Search Results (3,954)

Silicone elastomers are attractive matrices for transdermal drug delivery systems, but the controlled release of poorly water-soluble drugs from hydrophobic silicone networks remains challenging. Medical-grade silicone elastomers are generally regarded as chemically stable, biologically inert, and highly biocompatible polymer matrices, which supports their use in biomedical and pharmaceutical materials. Here, ibuprofen-loaded silicone/polyol composite films were prepared from hydroxyl-terminated polydimethylsiloxane (PDMS-OH) using glycerol- and 1,2-propylene glycol-derived alkoxysilane cross-linkers and amino-terminated PDMS as a metal-free room-temperature-vulcanising catalyst. The effects of cross-linker composition, glycerol, PEG 200 and selected functional additives on film formation, morphology, apparent ibuprofen release and preliminary Strat-M^® permeation were evaluated. FTIR analysis indicated no covalent reaction between ibuprofen and the silicone network, but suggested hydrogen-bonding interactions with polyol-rich domains, particularly in glycerol-containing systems. Raman mapping supported ibuprofen incorporation within the films, while SEM showed phase-separated microdomains whose morphology depended on the formulation. Apparent release into 0.9% NaCl at 37 °C was formulation-dependent over 72 h. The optimised F-9 film showed approximately 83% cumulative apparent release, whereas the F-10 film containing copper oxide nanoparticles and sea buckthorn oil showed the highest numerical cumulative apparent release, approximately 94%. Kinetic analysis of the apparent release data supported a mainly diffusion-controlled contribution, modulated by hydrophilic microdomains. These results provide preliminary materials-development evidence that silicone/polyol films can be used to tune apparent ibuprofen release and merit further optimisation for local topical or transdermal applications; however, efficient skin permeation and biological performance require dedicated validation. Full article

Punica granatum L. (pomegranate) is one of the oldest medicinal plants known to humankind, valued across ancient civilisations for treating parasitic, microbial, and metabolic diseases. Its exceptionally rich phytochemical composition, dominated by punicalagins, ellagic acid, anthocyanins, flavonoids, piperidine alkaloids, and the unique conjugated fatty acid punicic acid, confers a remarkably broad spectrum of biological activities of direct relevance to contemporary veterinary medicine. While human-health applications have been extensively reviewed, a comprehensive synthesis of veterinary evidence across multiple species remains lacking. This review consolidates current preclinical and field knowledge on the pharmacological effects of pomegranate preparations in poultry, ruminants, swine, fish, companion animals, and laboratory models. In poultry—the most extensively studied taxon—dietary inclusion of pomegranate peel powder or extract consistently enhances growth performance, antioxidant status, and humoral immunity while exerting meaningful anticoccidial activity. The antiparasitic properties are compellingly supported by evidence against gastrointestinal nematodes of ruminants, tapeworms, schistosomes, and protozoa including Giardia, Cryptosporidium, and Leishmania spp., as well as monogenean fish parasites. Broad-spectrum antimicrobial activity extends to major veterinary pathogens such as Salmonella, Escherichia coli, Staphylococcus aureus (including MRSA), and Clostridium perfringens. Rodent models have validated antidiabetic, hepatoprotective, nephroprotective, and reproductive benefits, including improved post-thaw sperm quality and enhanced litter size. The safety profile is generally favourable at conventional doses, although high dietary inclusion elicits anti-nutritional effects from condensed tannins, and potential drug interactions via cytochrome P450 inhibition warrant clinical caution. Despite this substantial evidence, significant translational barriers persist, including extract heterogeneity, absence of pharmacokinetic data in target species, and scarcity of controlled clinical trials. By providing a species- and pathology-driven synthesis, this review identifies critical research priorities and highlights the immense potential of this ancient, accessible, and economically viable phytobiotic as a natural alternative to antibiotic growth promoters and synthetic antiparasitics in veterinary practice. Full article

