Search Results (2,193)

Diabetes mellitus remains a major metabolic disorder requiring the development of new and effective α-glucosidase inhibitors. The present study aimed to identify, design, and optimize novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-α]pyrimidine derivatives with promising inhibitory activity against the α-glucosidase enzyme using a comprehensive in silico strategy. Approximately 300 molecular descriptors were calculated to characterize a dataset of 32 compounds (Peytam et al.) and to investigate the structural factors governing their biological activity. Based on these descriptors, a multiple linear regression model was developed to predict the inhibitory activities of the compounds against alpha-glucosidase. The developed model demonstrated satisfactory predictive performance and was internally and externally validated to ensure its accuracy, robustness, and reproducibility. In addition, the applicability domain analysis confirmed the reliability of the predictions. Using the validated QSAR model, seven new derivatives were designed with predicted pIC₅₀ values exceeding the maximum activity of the parent compounds. The leverage analysis demonstrated that all newly designed compounds were located within the applicability domain of the model, supporting the reliability of the predictions. To further evaluate their inhibitory potential, molecular docking studies were performed to investigate the interactions between the designed compounds and the α-glucosidase active site. The docking results revealed favorable binding interactions comparable to those reported for known α-glucosidase inhibitors. Furthermore, ADMET analysis indicated generally favorable pharmacokinetic properties, although potential CYP3A4 inhibition-related pharmacokinetic risks were identified and discussed. Molecular dynamics simulations, including replicated runs and MM/GBSA binding free energy calculations, confirmed the stability of the most promising protein–ligand complexes throughout the simulation period. In conclusion, this study proposes a robust and integrated computational workflow combining descriptor generation, QSAR modeling, applicability domain analysis, molecular docking, ADMET prediction, and molecular dynamics simulations for the rational design of potential α-glucosidase inhibitors. The findings highlight the therapeutic potential of the designed derivatives and provide a valuable in silico framework for the future development of antidiabetic agents. Full article

Background/Objectives: Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog for type 2 diabetes and obesity, requires sensitive and high-throughput bioanalytical methods to support pharmacokinetic studies. However, previously reported liquid chromatography–tandem mass spectrometry (LC–MS/MS) assays have been limited by lengthy run times (~18 min) and suboptimal sensitivity. This study aimed to develop and validate a rapid, sensitive LC–MS/MS method for quantifying semaglutide in plasma. Methods: Plasma samples (50 μL) were prepared by acetone-mediated protein precipitation followed by solid-phase extraction. Chromatographic separation was performed on a Cadenza CD-C18 MF column within 9 min, using positive electrospray ionization in multiple reaction monitoring mode with the transitions m/z 1029.4 → 110.1 for semaglutide and m/z 938.9 → 109.9 for liraglutide (internal standard). Validation followed the U.S. Food and Drug Administration (FDA) bioanalytical guidelines. Results: The assay showed a lower limit of quantification of 1 ng/mL with linearity across 1–500 ng/mL (R² = 0.9999), with sharp peak shape and no carryover. Intra- and inter-day accuracies were 95.69–103.76% and 94.93–100.08%, with precision ≤4.50% and ≤5.88%. Recovery (93.05–107.95%) and matrix effects (96.34–104.12%) were consistent across quality control levels, and the analyte was stable under all tested conditions. The method was successfully applied to a pharmacokinetic study in Sprague–Dawley rats following subcutaneous administration of 50 μg semaglutide. Conclusions: The validated method offers shorter analysis time, improved sensitivity, and reduced sample volume compared with previously reported assays, supporting its application in preclinical pharmacokinetic studies of semaglutide and related GLP-1 analogs. Full article

