Search Results (2,621)

Glioblastoma (GB) is the most aggressive primary central nervous system tumor in adults and the most common malignant primary brain tumor, representing approximately 50.9% of all malignant CNS tumors, with a median overall survival of approximately 14.6 months despite standard multimodal treatment, consisting of surgical resection, concurrent radiotherapy, and temozolomide (TMZ), followed by adjuvant TMZ (Stupp protocol). Tumor recurrence is inevitable and attributed to diffuse infiltration of neoplastic cells into the brain parenchyma, marked intratumoral heterogeneity, the presence of glioma stem cells, and the protection conferred by the BBB. Flavonoids are plant-derived polyphenolic compounds with more than 8000 identified. They have attracted growing interest as potential therapeutic agents because of their capacity to modulate multiple oncogenic signaling pathways and their favorable toxicity profile. Here we synthesize the preclinical evidence on the main flavonoids with documented activity in GB models, with emphasis on quercetin, apigenin, luteolin, and EGCG, while distinguishing glioblastoma-specific evidence from indirect findings derived from other experimental systems. We analyze their underlying molecular mechanisms, including induction of apoptosis through the intrinsic and extrinsic pathways, inhibition of cell proliferation and angiogenesis, suppression of migration and invasion, epigenetic modulation, and, particularly, the capacity to target the glioma stem cell population. We also examine the limited oral bioavailability and restricted penetration across the BBB, as these factors remain major barriers to translational development. We conclude with an analysis of emerging nanotechnological strategies, targeted delivery systems, and synergistic combinations with conventional chemotherapeutic agents, together with a cautious assessment of the current clinical evidence, which remains insufficient to support the use of flavonoids outside controlled clinical trials. Full article

Background/Objective: Topical therapy remains a cornerstone in managing fungal infections due to the deep-seated nature of the pathogens and the persistence of the disease. Ketoconazole (KTZ) is a broad-spectrum antifungal agent, but its highly lipophilic nature presents considerable challenges in developing effective topical formulations. Additionally, oral KTZ has been subject to labeling restrictions and market withdrawal due to its association with severe hepatic adverse effects. This study was conducted to design, optimize, and evaluate KTZ-loaded nanolipid carriers (NLCs; KTZ-NLCs) as a delivery platform that could improve cutaneous bioavailability and enhance antifungal activity. Methods: The optimized KTZ-NLCs were further incorporated into a mucoadhesive system (KTZ-NLCs-C) through the inclusion of Carbopol^® 940 NF, aiming to improve the retention of the formulation on the skin surface. NLCs were characterized in terms of their physical appearance, particle size, polydispersity index, zeta potential, pH, viscosity, drug content, and entrapment efficiency. The optimized KTZ-NLC and KTZ-NLCs-C formulations were subsequently assessed for in vitro drug release, ex vivo skin permeation and deposition, as well as in vivo skin irritation. Results: In vitro release studies revealed that nanocarrier systems provided a sustained release of KTZ over 24 h. The ex vivo transdermal flux and permeability coefficient of KTZ from the lead KTZ-NLCs-C formulation were approximately 2.8-fold greater than those achieved with the marketed cream formulation. The in vivo skin irritation studies indicate that NLC-based formulations are suitable for topical applications. The lead formulation was stable for 90 days (the final time point evaluated) under refrigerated and room-temperature storage conditions. Conclusions: These findings suggest that the NLC-based system is a promising platform for the topical delivery of KTZ and has the potential to enhance the therapeutic outcomes for patients with superficial fungal infections. 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

Calcium-induced polysaccharide hydrogels have attracted growing interest in food science because of their mild gelation conditions, tunable structures, and compatibility with food-grade formulation. This review focuses on edible Ca²⁺-mediated polysaccharide hydrogels and related composite networks, focusing on alginate, low-methoxyl pectin, gellan gum, and carrageenan. Rather than treating all calcium-containing polysaccharide materials as well-defined complexes, we distinguish direct coordination, ionic bridging, charge screening, helix stabilization, and composite-assisted network regulation. Current evidence indicates that Ca²⁺-mediated assembly is governed by polysaccharide fine structure, calcium-release behavior, pH, ionic strength, and processing conditions, thereby determining crosslinking density, digestibility gel strength, water distribution, rheological properties, release behavior, and texture-related functionality. For texture-modified foods for older adults, these hydrogels may provide a useful material basis for designing swallowing-friendly matrices, sustained nutrient-delivery systems, and soft composite foods. However, available evidence is still largely derived from model gels, in vitro characterization, and static digestion models, while validation in real food matrices, dynamic gastrointestinal conditions, oral processing, sensory acceptance, and older-adult populations remains limited. Future studies should establish structure–function–population evidence chains linking molecular assembly to reliable geriatric food performance. Full article

