Adipokines play an important role in immunometabolic regulation and systemic inflammation, processes profoundly disturbed in COVID-19. Leptin and adiponectin have attracted particular interest because of their opposing biological effects. However, most studies have relied on single time-point measurements, and data on serial adipokine dynamics in critically ill patients with COVID-19-associated acute respiratory distress syndrome (ARDS) remain limited. This study aimed to evaluate circulating leptin and adiponectin concentrations and their temporal changes during the first week of intensive care unit (ICU) treatment. This single-center prospective observational study included 75 adults with COVID-19-associated ARDS admitted to the medical ICU (MICU). Serum leptin and adiponectin concentrations were measured on day 1 and day 7 using enzyme-linked immunosorbent assays. Clinical data, including respiratory support, vasopressor use, comorbidities, and 28-day survival, were prospectively collected. The overall 28-day mortality was 38.7%. Leptin concentrations did not significantly change between day 1 and day 7 in any subgroup. In contrast, adiponectin demonstrated significant temporal changes. Among non-survivors, adiponectin levels decreased markedly during the first week of MICU treatment (p<0.001), whereas no significant change was observed in survivors. Similar declines were observed in patients requiring invasive mechanical ventilation and vasopressor therapy, while patients managed without these interventions showed increasing adiponectin concentrations. The leptin-to-adiponectin ratio showed a trend toward higher values in non-survivors but did not reach statistical significance. In COVID-19-associated ARDS patients, adiponectin demonstrated dynamic changes associated with clinical deterioration, whereas leptin remained relatively stable. These findings suggest that serial adiponectin measurements may have potential for monitoring short-term disease progression in critically ill patients and warrant confirmation in larger prospective studies.

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, despite significant advances in diagnostics and pharmacotherapy. This persistent burden has shifted attention toward adjunct therapeutic strategies targeting key mechanisms of myocardial and vascular injury, including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, apoptosis, inflammation, endothelial dysfunction, and metabolic dysregulation. A particular interest of contemporary research is focused on bile acid (BA) signaling through nuclear and membrane receptors, primarily the Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), as central regulators of metabolic, inflammatory, and vascular responses. Ursodeoxycholic acid (UDCA), a hydrophilic BA widely used to treat hepatobiliary disorders, has emerged as a potential modulator of cardiometabolic processes. UDCA exerts direct effects through low-affinity but functionally relevant activation of the TGR5 receptor, as well as indirect effects through alterations in BA pool composition, thereby influencing FXR/TGR5 signaling pathways. Experimental studies suggest that UDCA reduces oxidative stress, stabilizes mitochondrial function, alleviates ER stress, suppresses apoptosis and inflammation, and improves endothelial function and nitric oxide (NO) bioavailability. Despite promising mechanistic evidence, currently available clinical data remain limited and are largely based on small studies and surrogate biomarkers, without confirmation of benefits in terms of major cardiovascular outcomes. This review summarizes current knowledge regarding the role of UDCA in the modulation of BA receptor signaling and its potential relevance for cardiovascular protection.

INTRODUCTION The increasing recognition of peripheral GABAergic signaling has renewed interest in the vascular effects of benzodiazepines (BDZs), particularly in light of their frequent use during pregnancy. Although BDZs have been studied in various vascular beds, their exact vasorelaxant mechanisms are still unclear. This study aimed to investigate the mechanisms underlying diazepam-induced vasodilation in human umbilical arteries (HUAs). METHODS Isolated endothelium-intact HUA rings were pre-contracted with serotonin, and concentration-response curves for diazepam (0.01-100 μM) were obtained using the tissue bath method. The roles of the endothelium, potassium and calcium channels, and TSPO were assessed using specific inhibitors or blockers: L-NAME, indomethacin, sildenafil, ODQ, glibenclamide, 4-aminopyridine, tetraethylammonium, and PK11195. The effects of diazepam pre-treatment on BaCl2-and serotonin-induced contractions were also investigated. RESULTS Diazepam induced a time- and concentration-dependent relaxation of HUA, with ⁓ 96% of the maximal effect being achieved at 100 μM. This response was endothelium-independent, as it was unaffected by eNOS or COX inhibition, but included an ODQ-sensitive component compatible with involvement of the soluble guanylate cyclase (sGC)-cGMP pathway. Potassium channel involvement was confirmed, and diazepam significantly suppressed BaCl2-and serotonin-induced contractions, suggesting calcium channel antagonism. PK11195 significantly attenuated diazepam-induced relaxation, implying involvement of TSPO. CONCLUSION Diazepam elicits near-complete relaxation in serotonin-precontracted HUA through endothelium-independent mechanisms that likely involve potassium channel activation, calcium channel inhibition, a component sensitive to ODQ suggesting possible involvement of the sGC-cGMP pathway, and interaction with TSPO. These results emphasize the remarkable vasoactivity of diazepam and its importance in the regulation of umbilical vascular tone.

