Search Results (13,862)

Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder characterized by chronic inflammation, insulin resistance, and reproductive dysfunction. Although empagliflozin, a sodium-glucose cotransporter-2 inhibitor, has demonstrated anti-inflammatory and metabolic benefits, its molecular mechanisms in PCOS remain poorly understood. This study investigated the anti-inflammatory mechanisms of empagliflozin in PCOS using network pharmacology, molecular docking, and molecular dynamics simulations. Potential drug targets were identified using SwissTargetPrediction and SuperPred, while PCOS- and inflammation-related genes were obtained from GeneCards. Overlapping targets were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein–protein interaction network, and hub gene analyses. Molecular docking and 50 ns molecular dynamics simulations were performed to evaluate binding affinity and complex stability. Key inflammatory targets identified included TNF, IL6, IL1B, TLR4, STAT3, and PTGS2, with significant enrichment in cytokine-mediated signaling, TNF signaling, and NF-κB pathways. Empagliflozin showed strong binding affinities for PTGS2 (−9.0 kcal/mol) and TLR4 (−8.8 kcal/mol), while molecular dynamics simulations demonstrated stable protein–ligand complexes throughout the simulation. These findings suggest that empagliflozin may alleviate PCOS-associated inflammation by modulating the TLR4/NF-κB/PTGS2 signaling axis, supporting its potential as a repurposed therapeutic agent for PCOS and providing a foundation for future experimental validation. Full article

Liver-targeted drug delivery offers opportunities to increase therapeutic exposure at sites of hepatic disease while limiting systemic toxicity; however, successful targeting requires more than preferential accumulation of a carrier within the liver. This narrative review critically summarizes recent advances in synthetic, biological, and biomimetic delivery platforms, including lipid, polymeric, inorganic, and protein-based nanoparticles, nucleic acid nanocarriers, extracellular vesicles, plant-derived nanovesicles, cell-mediated systems, and cell membrane-coated nanoparticles. A literature search was conducted using PubMed, Web of Science, and Embase, with emphasis on studies published during the last decade and updated through 24 August 2026. Particular attention is given to the biological determinants of hepatic biodistribution, including sinusoidal architecture, physicochemical carrier properties, protein corona formation, receptor–ligand interactions, and disease-associated alterations in the hepatic microenvironment. The review distinguishes organ-level hepatic accumulation from cell-specific uptake and productive intracellular delivery and discusses strategies directed toward hepatocytes, hepatic stellate cells, Kupffer cells and other macrophages, liver sinusoidal endothelial cells, neutrophils, and additional immune-cell populations. Major delivery platforms are critically compared with respect to the evidence supporting targeting specificity, cargo compatibility, administration route, reported safety and immunogenicity, manufacturability, analytical characterization, and translational maturity. Particular consideration is given to extracellular vesicle- and plant-derived nanovesicle-based approaches, for which biological activity, biodistribution, standardization, and scalability remain important areas of investigation. Overall, current research in liver-targeted delivery is increasingly focused on moving beyond nonspecific organ accumulation toward disease-adapted, cell-specific, and intracellularly productive delivery, although substantial biological, manufacturing, and regulatory challenges remain before many emerging approaches can achieve routine clinical translation. Full article