Pseudomonas aeruginosa (PA) is a clinically relevant opportunistic pathogen whose persistence and antimicrobial tolerance are largely driven by biofilm formation and quorum-sensing (QS)-regulated virulence. Targeting QS has therefore emerged as an antivirulence strategy that attenuates pathogenicity without exerting strong selective pressure on bacterial growth. This systematic review (2020–2024) analyzes recent advances in the identification of QS inhibitors against PA, emphasizing studies that integrate in silico approaches. Forty-six studies met the inclusion criteria. All employed molecular docking, and 36.9% (n = 17) incorporated molecular dynamics simulations. While valuable for initial detection, these computational predictions have inherent limitations in accurately estimating binding energy and conformational dynamics, requiring empirical validation to confirm actual biological activity. Approximately one-fifth of the studies were exclusively computational, whereas the remainder combined in silico screening with in vitro and, in some cases, in vivo assays. The most frequently investigated QS regulators were LasR, PqsR, and RhlR, alongside additional virulence-associated proteins. The evaluated compounds encompassed phytochemicals, synthetic molecules, nanomaterials and natural product-derived compounds, several of which demonstrated experimental evidence of biofilm attenuation and reduction in QS-regulated virulence factors. Overall, the findings highlight the value of integrating computational and experimental strategies to rationally prioritize antivirulence candidates. However, the intrinsic complexity and redundancy of the QS network suggest that future research should increasingly focus on multitarget approaches and on the exploration of chemically diverse and previously underexplored compound libraries to improve efficacy against PA biofilms. Full article

Sesquiterpene lactones (SLs) are privileged medicinal scaffolds, offering potent bioactivities driven by their reactive α-methylene-γ-lactone motif. This review highlights the literature published up to the first half of 2026, detailing the synthetic methodologies utilized to optimize SLs via Michael addition. We critically evaluate how these structural transformations translate into biological and pharmacokinetic improvements. Specifically, the resulting Michael adducts achieve significantly enhanced solubility in aqueous media and highly refined drug–target interactions. Addressing a clear literature gap unaddressed since earlier foundational reviews, this focus review highlights the literature published up to the first half of 2026. By explicitly correlating synthetic strategies with pharmacological outcomes, such as enhanced efficacy and target specificity, this review provides medicinal chemists with a robust framework to accelerate the development of next-generation SL-based therapeutics. Full article

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine phosphorylase-deleted (MTAP-null) cancers. Second-generation methylthioadenosine (MTA)-cooperative PRMT5 inhibitors preferentially target MTAP-null cells while largely sparing MTAP-wildtype (MTAP-WT) cells, thereby improving tumor selectivity over first-generation PRMT5 inhibitors. Despite encouraging efficacy and safety signals in early clinical studies, the modest objective response rates (ORRs) observed with these inhibitors suggest that intrinsic or acquired resistance may limit their clinical benefit. Here, we investigated acquired resistance to the MTA-cooperative PRMT5 inhibitor BMS-986504/MRTX1719 in MTAP-null non-small cell lung cancer (NSCLC) cells and sought to identify therapeutic vulnerabilities that emerge upon resistance. Using multiple in vitro-derived resistant models, we found that acquired resistance was accompanied by cross-resistance to mechanistically distinct PRMT5 inhibitors. Notably, this phenotype was not fully explained by altered PRMT5 activity or changes in MTA levels. High-throughput drug screening of paired sensitive and resistant cells revealed increased sensitivity to MEK inhibitors following acquisition of MRTX1719 resistance in KRAS-wildtype NSCLC cells. Consistently, resistant cells exhibited rewired MAPK-related transcriptional programs. Together, these findings identify MEK inhibition as a reproducible collateral vulnerability associated with acquired MRTX1719 resistance in MTAP-null NSCLC models and support further evaluation of MEK inhibition as a potential treatment-switching strategy following resistance. Full article

