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.

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.

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.

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.

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.

Background Recent research highlights the pivotal role of gut microbiota and bile acids as modulators of metabolic homeostasis in type 2 diabetes (T2D). The concomitant use of probiotics and ursodeoxycholic acid (UDCA) may potentiate glycemic and lipid control via complementary mechanisms. Objective To evaluate the metabolic effects of probiotic supplementation and its combination with UDCA in metformin-treated T2D patients. Methods In this monocentric, prospective, randomized, double-blind, controlled trial, 90 patients with T2D on metformin therapy were randomized into three groups: metformin-only (MG), metformin plus probiotic (MPG), and metformin plus probiotic plus UDCA (MPUG). The intervention lasted 4 weeks. Primary outcomes included changes in fasting glucose, postprandial glucose and HbA1c. Secondary outcomes included lipid profile, C-reactive protein (CRP), and fecal levels of probiotics and UDCA. Two visits were conducted during the study - at the beginning and at the end. Visits involved patient interviews, clinical data collection, anthropometric measurements, blood biochemical analyses, and stool sample analysis for the presence of probiotic culture and UDCA concentrations. Results After 4 weeks, the MPUG group showed a significant reduction in fasting glucose (−1.7 mmol/L; 95% CI: −2.2 to −1.2), postprandial glucose (−1.3 mmol/L; 95% CI: −1.8 to −0.7), and HbA1c (−0.49%; 95% CI: −0.66 to −0.31) compared to the MG group. Total cholesterol and LDL cholesterol were also significantly reduced, while HDL increased. The concentration of Lactobacillus rhamnosus GG was highest in the MPUG group. No serious adverse events were reported. Conclusion Co-administration of probiotics and UDCA for four weeks in metformin-treated T2D patients significantly improves short-term glycemic control and lipid profiles. These promising results warrant validation in larger, longer-term clinical trials.

Oxidative stress is a critical pathophysiological factor in sepsis. Ursodeoxycholic acid (UDCA), a bile acid with anti-inflammatory, antioxidant, and anti-apoptotic properties, may protect against lipopolysaccharide (LPS)-induced myocardial injury. In an experimental study, 32 male Wistar rats were randomly assigned to four groups: control, LPS, UDCA, and UDCA + LPS. UDCA was administered orally for 10 days prior to LPS-induced endotoxemia. Serum levels of high-sensitive troponin I (hsTnI), homocysteine, and oxidative stress markers were measured, and immunohistochemistry and immunofluorescence were used to assess inflammation (nuclear factor kappa B, NF-κB), apoptosis (caspase 3), and signaling pathways related to protein kinase B (Akt)/NF-κB and silent information regulator 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1). UDCA pretreatment significantly reduced myocardial pathological changes, serum hsTnI, homocysteine, and total oxidative stress compared with LPS alone. It enhanced catalase (CAT) activity and glutathione (GSH) levels while lowering thiobarbituric acid reactive substances (TBARS) and nitrite concentrations in cardiac tissue. UDCA modulated cellular signaling by decreasing Akt phosphorylation and activating the SIRT1/Nrf2/HO-1 pathway. These results indicate that UDCA protects the heart from LPS-induced damage by reducing oxidative stress, inflammation, and apoptosis. UDCA modulates cellular signaling by decreasing pro-inflammatory pathways and activating anti-inflammatory pathways associated with SIRT1/Nrf2/HO-1 signaling, emphasizing its key role in myocardial protection during sepsis.