Honey bee populations face significant threats from viral pathogens, Nosema ceranae, Varroa destructor, and the small hive beetle (Aethina tumida), all of which contribute to colony losses worldwide. RNA interference (RNAi) has emerged as a promising molecular tool for controlling these pathogens and pests through sequence-specific gene silencing. This review summarizes current advances in RNAi applications against major honey bee diseases and parasites, including antiviral strategies, suppression of Nosema development, interference with Varroa reproduction, and RNAi-based control of small hive beetles. Particular attention is given to recent developments in delivery technologies, including oral administration, nanoparticle-assisted formulations, and symbiont-mediated RNAi systems. The opportunities, limitations, and future challenges associated with large-scale implementation, environmental safety, regulatory approval, and field deployment are also discussed. Collectively, these advances highlight the potential of RNAi as a valuable component of sustainable honey bee health management and integrated pest management programs. Full article

Laser acupuncture, defined as photobiomodulation or low-level laser therapy applied to specific acupuncture points, has been proposed as a non-invasive adjunctive strategy in oral and dental care. This umbrella review aimed to synthesize and critically appraise systematic reviews evaluating laser acupuncture in dental and orofacial conditions. The review followed PRISMA 2020 recommendations and was prospectively registered in PROSPERO. PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 12 May 2026. Systematic reviews with or without meta-analysis were included. Methodological quality was assessed using AMSTAR 2, and findings were narratively synthesized considering methodological quality, overlap, consistency, dosimetric heterogeneity, and clinical applicability. From 263 records identified, six systematic reviews published between 2021 and 2024 met the eligibility criteria. The included reviews addressed three main domains: temporomandibular disorders, dental-related neuropathies, and pediatric dental outcomes. Laser acupuncture protocols used red to near-infrared wavelengths, mainly between 690 and 980 nm, but varied substantially in fluence, energy delivery, irradiation time, session frequency, and acupoint selection. The most consistent signal was observed for short-term pain reduction in temporomandibular disorders, although comparative evidence did not support laser acupuncture as superior to established conservative therapies. Evidence for dental-related neuropathies was associated with possible improvements in neurosensory and motor outcomes, while pediatric evidence suggested possible short-term changes in gag reflex, procedural pain, and bruxism-related outcomes; however, both domains were supported by only one systematic review each and should be considered preliminary and hypothesis-generating. No serious adverse events were reported, but harm reporting was limited. Overall, this umbrella review should be interpreted as an evidence map rather than as a source of high-certainty clinical recommendations. Laser acupuncture may represent an emerging adjunctive approach for selected dental and orofacial indications; however, current evidence remains limited and heterogeneous and does not support standardized protocols, stand-alone use, or definitive clinical recommendations. Full article

Tobramycin is a highly hydrophilic aminoglycoside antibiotic with limited cellular permeability and negligible oral bioavailability, necessitating parenteral administration. This study aimed to develop drug delivery systems based on nano-sized colloidal assemblies (NCAs) incorporating tobramycin ion pairs to enhance its lipophilicity, potential for transition to the oral route, and antimicrobial activities. Tobramycin was ionically paired with oleic acid, lauric acid, and fluorescein and formulated into NCA preconcentrates (F1–F5) using combinations of Tween 80, DMSO, and propylene glycol. The resulting formulations formed stable nanodroplets upon dilution (9.50–16.30 nm) with narrow size distributions (polydispersity index; PDI < 0.3) and moderate negative zeta potentials (−4.99 to −11.13 mV). In vitro release studies indicated sustained drug release for ion-paired systems compared to the rapid release of free tobramycin. Cytotoxicity evaluation in Caco-2 cells demonstrated high biocompatibility at 1:10,000 and 2:10,000 dilutions, while concentration-dependent toxicity at higher doses suggested enhanced intracellular delivery. Cellular uptake studies revealed significantly higher tobramycin internalization (p < 0.001) from formulations F1–F3, with uptake values in the range of 81.76–96.14% compared to free drug, which showed zero or negligible uptake. Fluorescein-labeled formulations (F4 and F5) further confirmed enhanced uptake, demonstrating strong intracellular fluorescence. This was supported by visual observation, UV–Vis absorbance (70.5–84.8% relative to positive control), and confocal microscopy imaging. Antimicrobial activities against P. aeruginosa and S. aureus were comparable between formulations F1–F5 and free tobramycin (inhibition zones of 16–18 mm), utilizing the same tobramycin concentration in the diluting medium. These findings validate the effectiveness of the formulated NCAs in facilitating intracellular delivery of tobramycin while preserving biocompatibility and similar antimicrobial activities. Moreover, the uptake of fluorescein provides indirect evidence supporting the enhanced internalization of tobramycin in analogous ion-paired formulations. This strategy holds promise for overcoming intestinal barriers and improving oral bioavailability, potentially enabling the transition of tobramycin from parenteral to oral administration. Full article

