drug concentrations with relatively low systemic toxicity. Consequently, PTX-based CBIP represents a biologically rational and clinically feasible treatment strategy for PM. This review summarizes the pharmacological rationale, clinical evidence, and emerging innovations in drug formulation and delivery that may further enhance the efficacy of PTX-based intraperitoneal chemotherapy for this challenging disease.