Standard pharmacotherapy for mental disorders, including depression and anxiety, is supported by extensive clinical validation and international treatment guidelines. However, it is frequently associated with limitations such as adverse side effects, low patient adherence, and the risk of relapse. Conventional approaches rely primarily on antidepressants, anxiolytics, mood stabilizers, neuroleptics, and stimulants, which modulate monoaminergic, GABAergic, and dopaminergic neurotransmission. Recently, preclinical and emerging clinical studies have suggested that selected natural substances—specifically mushroom-derived compounds and well-established medicinal plants—may offer complementary therapeutic pathways. This narrative review critically evaluates the pharmacological efficacy, mechanisms of action, and safety profiles of selected natural compounds, including psilocybin-related tryptamines, Hericium erinaceus, ibotenic acid/muscimol from Amanita muscaria, ergothioneine, as well as notable botanical agents (e.g., Hypericum perforatum, Valeriana officinalis). We systematically distinguish between robust human clinical data (e.g., psilocybin-assisted therapy) and preliminary in vitro/in vivo findings. Particular attention is paid to their neurotrophic, anti-inflammatory, and neuromodulatory properties, while emphasizing substantial safety concerns, including intoxication risks associated with isoxazole derivatives, and potentially severe cytochrome P450-mediated drug–drug interactions. Ultimately, while certain natural compounds show promise as adjunctive interventions, most remain strictly investigational and cannot replace evidence-based conventional pharmacotherapy without further long-term, large-scale randomized controlled trials. Full article

Invasive fungal infections can be life-threatening, particularly in patients with impaired immunity, yet treatment remains limited to a few antifungal drug classes. During infection, fungal pathogens encounter changes in temperature, nutrient availability, immune pressure and drug exposure that challenge their growth and survival. tRNA modifications may contribute to adaptation by supporting tRNA stability, aminoacylation and codon decoding. Studies in Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans have linked conserved tRNA-modification pathways to fungal development, host interaction, stress adaptation, virulence and the response to 5-fluorocytosine, with evidence ranging from genetic and infection phenotypes to biochemical characterization of modification reactions. In this Review, we examine how these studies connect modification chemistry and substrate tRNAs with translation, protein output and infection phenotypes. We also draw on mechanistic studies from model organisms and plant-pathogenic fungi to clarify translational links that remain unresolved in human fungal pathogens. We conclude by discussing when tRNA-modification pathways become functionally limiting under host-associated conditions and how they may alter antifungal responses. Full article

The growing accumulation of microplastics in marine ecosystems, coupled with the presence of emerging contaminants such as pharmaceuticals, represents an environmental problem that has received little attention to date. The present study evaluates the potential of microplastics to act as transport vectors for pharmaceuticals through their adsorption onto two plastic polymers widely used today: polyethylene terephthalate (PET) and medium-density polyethylene (MDPE) in seawater. As a control, the same experiments were conducted in ultrapure water (Milli-Q). Both plastics were exposed to a mixture of 29 pharmaceuticals belonging to different therapeutic classes over a 28-day period, with sampling conducted at various time intervals. The identification, quantification, and characterization of the compounds were performed using ultra-high-performance liquid chromatography coupled with mass spectrometry detection. Statistical analysis was performed using R-Studio software. Outcomes reveal that the type of polymer significantly influences adsorption, with MDPE being more efficient than PET. In contrast, the type of water and the therapeutic class of the drugs were not identified as determining factors. Furthermore, a positive, albeit moderate, correlation was observed between the hydrophobicity of the pharmaceutical and its adsorption efficiency on MDPE. These findings suggest that hydrophobic interactions play a key role in the adsorption of drugs onto microplastics, providing a solid foundation for future research, such as predictive models or mitigation strategies in aquatic ecosystems. Full article

Nanoparticle-based drug delivery systems have become an important component of modern nanomedicine, enabling improved drug protection, controlled release, targeted delivery, and the modulation of pharmacokinetic behavior. Their therapeutic performance is governed by physicochemical properties such as size, shape, surface chemistry, and material composition, which influence biological interactions, biodistribution, cellular uptake, and clearance. This review examines major nanoparticle platforms, including polymeric, lipid-based, inorganic, carbon-based, and hybrid systems, together with passive and active targeting and endogenous and externally triggered release strategies. Current and emerging applications in oncology, infectious diseases, central nervous system disorders, gene therapy, and vaccines are discussed alongside theranostic and combination-delivery approaches. Particular emphasis is placed on computational modeling, artificial intelligence, and digital twins for formulation optimization and personalized nanomedicine. Key barriers to clinical translation, including manufacturing scalability, biological variability, limitations of EPR-mediated targeting, regulatory standardization, and long-term safety, are critically evaluated. Finally, emerging directions in sustainable nanomanufacturing and biomimetic delivery are discussed. By integrating biological mechanisms with computational, manufacturing, regulatory, and clinical considerations, this review provides a translational perspective on advancing nanoparticle drug-delivery systems from laboratory development toward clinical implementation. Full article