Background: Effective strategies for delivering neuroprotective agents to the brain remain a major challenge due to the poor solubility, rapid metabolism, and low bioavailability of promising molecules, such as 7,8-dihydroxyflavone (7,8-DHF). This small-molecule TrkB receptor agonist exhibits significant antioxidant, neuroprotective properties, and additional effects on metabolic regulation, but its therapeutic potential is limited by unfavorable pharmacokinetic characteristics. Nanotechnology-based delivery systems are increasingly explored to improve drug stability, enhance bioavailability, and facilitate direct nose-to-brain transport following intranasal administration. In this study, lipid nanoparticles encapsulating 7,8-DHF were developed using a fish-oil-based lipid core enriched with ω-3 polyunsaturated fatty acids (DHA and EPA) and naturally derived excipients, including soybean lecithin and ε-polylysine. Methods: The formulation was optimized using a Design of Experiments (DoE) approach based on a 2³ full factorial design, evaluating drug concentration, lecithin concentration, and surfactant type (Pluronic^® F127 or Tween^® 80). The main formulation responses considered were particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency. Results: The optimized nanoparticles exhibited nanometric dimensions (<250 nm); spherical morphology, confirmed by TEM; low polydispersity (PDI < 0.3); and adequate encapsulation efficiency. Stability studies in simulated biological fluids indicated good physicochemical stability for up to 48 h, while interaction studies with mucin suggested a good interaction within the mucus environment. ROS scavenging capacity was confirmed through the DPPH chemical assay, and in vitro experiments on olfactory ensheathing cells, selected as a biologically relevant model for their anatomical localization along the olfactory pathway, showed reduced cytotoxicity of the encapsulated drug compared with the free form. Conclusions: Collectively, these results support the potential application of the developed nanoformulation in the intranasal delivery of 7,8-DHF. Full article

2-Ethylhexyl-4-methoxycinnamate (EHMC) is among the most widely adopted organic UVB filters in commercial sunscreens. Nevertheless, its practical application potential is limited by unfavorable formulation compatibility and safety risks stemming from systemic exposure after topical administration. In this study, an oil-continuous structured gel matrix consisting of EHMC, disteardimonium hectorite (DDH) and dextrin palmitate (DP) was constructed to enhance UVB photoprotection and modulate the plasma exposure profile of EHMC following topical application. Comprehensive characterizations including rheology, XRD, Raman spectroscopy, FTIR spectroscopy, TGA and SEM collectively revealed that the combined incorporation of DDH and DP facilitates matrix structural rearrangement, enables EHMC to bind within the structured network, and promotes the formation of more intact continuous surface films. In vitro SPF assays demonstrated that the finished topical formulation SC-4 delivered superior UVB blocking efficacy compared with the EHMC-only control SC-1; furthermore, SC-4 exhibited improved short-term physical stability under the preset thermal and centrifugal acceleration test conditions. Follow-up skin safety assessments, mass spectrometry imaging (MSI) and pharmacokinetic assays verified that SC-4 elicited no remarkable acute skin irritation across all experimental conditions. Relative to SC-1, the reference formulation with EHMC as the sole UV filter, SC-4 displayed weaker EHMC-related distribution signals in skin tissues, accompanied by lower early plasma EHMC concentrations and a slightly lower AUC_0–48h trend. Collectively, these findings indicate that DDH/DP co-assembly serves as a viable matrix-structuring strategy to modulate EHMC-related skin distribution and early plasma exposure. Further research into UVA blocking performance, photostability, skin retention and transdermal permeation profiles, as well as long-term storage stability, is required to advance the development of broad-spectrum sunscreen formulations built on this novel matrix platform. Full article

Olfactory detection of essential oils (EOs), natural plant-derived mixtures of odorous volatile compounds, stimulates neural pathways involved in emotion, cognitive function, and memory in humans and significantly influences insect behavior (inducing attractiveness or repellency). In this study, the olfactory perception of rose (EO 1, a synthetic mixture with rose aroma), eucalyptus (EO 2), lemon (EO 3), clove (EO 4), rosemary (EO 5), and caraway (EO 6) EOs in untrained human participants was compared to the behavioral responses induced in Tenebrio molitor (adult insects) by EO exposure. Significant differences emerged in the perception of EO odor dimensions (pleasantness, intensity, and familiarity) using a Likert-type scale in untrained participants. The tested EOs elicited different behavioral responses in T. molitor insects, as assessed by repellency, escape, and choice tests. A positive correlation (r = 0.7861, p < 0.05) emerged between EO odor intensity perceived by participants and escape induction in T. molitor adults. GC–MS analysis revealed citronellol, 1,8-cineole, limonene, eugenol, α-pinene, and carvone as the most abundant volatile compounds in EO 1, EO 2, EO 3, EO 4, EO 5, and EO 6, respectively. The EO odor dimensions in participants and insect behavioral responses were also related to the in silico physicochemical/pharmacokinetic properties of the main EO components. Our results provide new insights into the chemical basis of olfactory preferences both in T. molitor adults and humans. Full article