Oral administration remains the most convenient and favored route for systemic delivery of small-molecule drugs, primarily due to patient compliance and the absence of invasive procedures. Yet, poor aqueous solubility, chemical/enzymatic instability, and limited permeability in the gastrointestinal (GI) tract often result in low bioavailability (BA) of many therapeutic agents. Polymeric micelles formed from the self-assembly of amphiphilic block copolymers have gained considerable attention as a nanotechnology-driven solution to overcome these challenges. Their hydrophobic core–hydrophilic shell structure enables efficient encapsulation of poorly soluble small molecule drugs, providing protection from acidic or enzymatic degradation while potentially enhancing drug transport across the intestinal epithelium. This review examines the design principles, formulation strategies, and in vivo performance of polymeric micelles for oral delivery of small molecule drugs. We discuss strategies to improve micelle stability in the GI environment, including optimization of core hydrophobicity, kinetic stabilization, and corona engineering, and compare polymeric micelles with established alternatives such as self-micro emulsifying drug delivery system (SMEDDS) and amorphous solid dispersions (ASDs) across critical performance parameters. Despite decades of preclinical progress, no oral polymeric micelle formulation has reached regulatory approval, underscoring the persistent challenge of maintaining micellar structural integrity under the dynamic conditions of the GI environment. This review therefore examines not only the promise but also the structural vulnerabilities of oral micelles, proposing a stability-centered framework for interpreting micelle function under GI conditions. Finally, we discuss current translational challenges and suggest directions for future research toward clinical application of oral polymeric micelle systems. Full article

The immune response is essential in the protection of our body against pathogens; however, the inflammatory response caused by the immune system can become a disease itself. In fact, anti-inflammatory and immune-suppressive drugs are applied to limit the immune response to treat inflammatory diseases. Flavonoids are plant-derived polyphenols extensively investigated for their anti-inflammatory and antioxidant properties in inflammatory diseases. Studies applying isolated compounds as well as using supplements as nutraceuticals based on flavonoids have been conducted. Our review systematically analyzed the top five studied flavonoids between 2020 and 2025: quercetin (1742 articles), kaempferol (642), luteolin (589), apigenin (419), and epicatechin (354), highlighting their major therapeutic applications in diseases affecting the liver (12%), nervous system (11%), and lungs (10%). Mechanistically, these compounds act as multi-target agents mainly by inhibiting NF-κB and inducing Nrf2-dependent antioxidant programs. Application of advanced delivery systems, which increase oral bioavailability by up to 20-fold, overcomes pharmacokinetic bottlenecks. Clinical highlights demonstrated promising therapeutic effects, including reduced intrahepatic lipid accumulation in non-alcoholic fatty liver disease patients following quercetin supplementation (11.5% to 9.6%) and accelerated SARS-CoV-2 clearance after quercetin phytosome administration. The translation of flavonoids into standardized clinical therapies remains limited by the lack of large-scale, well-controlled clinical trials. Full article