Bioactive polysaccharides (e.g., fucoidan, β-glucans, and medicinal plant polysaccharides) contain functional groups that interact with drug molecules, and some also retain their own biological activities. Through reversible noncovalent interactions, they can associate with small-molecule drugs and form supramolecular nanocomplexes, defined here as nanoscale assemblies in which the polysaccharide is a main structural component and its association with the drug contributes to assembly or drug retention. Multicomponent composites and bulk local matrices are discussed separately as related or extended systems. The review covers hydrogen bonding, hydrophobic association, electrostatic complexation, π–π stacking, and the cooperation among these interactions, together with the effects of pH, ionic strength, concentration, and solvent composition. Nanoprecipitation/solvent exchange, polyelectrolyte complexation, direct aqueous self-assembly, and microfluidic-assisted assembly are compared with respect to nanostructure formation, process control, and reproducibility. Molecular, colloidal, solid-state, and computational evidence is examined together when interpreting structure–assembly–performance relationships. Reported advantages include improved drug dispersibility, colloidal stability, release control, bioavailability, cellular uptake, biodistribution, and safety. In some systems, the polysaccharide itself may also contribute to therapeutic effects in tumors, inflammatory diseases, and wound healing. Related local-matrix systems are considered separately. Further development of these nanocomplexes will require better quantitative analysis of assembly mechanisms, more consistent polysaccharide characterization, careful biocompatibility assessment, scalable preparation, and longer-term safety evaluation. Full article

Cancer remains a major global health challenge, requiring innovative diagnostic and therapeutic strategies. Cell culture models are essential tools in cancer research. While traditional two-dimensional (2D) cultures are widely used because of their accessibility and simplicity, they inadequately represent the tumor microenvironment. This review provides a molecular perspective on the biological differences between 2D and 3D cancer models, emphasizing extracellular matrix signaling, mechanotransduction, metabolic adaptation, tumor heterogeneity, and therapeutic resistance rather than a general comparison of culture systems. It discusses the limitations of 2D models and highlights the advantages of 3D systems, including spheroids and organoids, for more accurately recapitulating the tumor microenvironment and improving the predictive value of anticancer drug testing. This narrative review synthesizes current evidence on the roles of 2D and 3D cell culture methods in oncology. The literature was searched in PubMed, Google Scholar, and Web of Science from 2015 to 2026 using keywords including “2D cell culture,” “3D cell culture,” “spheroids,” “organoids,” and “cancer.” Studies were eligible for inclusion if they addressed cancer research using 2D or 3D cell culture models and provided relevant experimental, preclinical, or translational evidence, particularly regarding tumor microenvironment, extracellular matrix signaling, cellular interactions, therapeutic response, or molecular mechanisms. Studies unrelated to cancer or 2D/3D culture models, duplicate records, and publications lacking relevant primary data were excluded. Study selection was performed by screening titles and abstracts followed by full-text assessment according to the predefined eligibility criteria. Seminal studies were also included when considered relevant to the conceptual framework of the review. Findings were synthesized narratively without quantitative analysis. 2D cultures limit cell–cell and cell–extracellular matrix interactions, reducing the applicability of findings to in vivo conditions. In contrast, 3D cultures better reproduce oxygen and nutrient gradients and cellular interactions, providing a more realistic representation of the tumor microenvironment. Recent advances in 3D systems have improved predictive accuracy for drug screening and personalized medicine. Both 2D and 3D culture methods possess unique strengths and limitations. Used in complementary ways, they can improve the translation of in vitro findings to in vivo and clinical applications, accelerating progress in cancer research and therapeutic development. Full article