Purpose: To investigate the agreement on perfusion parameters derived from two different commercially available solutions for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with prostate cancer (PCa). Methods: A total of 50 patients (mean age, 71.6; range 56–86) who had undergone radical prostatectomy between December 2021 and September 2022 were included in this retrospective study. All patients had undergone DCE-MRI on a single 3T-MR scanner. Tumor segmentation on MR images was performed by two radiologists in consensus after radiologic-pathologic correlation using topographic maps as a reference standard. Subsequently, four perfusion parameters were calculated by dedicated commercially available solutions from two different vendors. Both solutions adopted a population-based arterial input function and an extended Tofts model as the pharmacokinetic model. The perfusion parameters were as follows; volume transfer constant (K^trans), rate constant (k_ep), volume fraction of extravascular extracellular space (v_e), and volume fraction of plasma (v_p). The differences between paired measurements were compared by Bland–Altman analyses and the reproducibility was evaluated using the intraclass correlation coefficient (ICC). Results: The study population consisted of Gleason score (GS) 6 (n = 12), GS 7 (n = 34), GS 8 (n = 1), and GS 9 (n = 3). Significant differences were found for all parameters (p < 0.0001). Mean differences were as follows: K^trans, −0.2102 (95% confidence interval; −0.2687 to −0.1518); k_ep, −0.7632 (−0.9005 to −0.6258); v_e, −0.1507 (−0.2422 to −0.05907); v_p, −0.02929 (−0.03383 to −0.02476). ICCs for average measures were as follows: K^trans, 0.2989 (−0.2355 to 0.6021); k_ep, 0.6883 (0.4507 to 0.8231); v_e, −0.1331 (−0.9967 to 0.3570); v_p, 0.2653 (−0.3106 to 0.5881). Conclusion: All perfusion parameters were significantly different between the two solutions. Therefore, comparison of perfusion parameters across different solutions is not recommended. Full article

Background/Objectives: Sex-specific differences in the pharmacokinetics of psychotropic drugs are gaining increasing clinical relevance, but only limited data are currently available on sex-specific effects within genetically defined metabolizer phenotype categories. The objective of this study was to assess genotype-dependent sex differences in the metabolic capacity of the drug-metabolizing enzymes CYP2D6 and CYP2C19. Methods: Statistical analyses were performed using linear mixed-effects models with subject-level random intercepts to account for repeated therapeutic drug monitoring (TDM) measurements. Venlafaxine and risperidone were used as probe drugs to find differences in the metabolic capacity of CYP2D6 and escitalopram for CYP2C19. Pharmacokinetic surrogate parameters were the metabolite-to-parent ratio (MPR) for venlafaxine and risperidone and the dose-corrected serum concentration (CD) for escitalopram. Models included sex, metabolizer phenotype, and their interaction, adjusted for age and creatinine production rate (CPR). Sex-specific differences within phenotype groups were assessed using estimated marginal means. Results: Among venlafaxine samples (N = 117) and risperidone samples (N = 73), no significant sex-specific differences in MPR were observed within CYP2D6 metabolizer groups. For escitalopram samples (N = 51), a significant sex difference was observed among CYP2C19 normal metabolizers (NMs), with higher CD in males compared to females. Conclusions: Exploratory analyses suggested a higher metabolic capacity in CYP2C19 NM females treated with escitalopram. Due to the limited sample size, however, this finding should be considered hypothesis-generating. Future studies in larger samples are needed to corroborate whether sex and other factors modulate the metabolic capacity of CYP2C19, e.g., by epigenetic mechanisms. Full article