This study aimed to determine the absolute bioavailability of quercetin and quantitatively evaluate its pharmacokinetic–pharmacodynamic (PK-PD) relationship regarding acute glucose-lowering effects in normoglycemic and alloxan-induced diabetic rats, addressing whether its in vivo efficacy is driven by the free aglycone or its biotransformed intermediates. Healthy and diabetic rats received single doses of quercetin either orally (75 mg/kg) or intravenously (38 mg/kg). Plasma concentrations of free quercetin were quantified using a validated HPLC-DAD method, and temporal PK-PD relationships between systemic exposure and the percentage variation of glycemia were mathematically evaluated employing Pearson correlation analysis. The absolute bioavailability of free quercetin was significantly impaired by the pathophysiological state, dropping from 59.7% in healthy rats to 40.9% in diabetic subjects. Despite this diminished systemic exposure, oral administration elicited significant hypoglycemic responses. Crucially, the Pearson correlation analysis revealed a pronounced temporal dissociation: the onset of glycemic reduction occurred independently of the maximal circulating concentration of free quercetin. Furthermore, intravenous delivery bypassed first-pass barriers and induced a markedly faster and deeper hypoglycemic effect (up to −47% in diabetic rats). Finally, the diminished bioavailability under diabetic conditions and the stark PK-PD temporal dissociation strongly suggest that quercetin’s acute antihyperglycemic effect is driven by rapid hepatic Phase II biotransformation, implicating conjugated metabolites (rather than the free aglycone) as the principal pharmacological effectors. Full article

Background/Objectives: Cyclotides are plant-derived macrocyclic peptides distinguished by their head-to-tail cyclized backbone and cystine knot motif, which confer remarkable stability against thermal, enzymatic, and chemical degradation. These features, combined with a compact and rigid structure, position cyclotides as promising scaffolds for future antibacterial agents in response to the escalating threat of multidrug-resistant (MDR) pathogens and the stagnation of conventional antibiotic discovery pipelines. This review summarizes the structural features, antibacterial mechanisms, bioengineering strategies, and translational potential of cyclotides against MDR infections. Methods: A narrative review of the literature was conducted using recent original research articles and reviews on cyclotide structure, antibacterial activity, bioengineering, computational modeling, and pharmaceutical applications. Results: Cyclotides exhibit potent antimicrobial activity, primarily through membrane disruption mediated by amphipathic surfaces and affinity for anionic bacterial membranes. Some variants also demonstrate anti-virulence and antibiofilm properties, broadening their therapeutic relevance for difficult-to-treat infections. Bioengineering approaches, including epitope grafting and rational design, have improved selectivity and potency while reducing cytotoxicity. Advances in computational modeling, molecular dynamics, and artificial intelligence have accelerated the prediction and optimization of antimicrobial activity, toxicity, and pharmacokinetic properties. Conclusions: Innovations in synthesis, including recombinant expression and enzymatic ligation, are helping overcome translational barriers related to cost and scalability. Although challenges remain in oral bioavailability and systemic delivery, strategies such as lipidation and scaffold modification support the development of cyclotide-based therapeutics as adaptable platforms for peptide drug discovery. Full article

Objectives: A customizable 3D-bioprinted core-in-shell platform was developed for time-dependent oral colon delivery of live microorganisms. The system conveyed Lacticaseibacillus paracasei as a model bacterial species within a monolithic core, which was surrounded by a swellable hydroxypropyl cellulose barrier, imparting a lag phase of programmable duration, and by an enteric outer layer, protecting the dosage form during unpredictable gastric residence. Methods: Pastes of different compositions were investigated to shape the core. Core and core-in-shell units were fabricated from digital models using a bioprinter equipped with a high-precision plunger dispenser and pressure-based thermoplastic printhead. The printed units were characterized in terms of mass, dimensions, mechanical properties and release performance using paracetamol as a reference tracer. Bacterial viability was evaluated during screening of the formulation components and after each processing step by manual counting of colony-forming units. Results: A mannitol-based formulation was selected for fabrication of the core, offering a favorable balance of printability, physico-technological properties, release behavior and ability to preserve bacterial viability. Two-layer core-in-shell systems were manufactured via a dual-printing operating mode. The desired in vitro performance was attained, with no release under acidic conditions, a lag phase in pH 6.8 fluid and a subsequent release profile comparable with that generated by the core as such. Viability studies demonstrated that compounding, core printing, shell deposition and drying did not adversely affect L. paracasei survival. Conclusions: 3D bioprinting was proved to be a versatile technique for the manufacturing of oral colon delivery systems containing probiotics or live biotherapeutics. Full article