Background: In this study, two cocrystals of diclofenac acid (DCA) with the coformers theophylline (THEO) and isonicotinamide (ISNT) were prepared. Subsequently, nanococrystals were generated from these cocrystals using a top-down wet media milling approach. Methods: Critical process parameters such as milling time, milling volume, drug loading percentage, bead volume, and dispersion media were optimized to achieve the desired particle size distribution. The nanococrystals were characterized using dynamic light scattering (DLS), polarized light microscopy (PLM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Results: In vitro dissolution studies revealed that nanococrystals of DCA-ISNT (DE_0–120 = 22.5% at pH 1.2 and DE_0–120 = 58.7% at pH 4.5) and DCA-THEO (DE_0–120 = 18.5% at pH 1.2 and DE_0–120 = 48.2% at pH 4.5) exhibited superior dissolution performance compared to DCA nanocrystals (DE_0–120 = 12.5% at pH 1.2 and DE_0–120 = 39.0% at pH 4.5), with the dissolution advantage decreasing as the pH of the medium increased. The improved dissolution behaviour was a complex interplay of factors including particle size distribution, surface wetting kinetics, exposure of hydrophilic/hydrophobic functional groups during dissolution, nanococrystal microenvironmental pH, DCA’s ionization behaviour, lattice energy, and intermolecular interaction strengths. Additionally, nanococrystals exhibited a significantly higher flux rate in simultaneous gastric transfer dissolution and flux studies compared with DCA, likely due to higher apparent solubility and superior diffusion through the unstirred water layer (UWL). Pharmacokinetic studies confirmed that nanococrystals DCA-ISNT NCC (AUC_0–∞ = 3062.65 ± 526.91 ng/mL·h) outperformed DCA nanocrystals (AUC_0–∞ = 2352.53 ± 537.78 ng/mL·h), DCA-THEO NCC (AUC_0–∞ = 2222.96 ± 151.19 ng/mL·h) and the cocrystals in terms of pharmacokinetic performance. Conclusions: The findings indicate that DCA-ISNT NCC exhibited superior pharmacokinetic performance and, together with the enhanced dissolution and flux properties of the nanococrystals, demonstrates their potential for enhanced therapeutic efficacy. Full article

Antimicrobial resistance is a growing global health challenge, highlighting the need for new bioactive compounds from medicinal plants. Vepris nobilis is traditionally used in East Africa for treating infections and respiratory disorders; however, its essential oil (EO) composition and antimicrobial mechanisms remain poorly characterized. This study investigated the chemical composition and antimicrobial activity of V. nobilis EO, along with an in silico evaluation of its major constituent, germacrene D. The EO was extracted by hydrodistillation and analyzed using gas chromatography-mass spectrometry (GC–MS). Its antimicrobial activity was evaluated against 26 bacterial and 4 fungal strains using disc diffusion, broth microdilution, and MBC/MFC (Minimum Bactericidal Concentration/Minimum Fungicidal Concentration) assays. Germacrene D showed stronger activity than the EO, particularly against both multidrug resistant (MDR) and non-MDR Gram-negative bacterial strains (MIC = 10 µg/mL), with bactericidal and fungicidal effect. Molecular docking of germacrene D against two clinically relevant enzymes—dehydrosqualene synthase (CrtM) from Staphylococcus aureus and SWISS-modeled sterol 14-α-demethylase (CYP51) from Penicillium funiculosum—suggested potential interactions with both targets, with a favorable predicted binding affinity for CrtM (−7.654 kcal/mol) and for CYP51 (−5.898 kcal/mol). These findings provide preliminary insights into a possible antimicrobial mechanism, although experimental validation is needed to confirm this hypothesis. ADMET analysis suggested favorable drug-like properties despite limited solubility. These findings provide scientific support for the traditional use of V. nobilis leaves in the treatment of respiratory infections and highlight germacrene D as a promising lead compound for further antimicrobial development. Full article