The mechanisms linking chronic hyperglycemia to intestinal inflammation and epithelial dysfunction remain incompletely understood, highlighting an important gap in our understanding of diabetes-associated gastrointestinal pathology. In this study, we investigated the effects of sustained hyperglycemia on intestinal inflammation, endoplasmic reticulum (ER) stress, and autophagy in a translational porcine model of diabetes. Diabetes was induced in Yucatan mini pigs using a high-fat, high-carbohydrate/fructose diet (HFHFD) followed by streptozotocin administration. Intestinal tissues from the terminal ileum and sigmoid colon were analyzed using histological evaluation, quantitative real-time PCR, and immunohistochemistry. Histological analysis revealed structural alterations in diabetic animals, including villous degeneration, crypt depletion, goblet-cell loss, and increased inflammatory-cell infiltration. Gene expression analysis revealed significant upregulation of inflammatory mediators (NF-κB, TNF-α, IL-6, IL-1β), inflammasome components (NLRP3), and macrophage markers (CD68, CD86, CD163). In parallel, ER stress-related genes (ORMDL3, ATF6) and autophagy-associated genes (NOD2, ULK1, ATG4a) were significantly elevated in diabetic pigs. At the protein level, increased expression of ER stress markers was confirmed in both intestinal regions, while autophagy-related proteins showed less consistent changes and did not fully reflect the observed transcriptional patterns, suggesting a potential disconnect between transcriptional activation and downstream autophagy-related protein expression under diabetic conditions. Chronic hyperglycemia is associated with intestinal inflammation and disruption of cellular stress pathways, including ER stress and autophagy, in a porcine model. These findings provide mechanistic insight into how chronic hyperglycemia contributes to intestinal dysfunction through coordinated alterations in inflammatory signaling, ER stress, and autophagy pathways, identifying these processes as potential targets for therapeutic intervention in diabetes-associated gastrointestinal disease.

Background: Hofbauer cells (HBCs) are the only immunocompetent cells within the stroma of chorionic villi and play a key role in immune regulation and placental development throughout gestation. Their phenotype, abundance, and proliferative activity change in accordance with the needs of the fetoplacental unit. Methods: Thirty healthy human placentas across all three trimesters were analyzed. Samples were processed using standard histological protocols and immunohistochemically stained with CD45, CD68, CD86, and Ki-67 markers. Morphometric analysis was performed to determine the following parameters: percentage of HBCs, numerical areal density, and proliferative index. Results: HBCs were immunoreactive for CD45 and CD68, while CD86 immunoreactivity was not observed in any trimester. The proportion of HBCs was highest in the second trimester and lowest in the third. Numerical areal density was highest in the second trimester (22.21 ± 3.86) and lowest in the first (8.27 ± 4.18). The proliferative index was highest in the first trimester (82.45 ± 10.19%), decreased significantly in the second, and was completely absent in the third trimester. Conclusions: During physiological placental development, Hofbauer cells maintain a predominantly non-M1 macrophage phenotype, accompanied by a gradual reduction in proliferative activity.