Translocator protein (TSPO) regulates mitochondrial function, inflammation, and oxidative stress; however, its role in acute myocardial injury (MI) remains incompletely understood. While previous studies have examined TSPO ligands in cardiac injury, the interplay between TSPO modulation and nitric oxide (NO) signaling in AMI has not been systematically investigated. The aim of this study was to investigate the effects of TSPO modulation by PK11195, alone or in combination with nitric oxide synthase (NOS) inhibition by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME), on cardiometabolic, inflammatory, oxidative stress, and histopathological parameters in an experimental model of isoprenaline-induced MI in rats. Male Wistar albino rats were divided into four groups: control (C); isoprenaline + saline-treated (ISO); isoprenaline + PK11195-treated (IP); and isoprenaline + PK11195 + L-NAME-treated (IPLN) groups. Isoprenaline administration induced MI, evidenced by elevated cardiac biomarkers, electrocardiographic (ECG) alterations, and histopathological damage. PK11195 treatment significantly attenuated MI and reduced pro-inflammatory cytokine levels while increasing anti-inflammatory cytokine levels, indicating protective effects. Nevertheless, TSPO modulation was associated with adverse metabolic effects, notably elevated fibrinogen and plasma homocysteine levels. Co-administration of L-NAME mechanistically demonstrated that NO availability is essential for PK11195 cardioprotective effects, as NOS inhibition partially abolished cardioprotection and modified oxidative stress parameters. Overall, TSPO modulation exerts complex actions in acute MI through regulating mitochondrial function, inflammatory signaling, and NO pathways, suggesting that TSPO is a potential, multifaceted therapeutic target.

Diabetes mellitus and inflammatory bowel disease are chronic inflammatory disorders characterized by immune dysregulation and rising global prevalence. Epidemiological studies increasingly suggest a bidirectional association between the two conditions, linked through shared mechanisms of intestinal barrier dysfunction, microbial dysbiosis, and sustained innate immune activation. Activated macrophages play a central role in driving mucosal inflammation through polarization toward a pro-inflammatory M1 phenotype, accompanied by increased production of inflammatory cytokines. These mediators disrupt tight junctions, induce epithelial apoptosis, and perpetuate cycles of immune activation and tissue injury. This macrophage–cytokine axis not only amplifies local inflammation but also sustains chronic barrier dysfunction, creating a pathogenic overlap between diabetes mellitus-associated intestinal injury and intestinal bowel disease. In this study, we used a low dose streptozotocin and high-fat diet-induced diabetic Sprague–Dawley rat model in both sexes to investigate the effects of chronic hyperglycemia on intestinal inflammation, with particular emphasis on macrophage activation and pro-inflammatory cytokine responses. We found inflammation in both small and large intestines with mucosal injury and barrier disruption, and immune activation involving macrophages and enhanced expression of CD68, iNOS, TNF-α, and IL-6. Female rats were more susceptible to gut-related inflammatory changes due to diabetes. These findings suggest a complex interplay between epithelial stress, immune signaling, and microbial factors supporting the role of intestinal inflammation in the immune–metabolic interaction in diabetes-associated intestinal changes, which may contribute to the pathogenesis of inflammatory bowel disease.

In obstetrics, diazepam is commonly used to treat anxiety, insomnia and as a second‐line treatment for seizures in preeclampsia and eclampsia. However, the effects of diazepam on the oxidative balance and vascular function of the umbilical circulation are still insufficiently studied. In this study, we investigated the effects of suprapharmacological concentrations of diazepam in an in vitro model of human umbilical artery (HUA) injury, induced by incubation with 1 mM homocysteine, representing experimental conditions that mimic hyperhomocysteinemia. HUAs were divided into four groups: control (C), diazepam (D) alone (100 μmol/L), homocysteine (Hcy) alone (1 mM), and combined treatment (HcyD). For oxidative stress assays, data were obtained from 8–10 individual HUA samples per group, with lipid peroxidation, nitrite (NO2 −) levels, and SOD, CAT, and GSH activities determined spectrophotometrically. Histological and TUNEL analyses were performed in triplicate (n = 3 per group), whereas vascular reactivity experiments, using an organ bath system, included six individual vessel samples per group. Statistical analysis was performed using the paired Student′s t‐test (p < 0.05). Diazepam alone significantly reduced superoxide dismutase (SOD) activity, indicating an apparent impairment of antioxidant defenses. In contrast, concomitant treatment under hyperhomocysteinemia lowered the levels of thiobarbituric acid reactive substances (TBARSs) and NO2 −, suggesting partial protection against lipid peroxidation and nitrosative stress. Histologically, diazepam preserved arterial structure with minor subendothelial changes, whereas cotreatment reduced homocysteine‐induced endothelial disruption, smooth muscle disarray, and medial connective tissue loss. Apoptotic index was significantly reduced with cotreatment comparing to hyperhomocysteinemia, whereas diazepam alone showed values similar to control. Functionally, diazepam significantly reduced serotonin‐induced contraction of HUAs, but this vascular effect was attenuated under hyperhomocysteinemic conditions. Overall, concomitant treatment with diazepam partially attenuated oxidative and structural changes induced by hyperhomocysteinemia in our experimental setting, in a preclinical model mimicking selected pathophysiological aspects of preeclampsia.