The progressive integration of Whole Slide Imaging (WSI) technology and Artificial Intelligence (AI) architectures is driving a structural transformation in pathology and precision oncology. This structured critical review analyzes and systematizes the impact of this technological transition along two fundamental operational dimensions of the modern biopharmaceutical industry: pre-registration Clinical Research and post-launch strategies governed by Medical Affairs. The first section explores how computational pathology is improving efficiency and reducing risk in drug development. Replacing analog visual assessment—intrinsically subject to inter-observer and intra-observer variability—with quantitative algorithms for cellular classification and segmentation enables optimization of patient recruitment in clinical trials, reducing screening failure rates. This review also examines the emerging role of Spatial Biology in extracting complex topological metrics from the Tumor Microenvironment (TME) and the use of AI for the objective and auditable quantification of critical surrogate endpoints, such as Pathological Complete Response (pCR), while acknowledging that algorithmic precision remains sensitive to pre-analytical variables and dataset biases. In the second section, the study investigates the strategic evolution of Medical Affairs, acting as a vital scientific communication and translational bridge between the complexity of Data Science and clinical hospital practice. Challenges related to AI adoption by clinicians are examined, emphasizing the importance of educational programs based on Explainable AI (XAI) to overcome the cognitive limitations of the black-box paradigm and the complex regulatory validation pathway for Software as a Medical Device (SaMD) under the stringent European IVDR framework—supported by an analysis of historical regulatory benchmarks such as the Paige Prostate case. The paper also explores the potential of AI in the large-scale generation of Real-World Evidence (RWE), applied to the creation of synthetic control arms in pharmacoeconomic settings. In conclusion, the study highlights that the diagnostic algorithm has ceased to be merely a laboratory support tool and has become a strategic asset and an integral adjunct to therapeutic decision-making. Overcoming current challenges related to data privacy through Federated Learning architectures, together with the imminent transition toward Foundation Models, foreshadows a fully data-driven healthcare ecosystem, making continuous skills development (digital upskilling) an essential requirement for professionals in the biopharmaceutical sector. Full article

Background/Objectives: Synthetic compounds, particularly thiadiazine derivatives with antibacterial properties, have emerged as promising candidates in addressing the growing challenge of bacterial multidrug resistance. Thiadiazine derivatives are six-membered heterocyclic compounds containing two nitrogen atoms and one sulfur atom, exhibiting diverse medical and pharmacological activities. This study aimed to evaluate the potentiating activity of thiadiazine derivatives against multidrug-resistant bacteria. Methods: ADMET (absorption, distribution, metabolism, excretion, and toxicity) assays were performed to assess similarity with more than 370,000 three-dimensional structures of bioactive compounds. The multidrug-resistant bacterial strains Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to investigate both the direct antibacterial activity and the antibiotic-modifying activity of thiadiazine derivatives. Results: The thiadiazine analogs did not exhibit direct antibacterial activity, presenting a minimum inhibitory concentration of 1024 μg/mL. However, they demonstrated a significant antibiotic-modifying effect, potentiating the activity of conventional antibiotics, particularly norfloxacin, against the tested strains. In silico analyses indicated that the analogs predominantly exhibited affinity for G protein-coupled receptors and possessed physicochemical characteristics compatible with potential drug candidates. Conclusions: Although the evaluated thiadiazine derivatives lacked direct antibacterial activity, they significantly enhanced the efficacy of antibiotics against multidrug-resistant bacteria. Combined with their favourable in silico pharmacokinetic and physicochemical profiles, these findings suggest that thiadiazine derivatives may represent promising antibiotic adjuvants for combating multidrug-resistant bacterial infections. Full article

Spinal pathologies, including degenerative disc disease, spinal cord injury, and conditions requiring spinal fusion, pose a substantial global health burden. While contemporary interventions provide symptomatic relief, achieving durable tissue repair in biologically compromised environments remains a critical challenge. This narrative review synthesizes the current literature on three major nanotechnology applications in spine care: nanostructured implant surfaces, nanoparticle-enhanced bone grafts, and nano-drug delivery systems (NDDSs). Preclinical evidence indicates that nanoscale surface modifications and nanoparticle-augmented synthetic grafts significantly enhance osseointegration and bone fusion by mimicking the native extracellular matrix. Furthermore, in animal models of intervertebral disc degeneration, NDDSs utilizing polymeric nanoparticles and exosomes facilitate sustained, stimuli-responsive therapeutic delivery into the avascular disc space. Although early clinical data on nanostructured cages demonstrate reduced subsidence and stable long-term fusion, the direct translation of these robust preclinical outcomes to widespread clinical efficacy faces substantial hurdles. Significant translational barriers include stringent Class III regulatory classifications, sparse long-term safety data regarding nanoparticle biodistribution, and scale-up manufacturing challenges such as batch variability. Future progress relies on artificial intelligence-guided design, three-dimensional (3D) bioprinting, and multifunctional “smart” nanomaterials. Ultimately, close collaboration among materials scientists, clinicians, and regulatory bodies is essential to safely bridge the gap between preclinical innovation and predictable clinical therapeutic success. Full article