Flavonoids are a structurally diverse class of plant-derived polyphenolic compounds widely recognized for their pleiotropic biological activities, including antioxidant, anti-inflammatory, and anticancer effects. In oncology, these compounds have demonstrated the ability to modulate key signaling pathways involved in cell proliferation, apoptosis, angiogenesis, and metastasis, highlighting their potential as multitarget therapeutic agents. However, their clinical translation remains significantly limited by unfavorable pharmacokinetic properties, such as poor aqueous solubility, extensive first-pass metabolism, rapid systemic clearance, and consequently low oral bioavailability. In this context, nanotechnology has emerged as a promising strategy to overcome these limitations. This review provides a comprehensive and critical analysis of current nanocarrier-based delivery systems for flavonoids, including polymeric nanoparticles, lipid-based nanocarriers (liposomes, solid lipid nanoparticles, and nanoemulsions), micelles, and cyclodextrin complexes, emphasizing their role in improving drug stability, enhancing cellular uptake, and enabling targeted delivery to tumor tissues through both passive mechanisms, such as the enhanced permeability and retention effect, and active targeting approaches. In addition, recent in vitro and in vivo studies demonstrating the superior antitumor efficacy of nanoencapsulated flavonoids compared to free compounds are discussed. Finally, the major translational challenges, safety considerations, and future perspectives for the clinical application of flavonoid-based nanomedicines in cancer therapy are highlighted. Full article

Background and Objectives: Recent studies suggest that remimazolam, a novel ultra-short-acting benzodiazepine, has an excellent pharmacokinetic and safety profile, favourable for ambulatory procedures. Although remimazolam has been studied as a sole agent for anaesthesia in day case gynaecological surgery, studies assessing its use in combination with other anaesthetics remain scarce. The aim of this study was to investigate the effects of a low-dose remimazolam adjunct on the characteristics of an intravenous propofol–remifentanil anaesthesia regimen. Materials and Methods: A single-centre retrospective observational cohort study was conducted on patients who underwent brief day case gynaecological surgery under general intravenous anaesthesia using remifentanil and propofol from November 2024 to January 2025. The patients were divided into two groups depending on whether they received remimazolam as an adjunct. To account for confounding, propensity scores (PSs) were estimated from baseline characteristics and used to derive stabilised inverse probability of treatment weights (IPTWs). Weighted regression models were then applied to estimate treatment effects on postoperative recovery time measures, consumption of anaesthetics, and incidence of any adverse effects intraoperatively and postoperatively. Cost effectiveness was evaluated using the incremental cost-effectiveness ratio (ICER). Results: The clinical data of 51 patients were retrospectively examined: 32 patients were assigned to the intervention group, and 19 patients were assigned to the reference group; after IPTW and PS trimming, the sum of weights was 22 in the intervention group and 58.8 in the reference group. The use of remimazolam as an adjunct was associated with 3.5 min shorter time to eye opening (p < 0.001) and 3.6 min shorter time to full consciousness (p = 0.002); the total consumption of propofol was decreased by 3 mg/kg (p < 0.001); the median dose of remimazolam adjunct was 0.12 mg/kg, or 10 mg per case. There were no statistically significant adverse effects. ICER was 2.35 € per minute of operating room (OR) time saved. Conclusions: In the setting of day case gynaecological surgery, the addition of remimazolam to a propofol–remifentanil regimen reduced propofol requirements and shortened recovery time without an increase in adverse effects. This may represent a more efficient anaesthetic approach for ambulatory procedures with a comparable safety profile. Full article

Monitoring immunosuppression in kidney transplant recipients remains challenging, as conventional therapeutic drug monitoring (TDM) reflects pharmacokinetic exposure rather than the overall functional immune state. Torque teno virus (TTV), a non-pathogenic virus, has emerged as a potential complementary biomarker of the net state of immunosuppression. This review evaluates the current evidence regarding the utility of TTV load in this context, focusing on its correlation with standard pharmacokinetic markers, the analytical performance of quantitative PCR assays, its role as an integrated marker of immunosuppression, and its predictive value for clinical outcomes. Available data indicate that TTV load shows weak and inconsistent correlations with individual drug levels, such as tacrolimus trough concentrations, supporting its role as a complementary rather than substitutive tool. qPCR-based assays demonstrate generally good sensitivity and reproducibility, although inter-assay variability and lack of standardization remain important limitations. Clinically, higher TTV levels have been associated with an increased risk of opportunistic infections, whereas lower levels have been linked to acute rejection, suggesting a potential association between TTV viremia and immune status. TTV monitoring may represent a promising complementary approach for a more individualized assessment of immunosuppression. However, further prospective and interventional studies are required to validate standardized thresholds and determine whether TTV-guided strategies improve transplant outcomes compared with conventional monitoring. Full article