Chronic kidney disease (CKD) affects more than 10% of the global population and represents one of the leading causes of mortality. This study aimed to assess the pharmacotherapy of hospitalized patients aged ≥ 65 years with CKD, focusing on the prevalence of polypharmacy, potentially inappropriate medications (PIMs), potentially clinically significant drug–drug interactions (DDIs), the use of renal-risk drugs (RRDs). A prospective observational study was conducted at the Department of Nephrology and Dialysis of University Hospital Dubrava, including 100 participants. A clinical pharmacist obtained the Best Possible Medication History (BPMH) within 24 h of hospital admission. A total of 1324 comorbidities were recorded (median 12 per patient), along with 985 prescribed medications. Polypharmacy (5–9 drugs) was observed in 43% of patients, while excessive polypharmacy (≥10 drugs) was present in 48%. A total of 258 PIMs were identified, with 89% of patients having at least one PIM (mean 2.6 per patient). Nearly 94% of patients had significantly impaired renal function (G3–G5), and 82% were exposed to inappropriately prescribed RRDs. Contraindicated medications based on renal function were identified in 62% of patients, while 52% had at least one medication prescribed at an unadjusted dose. A total of 1097 potentially clinically significant DDIs were identified, with a mean of 10.9 interactions per patient. The results indicate a high prevalence of polypharmacy, PIMs, potentially clinically significant DDIs and inappropriately prescribed RRDs among older hospitalized patients with CKD, increasing the risk of adverse events and unfavorable treatment outcomes. The findings highlight the importance of the 24 h period following hospital admission as an early opportunity for identifying medication-related problems and optimizing pharmacotherapy in highly vulnerable patients, such as elderly patients with CKD. The study also emphasizes the importance of early involvement of a clinical pharmacist in the pharmacotherapy review and obtaining the BPMH. Full article

Starch, a natural source of energy in the form of glucose chains, is widely utilized in various industrial and scientific fields. In its native state, starch is thermally unstable and undergoes gelatinization. Physicochemical modifications of starch aim to increase its thermal and structural stability while simultaneously enhancing its reactivity by introducing new functional groups. The primary objective of this study was to develop thermally stable and economically viable starch-based drug carriers capable of the controlled release of a negatively charged component sourced from aronia extract. Potato starch underwent a series of chemical modifications, specifically quaternary amine etherification, citric acid esterification, and/or hydrothermal modification. The characterization involved determining several parameters: the degree of amino substitution groups; starch particle size using a laser particle size analyzer; viscosity and pH; gelation temperature and heat capacity measured by scanning calorimetry (DSC); mass degradation analyzed via thermogravimetric analysis (TG); crystallinity determined by X-ray diffraction (XRD); potential intermolecular interactions studied by Fourier-Transform Infrared Spectroscopy with Attenuated Total Reflectance (FTIR-ATR); and the rate of chlorogenic acid release from aronia extract tablets quantified by spectrophotometry. The highest cationization results were achieved using citrate starches, reaching up to 86%. The combined application of citric acid esterification and cationization, coupled with an annealing process, resulted in increased viscosity, amorphousness, and enzyme resistance of the starch. Citric acid esterification significantly improved the thermal stability of the starch. Furthermore, FTIR studies revealed the formation of electrostatic interactions between the functional groups of the starch and the components of aronia extract. The amount of chlorogenic acid released showed significant variation (70–100%) depending on the type of starch modification. Collectively, these studies confirmed that both hydrothermal and chemical modifications influence the thermal and structural stability of the starch. Utilizing all combination modification strategies ensured the production of highly promising carriers for active substances. Full article