Poor aqueous solubility remains one of the most persistent challenges in pharmaceutical development, limiting clinical translation and requiring innovative formulation strategies; approximately 40% of newly discovered pharmaceutical compounds are affected, underscoring the scale of the problem. Emulsion-based delivery systems overcome this limitation by maintaining drugs in a dissolved state, increasing absorption surface area, and enabling controlled release; however, conventional emulsions face thermodynamic instability and coalescence challenges. Cellulose and nanocellulose—cellulose nanocrystals (CNCs), cellulose nanofibers (CNFs), and bacterial cellulose (BC)—have emerged as sustainable, biocompatible alternatives to synthetic surfactants for stabilizing emulsions via Pickering mechanisms involving irreversible adsorption of solid particles at the oil–water interface. This review synthesizes 142 references across eight application themes: fundamentals and history, emulsion templating, drug encapsulation, antimicrobial and pathogen applications, vaccine adjuvants, topical and transdermal delivery, commercial translation, and regulatory gaps. Rather than treating all sources equally, 37 primary studies are examined in depth through structured critical-appraisal tables organized by system type, goal, key result, and limitation; the remainder are synthesized at the pattern level. A key mechanistic distinction is identified between BC as a standalone biomedical material (used in wound dressings, tissue scaffolds, and drug delivery membranes) and BC as a source for Pickering-emulsion stabilizers after disintegration into nanocrystals or nanofibrils. The review’s overall assessment is that the fundamental materials science of cellulose Pickering emulsions is mature and consistent across sources, while the translational evidence, including in vivo confirmation of drug release performance, biofilm-relevant antimicrobial testing, standardized nanocellulose characterization, and up-to-date intellectual property mapping, remains the binding constraint on clinical and commercial adoption. Six specific, evidence-linked research priorities are identified to advance cellulose emulsions toward regulatory approval and clinical use. Full article

C-C motif chemokine ligand 2 (CCL2) interacts with cytokines, adipokines, miRNAs, and multiple synovial cell populations. Experimental studies indicate that these interactions can form a CCL2-associated inflammatory amplification network across cell types. In cellular and animal models, increased CCL2 is associated with monocyte recruitment, synovial fibroblast activation, osteoclast-related bone remodelling, and vascular responses. Therapeutic strategies targeting the CCL2-centered inflammatory network include antagonists of the CCL2/CCR2 axis, natural products, synthetic compounds, conventional antirheumatic drugs, and emerging delivery-based approaches. Notably, direct CCL2/CCR2 inhibition has shown biological activity in experimental models but has not produced consistent clinical benefit in established rheumatoid arthritis (RA). Although these findings do not establish CCL2 as a dominant causal driver of RA, human observational studies suggest that circulating CCL2 may complement established markers in preclinical RA risk assessment, disease activity and remission classification, estimation of treatment response, and evaluation of RA-related complications such as interstitial lung disease. Of note, no validated concentration cut-off or standardized assay currently supports its routine clinical use. This review examines the CCL2-related inflammatory network in RA and evaluates its cellular mechanisms, therapeutic implications, and potential clinical applications. Full article