Pomegranate peel, an abundant agro-industrial by-product, represents a sustainable source of bioactive polyphenols, particularly punicalagin, which has been associated with antioxidant and photoprotective potential. This study aimed to develop microemulsions (MEs) containing pomegranate peel extract for dermal delivery of punicalagin using biocompatible surfactant systems. Three MEs differing in surfactant–cosurfactant composition (ME-A, ME-P, and ME-E) were prepared. Each formulation solubilized 1% (w/w) of pomegranate peel extract and was evaluated regarding in vitro release behavior, skin permeation/retention, antioxidant activity, and in vitro sun protection factor (SPF). All investigated MEs provided sustained release of punicalagin (≈10–17% of the applied dose in 8 h). ME-A, based on an alkyl polyglucoside surfactant, showed a significantly higher cumulative release of punicalagin (60.4 µg/cm2) compared with ME-E and ME-P. In skin penetration/permeation studies, ME-A also exhibited the highest numerical total delivery of punicalagin (≈48.2 µg/cm2 after 24 h), although differences among formulations were not statistically significant. All formulations demonstrated high antioxidant activity in the DPPH assay and measurable in vitro photoprotective potential, with SPF values ranging from approximately 11 to 14. Overall, pomegranate peel extract-loaded MEs showed potential as dermal delivery systems capable of improving solubilization and modulating skin delivery of punicalagin. The combination of agro-waste-derived bioactives with biocompatible surfactants highlights the potential of these systems as sustainable approaches for skincare formulations.

The mechanisms linking chronic hyperglycemia to intestinal inflammation and epithelial dysfunction remain incompletely understood, highlighting an important gap in our understanding of diabetes-associated gastrointestinal pathology. In this study, we investigated the effects of sustained hyperglycemia on intestinal inflammation, endoplasmic reticulum (ER) stress, and autophagy in a translational porcine model of diabetes. Diabetes was induced in Yucatan mini pigs using a high-fat, high-carbohydrate/fructose diet (HFHFD) followed by streptozotocin administration. Intestinal tissues from the terminal ileum and sigmoid colon were analyzed using histological evaluation, quantitative real-time PCR, and immunohistochemistry. Histological analysis revealed structural alterations in diabetic animals, including villous degeneration, crypt depletion, goblet-cell loss, and increased inflammatory-cell infiltration. Gene expression analysis revealed significant upregulation of inflammatory mediators (NF-κB, TNF-α, IL-6, IL-1β), inflammasome components (NLRP3), and macrophage markers (CD68, CD86, CD163). In parallel, ER stress-related genes (ORMDL3, ATF6) and autophagy-associated genes (NOD2, ULK1, ATG4a) were significantly elevated in diabetic pigs. At the protein level, increased expression of ER stress markers was confirmed in both intestinal regions, while autophagy-related proteins showed less consistent changes and did not fully reflect the observed transcriptional patterns, suggesting a potential disconnect between transcriptional activation and functional autophagic response under diabetic conditions. Chronic hyperglycemia is associated with intestinal inflammation and disruption of cellular stress pathways, including ER stress and autophagy, in a porcine model. These findings provide mechanistic insight into how chronic hyperglycemia contributes to intestinal dysfunction through coordinated alterations in inflammatory signaling, ER stress, and autophagy pathways, identifying these processes as potential targets for therapeutic intervention in diabetes-associated gastrointestinal disease.

Clinical pharmacists enhance safe and high-quality patient care through effective interprofessional collaboration. This study aimed to evaluate pharmacotherapy counseling services provided by clinical pharmacists, assess physician acceptance of recommendations, and determine their impact on patients and the healthcare system. A retrospective observational study was conducted at the University Hospital’s Pharmacotherapy Counseling Unit over a 15-month period. Pharmacotherapy plans of 61 ambulatory patients were analyzed, and therapy modifications were classified according to PCNE V9.1. After clinical pharmacist intervention, the median (IQR) number of prescribed medications significantly decreased from 7.5 (8) to 3 (9) ( p < 0.05) and drug-related problems (DRPs) from 2 (4) to 0 (4) ( p < 0.05). Among patients aged ≥65 years ( n = 22), potentially inappropriate medications were significantly reduced ( p < 0.05). Most DRPs were related to inappropriate drug selection. This study demonstrates the positive impact of clinical pharmacists in improving pharmacotherapy quality in ambulatory care in Bosnia and Herzegovina.