Mucoadhesive drug delivery systems have emerged as a promising strategy to enhance the therapeutic efficacy of pharmaceuticals by improving drug residence time, bioavailability, and site-specific targeting. Among various materials investigated, biopolysaccharides have gained significant attention due to their biocompatibility, biodegradability, non-toxicity, and inherent mucoadhesive properties. Natural polymers such as chitosan, alginate, pectin, hyaluronic acid, and cellulose derivatives exhibit strong interactions with mucosal surfaces through hydrogen bonding, electrostatic interactions, and polymer chain entanglement. These properties enable prolonged drug retention at mucosal sites, controlled drug release, and enhanced permeation across biological barriers. Mucoadhesive biopolysaccharides have been explored for diverse routes of administration, including oral, buccal, nasal, ocular, vaginal, and pulmonary delivery. Furthermore, chemical modification and nanostructuring of these polymers have expanded their functionality, enabling targeted delivery of small molecules, proteins, peptides, and nucleic acids. This review highlights the mechanisms of mucoadhesion, key biopolysaccharides used in drug delivery, formulation approaches, and recent advances in their application as versatile platforms for novel therapeutic delivery systems. The continued development of mucoadhesive biopolysaccharide-based carriers holds substantial potential for improving treatment outcomes and patient compliance. Full article

GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity and are increasingly relevant in periodontal and implant practice. This review covers mechanisms, preclinical and early human evidence, and practical periodontal considerations; the structured database search is conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) and the International Committee of Medical Journal Editors (ICMJE) principles. Two pathways explain GLP-1RAs’ relevance: indirect effects from better glycemic control, weight loss, and reduced inflammation; and direct tissue effects involving GLP-1R signaling and the GLP-1/dipeptidyl peptidase-4 (DPP-4) axis. Preclinical studies show reduced inflammation, osteoclast activity, and alveolar bone loss, along with improved periodontal stem cell function under hyperglycemia or inflammation via Nuclear Factor-kappaB (NF-kappaB), Wingless-related integration site (Wnt)/beta-catenin, and Mitogen-Activated Protein Kinase (MAPK) pathways. Animal studies on implants and local delivery, including exendin-4 platforms, suggest osteometabolic benefits. Human data are limited and mostly observational, and confounders include metabolic status, smoking, medication, and nutrition. Oral side effects such as xerostomia and dehydration are also noted. At present, GLP-1RA therapy should be regarded as a contextual modifier of periodontal risk and healing capacity rather than as a stand-alone periodontal therapy. Full article

Background: Oral protein delivery is a major challenge in the field of pharmaceutical technology due to poor stability and limited permeability through intestinal barriers. Buccal delivery is a promising alternative with less restricting physiological conditions; however, low protein permeability is still a limiting factor. Multiple nanocarriers have been proposed to improve buccal protein delivery with lipid–polymer hybrid nanoparticles (LPHNs) combining the advantages of both polymeric and lipid-based systems. However, these conventional carriers rely on passive protein protection and lack adaptive release mechanisms. Objectives: This work aimed to develop and systematically optimize an ionic strength-responsive LPHN system that can minimize protein release in buccal ionic conditions while offering a triggered release in plasma after absorption. Methods: LPHNs were prepared by a two-step approach where polymeric cores of Eudragit-L100 were prepared by electrostatic complexation with Lysozyme (LYZ) followed by lipid shell formation by the ethanol injection method. Systematic optimization was performed using two-level factorial and central composite designs. Moreover, the ionic strength responsiveness and in vitro LYZ release were investigated in different ionic strength media. Results: The final optimized formulations, LPHNs and sodium deoxycholate-containing LPHNs (NaDC-LPHNs), exhibited a particle size of 257.2 ± 1.5 nm and 246 ± 5.7 nm, encapsulation efficiency of 69.89 ± 0.22% and 68.14 ± 0.16%, and high drug loading efficiency of 24.11 ± 0.06% and 23.65 ± 0.04%, respectively. Moreover, both formulations showed minimal protein release at low ionic strength (buccal-like) conditions while demonstrating a triggered release at higher ionic strength (plasma-like) conditions. Conclusions: The developed system may provide a promising smart strategy to improve buccal protein delivery by enhancing buccal protection and improving systemic delivery. Full article