Background: Staphylococcus aureus causes bloodstream and skin infections in humans. The prevalence of multidrug-resistant S. aureus strains means new antibiotics are needed. A novel antimicrobial drug named SK-03-92, a synthetic aromatic organic stilbenoid compound, kills S. aureus cells within 30 min, but an increase in both biofilm formation and persister cells occurs. SK-03-92 treatment downregulates transcription of the biofilm regulating protein regulator (brpR) gene and biofilm regulating protein sensor (brpS) gene in S. aureus. BrpR/BrpS system may be a LytTR regulatory system tied to biofilm formation, creation of persister cells, and late-stage competence in S. aureus. The aim of this study was to determine what biofilm, late-stage competence, and persister-associated genes were regulated in a brpR mutant compared to wild-type strains. Methods: In this study, involvement of BrpR in regulating other genes was assessed by comparing transcriptional changes in a brpR mutant strain to the S. aureus parent strain via RNA sequencing (RNA-Seq). Bioinformatic analysis was then performed on the RNA-Seq data to assess what biochemical pathways might be involved. Results: From these analyses, 440 genes were identified that had significant differences in transcript abundance when comparing the brpR mutant to wild-type strains. Quantitative reverse transcription polymerase chain reaction analysis confirmed bacA, icd, metE, and pdhA transcript levels were lower, whereas alr and mraY were higher in the brpR mutant versus wild-type strain. Furthermore, an enzymatic assay targeting NADH production from the pyruvate dehydrogenase complex showed lower levels in the mutant compared to wild-type strain. Conclusions: Overall, the study demonstrated several biosynthetic pathways tied to biofilm formation and late-stage competency may be regulated by BrpR and some potential leads for the mechanism of action of the SK-03-92 drug were uncovered. Full article

Cranial bone defects remain a significant clinical challenge due to their limited intrinsic regenerative capacity and the complexity of coordinating osteogenesis, angiogenesis, and immune responses within a confined and poorly vascularised environment. Conventional approaches, including autologous grafts and synthetic implants, provide structural support but fail to actively modulate the biological processes required for effective bone regeneration. In this context, hydrogel-based systems have emerged as versatile platforms for localized and controlled drug delivery in cranial bone tissue engineering (BTE). This review provides a comprehensive overview of hydrogel-based delivery strategies designed to regulate the spatiotemporal presentation of bioactive agents within cranial defects. The main classes of hydrogels, natural, synthetic, semi-synthetic, and hybrid systems, are discussed in relation to their physicochemical properties and suitability for drug delivery applications. Current delivery approaches are analysed, including cell-free systems (growth factors, peptides, bioactive ions, nucleic acids, and small molecules drugs), cell-based platforms, and multifunctional systems integrating secondary carriers such as nanoparticles (NPs), microparticles (MPs), and extracellular vesicles (EVs). Particular emphasis is placed on how hydrogel design parameters, including crosslinking density, degradation kinetics, and responsiveness to microenvironmental cues, govern therapeutic release and influence regenerative outcomes. Emerging strategies and key translational challenges are also highlighted. Full article

Antimicrobial resistance is a major global health challenge that has created an urgent need for new antibacterial agents capable of overcoming emerging resistance mechanisms. Among nitrogen-containing heterocycles, pyrrolidine has been widely investigated in medicinal chemistry due to its structural versatility, favourable physicochemical properties, and ability to enhance interactions with biological targets. This review provides a comprehensive and critical overview of pyrrolidine-based compounds investigated for antibacterial applications. Relevant studies describing clinically approved antibiotics, natural products, synthetic derivatives, hybrid molecules, and antibacterial adjuvants containing a pyrrolidine scaffold were collected, classified, and critically evaluated, with particular emphasis on structural features, antibacterial activity, and structure–activity relationships. The reviewed evidence demonstrates that the pyrrolidine moiety is present in several antibacterial drug classes, including carbapenems, cephalosporins, fluoroquinolones, lincosamides, streptogramins, and tetracyclines, where it contributes to improved target affinity, antibacterial potency, and pharmacokinetic behaviour. Numerous recently reported pyrrolidine derivatives have shown promising activity against clinically relevant, multidrug-resistant bacterial pathogens. The pyrrolidine scaffold is valuable for the design of next-generation antibacterial agents and resistance-modifying compounds, though further in vivo studies and pharmacological evaluation are required to support their clinical development. Full article