Fibroblast activation protein (FAP) has emerged as a promising target for the development of cancer radiotheranostics due to its selective overexpression in cancer-associated fibroblasts (CAFs) within the tumor stroma. Affinity and selectivity refer to the binding affinities of FAP inhibitors toward FAP and related family members, whereas the accumulation of radiolabeled-FAP inhibitors varies by tumor type. Although monomeric FAP inhibitors (FAPIs) have shown extraordinary utility in diagnostic imaging, their clinical application in radiotherapy has been limited by short tumor retention times and heterogeneous uptake. To address these challenges, homomultimeric FAPI ligands—featuring two or more identical FAP-targeting motifs—have been developed with the aim of enhancing binding avidity and prolonging tumor residence. This review comprehensively examines the evolution of homomultimeric FAPI ligands, from molecular design and preclinical validation to early clinical implementation. We highlight how dimeric and higher-order multimeric constructs improve tumor retention and therapeutic efficacy compared to monomers, while also discussing the impact of linker chemistry, valency, and scaffold architecture on pharmacokinetics and targeting efficiency. Preclinical studies demonstrate that optimized dimers and trimers achieve superior tumor-to-background ratios and sustained tumor uptake, whereas excessive multimerization can lead to steric hindrance and reduced efficacy. Clinical data from pioneering studies using agents such as [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ and [¹⁷⁷Lu]Lu-DOTAGA.Glu.(FAPi)₂ confirm prolonged tumor retention, encouraging therapeutic responses and a favorable safety profile in advanced cancers. However, translational challenges remain, including the need for better preclinical models that reflect stromal FAP heterogeneity, optimized radiometal–chelator pairs, and standardized dosing protocols for comparative clinical trials. Overall, homomultimeric FAPI ligands represent a significant advance in FAP-targeted theranostics, offering a robust platform for personalized cancer management. Full article

Background/Objectives: Microtubule-targeting agents represent a pillar of cancer chemotherapy; however, their clinical utility is constrained by significant toxicity, pharmacokinetic instability, and susceptibility to multidrug resistance transporters. This study aimed to explore the impact of replacing substituted phenyl rings with a naphthalene moiety in sulfonamide-based colchicine-site ligands, with the goal of identifying new antiproliferative candidates with improved profiles. Methods: We designed, synthesized, and evaluated a library of 35 naphthalene sulfonamides bearing varied aryl groups and sulfonamide nitrogen substituents. We assessed the antiproliferative activity against multiple cancer cell lines. Mechanistic studies, including fluorescence microscopy, cell cycle analysis, and cell death assays, were performed to evaluate the effect of these compounds on microtubule polymerization dynamics and cell fate. Molecular docking and in silico pharmacokinetic profiling were carried out to support the proposed binding mode at the colchicine site and to assess drug-likeness. Results: Exclusively, compounds bearing a trimethoxyphenyl group showed antiproliferative activity in the submicromolar range, thus identifying it as a structural requirement. The most potent compound (2) reached double-digit nanomolar IC₅₀ values (67–104 nM) across multiple cancer cell lines. Microscopy confirmed intracellular disruption of microtubule polymerization. Unlike colchicine, these compounds did not induce canonical mitotic arrest but instead triggered apoptotic cell death. In silico analyses supported binding at the colchicine site and revealed favorable predicted pharmacokinetic properties. Conclusions: The naphthalene sulfonamides described herein demonstrate potent antiproliferative activity through a distinct mechanism compared to colchicine, and their favorable in silico profiles position them as promising candidates for further development as antitumor agents. Full article