Cannabis use is expanding rapidly across the United States, yet product quality and consumer safety knowledge remain significant public health concerns. This cross-sectional study surveyed 325 adults in Florida dispensary customers (n = 185) and general public participants (n = 140) to compare cannabis use patterns, purchasing behaviors, and safety awareness. Cannabinoid gummy products were characterized using texture analysis; oil and topical formulations were evaluated for label accuracy by high-performance liquid chromatography (HPLC) against USP specifications (90–110% of label claim). Inter-laboratory variability accelerated stability testing, and a machine learning microsimulation projecting knowledge trend (2026–2031) were also conducted. Texture analysis revealed substantial variability in mechanical properties across gummy brands. Oil and topical formulations demonstrated generally acceptable labeling accuracy, though significant inter-laboratory variability in CBD quantification was observed. Dispensary respondents reported more frequent cannabis use, stronger brand loyalty, greater perceived quality-of-life benefits, and higher product knowledge than the general public; however, critical safety knowledge gaps regarding THC–cardiovascular drug interactions and pregnancy risks persisted across both groups. These findings highlight the need for stronger product quality standards, standardized analytical testing, and targeted public health education to promote safe and informed cannabis use. Full article

Drug–target interaction (DTI) prediction is a critical step in drug discovery, and accurate prediction of potential interactions can significantly accelerate the drug-development process. Although deep-learning approaches have achieved promising performance in DTI prediction, two challenges remain: single models often fail to comprehensively capture heterogeneous sequence information, resulting in limited stability and generalization, while insufficient integration of local and global features restricts interaction representation. To address these limitations, we propose HFEDTI, a DTI prediction model that integrates hierarchical feature fusion and weighted ensemble learning. Specifically, a residual convolutional neural network (ResCNN) is employed to extract local structural features of drugs and targets, while a self-attention-based hierarchical bidirectional long short-term memory network (SAHBiLSTM) captures global contextual dependencies. Furthermore, a hierarchical heterogeneous attention mechanism is introduced to align and fuse multi-level cross-modal representations, and a weighted ensemble strategy based on validation performance ranking is developed to enhance model robustness and generalization. Experimental results on three benchmark datasets demonstrate the effectiveness of HFEDTI. On the DrugBank dataset, HFEDTI achieves an AUC of 0.9238 and an AUPR of 0.9327, improving the best-performing baseline by 0.90 and 1.40 percentage points, respectively. Moreover, HFEDTI consistently achieves strong performance on the C. elegans and Human datasets, further validating its effectiveness and generalization capability for DTI prediction. Full article

Background: Effective topical management of sensitive skin remains challenging because inadequate cutaneous delivery limits the therapeutic performance of many anti-inflammatory agents. Glycyrrhetinic acid (GA) possesses well-recognized anti-inflammatory and barrier-protective activities, yet its clinical potential is constrained by poor aqueous solubility and inefficient skin delivery. This study aimed to develop a hyaluronic acid (HA)-engineered ethosomal system to enhance the local delivery and therapeutic efficacy of GA for sensitive skin. Methods: HA-coated GA-loaded ethosomes (HAGA-ETs) were prepared by electrostatic adsorption of HA onto a cationic ethosomal template. The physicochemical properties, release behavior, storage stability, skin retention, cellular uptake, and biological activities of HAGA-ETs were systematically evaluated using TNF-α/IFN-γ-stimulated HaCaT cells and an SLS-induced 3D reconstructed skin model. Results: HAGA-ETs exhibited a mean particle size of 140.1 nm, encapsulation efficiency exceeding 95%, sustained drug release, and good storage stability. Compared with Free-GA and unmodified ethosomes, HAGA-ETs showed improved cytocompatibility, enhanced skin retention, greater keratinocyte uptake, and stronger anti-inflammatory activity. HA pre-saturation attenuated the enhanced cellular uptake of HAGA-ETs, supporting the involvement of HA receptor-mediated cellular interaction. HAGA-ETs also more effectively restored barrier-related markers, suppressed hyper-reactivity- and allergy-associated mediators, and inhibited the activation of MAPK/NF-κB, JAK1/STAT1, and TRPV1-related signaling pathways in both cellular and 3D skin models. Conclusions: HA surface engineering effectively improved the topical delivery and local therapeutic efficacy of GA by enhancing skin retention and keratinocyte interaction. HAGA-ETs represent a promising nanoplatform for the local management of sensitive skin. Full article