The treatment of gastric ulcers based on antisecretory drugs is often associated with side effects and high recurrence rates, reinforcing the need for new therapeutic alternatives. Medicinal chemistry guided by natural prototypes represents a productive strategy in this context. The antiulcer potential of 2-phenylquinoline (2-PQ), an alkaloid from Conchocarpus longifolius (A.St.-Hil.) Kallunki & Pirani (syn. Galipea longiflora Krause), has been previously reported by our research group. In the present work, four 2-PQ derivatives were synthesized—2,4-diphenylquinoline (1), 2-(4-methoxyphenyl) quinoline (2), 2-phenylquinolin-4-ol (3), and 4-methoxy-2-phenylquinoline (4)—and evaluated for gastroprotective activity in the HCl/ethanol-induced gastric ulcer model in mice. The quinoline derivatives were prepared mainly by trifluoroacetic acid-catalyzed condensations of aminated benzaldehyde or benzophenone precursors with the corresponding ketones under reflux at 100 °C, affording yields of 68–94%. Compound 3 was synthesized via a two-step sequence involving the acylation of 2-aminobenzophenone followed by base-induced cyclization, providing an 85% yield. Compound 4 was obtained by O-methylation of compound 3 using iodomethane (MeI) and potassium carbonate (K₂CO₃) in dimethylformamide (DMF), affording a 95% yield. So, this study provides the first comparative analysis linking structural modifications to gastroprotective activity in synthetic quinoline derivatives inspired by 2-phenylquinoline, a natural alkaloid previously shown to exert gastroprotective effects. Carbenoxolone (200 mg/kg, p.o., positive control) inhibited gastric lesion formation by 94.1%. The synthetic quinoline derivatives also showed significant gastroprotective activity after oral administration (30 mg/kg), reducing ulcer area by 72.4% (compound 1), 76.1% (compound 2), 49.1% (compound 3), and 66.1% (compound 4). Compounds 2, 3, and 4 further retained efficacy following intraperitoneal administration (3 mg/kg), whereas compound 1 was inactivated by this route. Overall, compound 4 exhibited the greatest efficacy, significantly reducing the gastric lesion area, decreasing lipid hydroperoxide (LOOH) and tumor necrosis factor-alpha (TNF-α) levels, and increasing glutathione (GSH) content in ulcerated gastric tissue. These findings suggest that its gastroprotective effects are mediated by antioxidant and anti-inflammatory mechanisms, identifying compound 4 as the most promising candidate for the prevention and treatment of peptic ulcers. Its promising pharmacological profile warrants further investigation to elucidate its molecular mechanisms of action, assess its safety and efficacy in additional preclinical studies, and explore its potential for future therapeutic development. Full article

This study reports the design, synthesis, and biological evaluation of novel inhibitors targeting the epigenetic enzymes ALKBH2 and ALKBH5 as potential adjuvants to temozolomide therapy in glioblastoma. Given their critical role in DNA/RNA demethylation, tumor progression, and drug resistance, their inhibition represents a promising therapeutic strategy. Building on the previously identified lead compound MV1035, we employed structure-based drug design to develop new derivatives, including a second-generation series incorporating a fumarate hydrazide moiety to enhance binding affinity through interaction with both substrate- and cofactor-binding sites. Molecular docking studies predicted significantly improved binding for a set of new compounds but, due to multiple synthetic drawbacks, only a subset of the designed series was synthesized and evaluated biologically. MV3030 emerged as the most promising candidate. MV3030 demonstrated an inhibitory effect on ALKBH2 comparable to MV1035, also showing a more moderate inhibitory effect on ALKBH5. Notably, it exhibited intrinsic cytotoxicity in U87-MG cells and patient-derived glioma stem cells, whereas normal astrocytes exhibited markedly higher resistance to the treatment. Furthermore, MV3030 enhanced temozolomide efficacy and displayed favorable blood–brain barrier permeability both in silico and in vitro. Moreover, MV3030 modulated the FoxM1/Wnt/β-catenin axis. Overall, these findings identify MV3030 as a promising compound with the potential to overcome temozolomide resistance and improve glioblastoma treatment. Full article