The pharmacokinetics (PK) and pharmacokinetic–pharmacodynamic (PK/PD) relationships of cefquinome in small ruminants remain incompletely characterized, particularly for long-acting (LA) formulations. This study evaluated cefquinome disposition after intravenous (IV), subcutaneous (SC) and LA subcutaneous (SC-LA) administration in lactating sheep and goats using nonlinear mixed-effects models (NLMEs) and Monte Carlo (MC) simulations. Cefquinome exhibited low volumes of distribution (0.21–0.31 L/kg), with goats showing higher clearance and shorter terminal half-lives than sheep. The SC-LA formulation reduced the absorption rate constant and increased both the mean absorption time and terminal half-life by 4–6-fold, resulting in sustained systemic exposure over 48 h. PK/PD analysis showed higher PK/PD cut-off values for the LA formulation, with values of 0.125 μg/mL for the fT > MIC index and 0.25 μg/mL for the fAUC/MIC index, respectively, whereas IV and SC regimens achieved lower thresholds. MC simulations indicated that only the LA formulation achieved ≥ 90% probability of target attainment (PTA) values at MICs equivalent to tentative epidemiological cut-off values (TECOFF) for respiratory pathogens. Notably, fAUC/MIC provided a more informative descriptor of efficacy for the LA formulation. These findings highlight the advantage of LA formulations and demonstrate improved performance compared with conventional dosing regimens in sheep and goats. Full article

Extracellular vesicles (EVs), naturally secreted by cells as nanoscale lipid bilayer structures, have become a research hotspot in biomedicine owing to their excellent biocompatibility, low immunogenicity, and inherent ability to cross biological barriers. This review systematically summarizes recent advances in EVs as natural nanomaterials. The biogenesis mechanisms of EVs are outlined, followed by a comparative analysis of the advantages and limitations of mainstream isolation and purification methods, including ultracentrifugation, size-exclusion chromatography, and microfluidic technologies. The core guiding role of the MISEV 2023 guidelines in standardizing EV characterization is highlighted. Engineering strategies to enhance EV therapeutic efficacy—including parental cell modification, post-isolation physicochemical tailoring, and hybrid vesicle construction—are then reviewed, followed by a comparative analysis of mainstream isolation technologies, emphasizing the trade-offs between purity and yield. Distinct from conventional descriptive reviews, this article establishes a strong biomimetic framework to scrutinize engineering strategies, including parental cell genetic modification, post-isolation physicochemical tailoring, and the fabrication of hybrid bio-synthetic vesicles. The design principles governing targeted delivery, drug-loading physics, and in vivo pharmacokinetic stability are critically evaluated through the lens of biomimetic nanotechnology. Furthermore, we identify critical research gaps and technical bottlenecks impeding clinical translation, offering a forward-looking perspective on the evolution of EVs from natural messengers into standardized precision medicine platforms. Full article

Background: Dental caries is a chronic disease mediated by biofilm, which is caused by Streptococcus mutans, and enamel genetics modulates susceptibility. The variants of ENAM might alter the adhesion of enamel and bacteria. One important anti-viral target is sortase A (SrtA), which restricts colonization but does not have an impact on bacterial survival. Aim: The aim of this study was to find out the relationship between ENAM rs3796704 and dental caries vulnerability among adult Iraqi Arab females and to assess the antibiofilm capacity of eugenol and cinnamic acid against S. mutans SrtA using molecular docking, ADMET prediction, and molecular dynamics modeling. Methods: A case–control study was done on 240 women (aged 25–30 years; 120 caries, 120 controls). HRM real-time PCR was done to genotype ENAM rs3796704. An analysis of allelic and genotypic distributions was done using chi-square tests and odds ratios (p < 0.05). An in silico docking analysis aimed at SrtA (PDB: 4TQX) was performed in AutoDock Vina, and this was followed by ADMET profiling and a 50 ns molecular dynamics simulation (OPLS4/TIP3P, NPT 300 K/1 atm). Results: The level of the G allele was found to be lower in the cases than in the controls (60% vs. 70; OR = 0.6429; p = 0.02), but the level of the A allele was found to be higher in the cases (40% vs. 30; OR = 1.5556; p = 0.02). Docking showed a minor difference in binding affinities with eugenol (−4.961 kcal/mol) and cinnamic acid (−4.939 kcal/mol) as compared with chlorhexidine (−4.692 kcal/mol). Both compounds showed stable binding for more than 50 ns as well as desirable predicted pharmacokinetics. Conclusions: The caries vulnerability in this sample was associated with ENAM rs3796704. Eugenol and cinnamic acid undergo stable dissociative interactions with SrtA and were found to have favorable safety profiles in silico. Therefore, they may be considered as adjunctive anti-virulence agents in the prevention of caries. Full article