The development of advanced macromolecular systems with tailored structural and functional properties is a key objective in modern materials science, particularly for biomedical applications such as targeted drug delivery. In this study, hydrogel (HG), a polymer-based formulation, was investigated as a functional carrier for the enhanced intradermal and transdermal delivery of propranolol hydrochloride (PRO-HCl), a highly water-soluble model compound, and its potential was compared to other vehicles easily obtained by pharmacists: ointment (OM), liposomal cream (LCR), and microemulsion (ME). The formulations were characterized by their physicochemical and rheological characteristics, and evaluated in vitro and ex vivo using vertical diffusion cells equipped with synthetic membranes, intact porcine skin, and skin pretreated with solid microneedles (MNs). The HG formulation exhibited superior release performance (2396.85 ± 48.18 μg/cm2) and the highest intradermal drug deposition (19.87 ± 4.12 μg/cm2), while its combination with MNs significantly enhanced transdermal permeation (p = 0.0017). In contrast, the synergistic effect of MNs and ME led to a pronounced increase in drug accumulation within the skin (up to 60.3-fold). These findings highlight the crucial role of matrix composition and properties in modulating molecular transport through biological barriers. The study demonstrates that polymeric HGs represent versatile, functional materials with tunable structural and mechanical features, suitable for controlled release and potential systemic delivery applications.

Background/Objectives: The COVID-19 pandemic accelerated the inappropriate use of antibiotics, amplifying the global threat of antimicrobial resistance (AMR), particularly in resource-limited healthcare settings. This study investigated AMR patterns in a tertiary care hospital, focusing on the impact of the COVID-19 pandemic on invasive bacterial pathogens. Methods: This retrospective observational study was conducted at the University Clinical Centre of the Republic of Srpska, analyzing AMR data from invasive bacterial isolates collected between 2015 and 2024, and assessing correlations between antibiotic utilization and resistance patterns during the study periods. Results: Among 4718 invasive bacterial isolates, Acinetobacter spp. (26.7%) and K. pneumoniae (20.8%) were the most prevalent. A significant increase in invasive isolates was observed during the COVID-19 period, particularly for K. pneumoniae (p = 0.003), P. aeruginosa (p = 0.017), Acinetobacter spp. (p = 0.013), and E. faecium (p = 0.028). The highest multidrug-resistant (MDR) rates were observed in Acinetobacter spp. (97% during COVID-19) and K. pneumoniae (>80% post-COVID-19). Resistance increased significantly in K. pneumoniae to cephalosporins, fluoroquinolones, and carbapenems, and in P. aeruginosa and Acinetobacter spp. to carbapenems, while P. aeruginosa resistance to aminoglycosides declined. Strong correlations were found between carbapenems use and Acinetobacter spp. resistance (r = 0.861, p = 0.001), and vancomycin use and E. faecalis resistance (r = 0.798, p = 0.006). Moderate correlations were also observed between carbapenems use and resistance of K. pneumoniae and P. aeruginosa. Conclusions: These findings highlight the profound impact of the COVID-19 pandemic on AMR dynamics, particularly among Gram-negative pathogens, and underscore the urgent need for strengthened antimicrobial stewardship and targeted surveillance to curb the spread of MDR pathogens, especially in resource-limited hospitals.