Search Results (2,218)

Extended skin contact transforms white wines into polyphenol-rich “orange” wines, yet the optimal combination of harvest maturity and maceration time is not fully established. The evolution of physicochemical, phenolic, and chromatic properties was evaluated in Sauvignon blanc and Fetească regală wines produced with 1, 3, and 6 months of skin contact at technological and advanced phenolic maturity. Phenolic compounds were quantified by HPLC-DAD/MS, global indices by Folin–Ciocalteu (FCI) and total polyphenol index (TPI), and color by CIELAB. Skin-derived monomers were rapidly extracted, whereas seed-derived oligomers (procyanidins B2, C1) and ellagic acid required prolonged hydroalcoholic exposure. In phenolic-mature Sauvignon blanc, total phenolics reached 338.8 mg L⁻¹ after 6 months, with total flavonoids of 312.8 mg L⁻¹ and procyanidin B2 of 91.7 mg L⁻¹. In technologically mature Fetească regală, flavonoids declined from 266.8 mg L⁻¹ at 3 months to 201.7 mg L⁻¹ at 6 months. Three-way ANOVA identified significant main effects of cultivar, harvest maturity, and maceration duration on all evaluated phenolic responses (all p < 0.0001), together with significant interactions; cultivar × maturity for total phenolic acids was the only nonsignificant interaction (p = 0.071). In technologically mature Sauvignon blanc, titratable acidity decreased from 6.16 to 4.78 g L⁻¹ and pH increased from 2.98 to 3.32 between the unmacerated control and 6 months. Exploratory correlations showed inverse associations between titratable acidity and pH (r = −0.830) and between malic (MA) and L-lactic (LA) acids (r = −0.901), without implying causality. Under the conditions examined, 1–3 months of maceration generally provided substantial phenolic extraction while limiting some declines observed after 6 months, particularly in technologically mature Fetească regală. Full article

Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) with antipyretic, analgesic, and anti-inflammatory activity; however, its low aqueous solubility limits its dissolution rate and, consequently, its oral bioavailability. This study aimed to develop and physicochemically characterize an ibuprofen-loaded self-nanoemulsifying drug delivery system (SNEDDS) using a Box–Behnken experimental design. Fifteen formulations were prepared and evaluated based on CQAs: cloud point, robustness to dilution, self-emulsification time, droplet size, zeta potential, and polydispersity index (PDI). The experimental responses were subjected to statistical analysis; robustness to dilution as the only response yielding a statistically valid and predictive model within the studied design space, which was used as the sole optimization criterion. The optimal formulation was evaluated and characterized according to previously established CQAs and subjected to thermodynamic stability testing and stress testing over one month. The optimized formulation exhibited rapid self-emulsification, with a self-emulsification time of 37.02 s, a cloud point of 64.87 °C, and high robustness to dilution across different pH conditions and dilution volumes. Moreover, it exhibited a mean droplet size below 157 nm, a zeta potential of −15.43 ± 0.58 mV, and a PDI of 0.251, suggesting adequate colloidal stability and uniformity of the dispersed system. These physicochemical attributes support the potential of the developed system as a platform for further biopharmaceutical evaluation of ibuprofen oral delivery. Full article

Insulin amyloidosis poses challenges in diabetes therapy and biopharmaceuticals handling. Here, functionalized manganese-based nanoparticles (MnCO₃@TEG, MnCO₃@OAm, MnOHCO₃@TEG, MnO₂/Mn₂O₃@TEG, and Mn₃O₄@PG) were synthesized via solvothermal routes and evaluated in vitro using a fresh insulin aspart formulation (NovoRapid) and a separately aged insulin glargine formulation (Lantus). Structural and colloidal characterization (ATR-FTIR, XRD, TGA, DLS, zeta potential) confirmed phase purity and distinct surface profiles. In the fresh insulin aspart system, all nanoparticles extended the nucleation lag phase, with MnCO₃@TEG delaying fibrillogenesis from 21.16 h to 105.41 h. In the aged insulin glargine system containing pre-existing ThT-positive aggregates, small, negatively charged nanoparticles (MnOHCO₃@TEG, Mn₃O₄@PG) re-established a distinct lag phase and suppressed further aggregation. In the ThT decay assays, highly dispersed Mn₃O₄@PG produced the largest decrease in amyloid-associated fluorescence, to ~40% of the initial signal, whereas large clusters (MnO₂/Mn₂O₃@TEG, 624 nm) produced a smaller decrease; limited access arising from steric effects is one possible explanation. Additionally, structural hydroxyl groups and high colloidal stability enabled MnOHCO₃@TEG (−38.7 mV) to exhibit superior catalase-like H₂O₂ scavenging (42.27% inhibition at 250 μg/mL). Overall, fine-tuning nanoparticle size, surface charge, and core composition may offer a promising dual-action strategy for targeting insulin amyloidosis and associated oxidative stress across different stages of fibril formation, while further structural characterization and biological safety studies are needed to establish its therapeutic relevance. Full article

Plant molecular farming has emerged as a promising platform to produce recombinant biopharmaceuticals. The expression of foreign proteins changes the host proteome and metabolome, and these changes might have an effect on the accumulation of recombinant proteins. In this study, we investigated how fusion partners and ER-retention strategies influence host responses during transient production of recombinant human interleukin-15 (IL-15) in Nicotiana benthamiana. Four IL-15 constructs carrying either an 8 × His tag or an IgG1 Fc fusion, with or without an N-terminal signal peptide and C-terminal SEKDEL motif (KD), were compared at 4 days post-infiltration. Western blot analysis detected IL-15 only in the Fc-fusion constructs. Plants expressing IL15-Fc accumulated more antioxidant enzymes and phenylpropanoid-derived phenolics. Expression of IL15-Fc with the SP/KD construct showed increased abundance of proteins involved in protein folding and translation, together with reduced representation of secondary metabolic pathways. Overall, the results demonstrate that fusion partner and SP/KD targeting strategy jointly shape the host response to recombinant IL-15 expression and should therefore be evaluated together during construct design for plant molecular farming. Full article

Background/Objectives: Antimicrobial resistance has renewed interest in live therapeutic phages, including engineered candidates and defined phage cocktails, as antibacterial strategies. However, clinical translation requires evidence extending beyond phage isolation and computational prediction. This review examines how phage genomics and bioinformatics can support phage-based antibacterial development while remaining aligned with pharmaceutical requirements for safety, quality, pharmacology, and clinical validation. Methods: This narrative review synthesizes the literature on the generation, interpretation, and experimental validation of genomic and bioinformatic evidence for live therapeutic phages. Representative approaches for viral identification, genome-quality assessment, annotation, comparative genomics, lytic–temperate lifestyle classification, host prediction, receptor analysis, antiphage-defence profiling, and artificial-intelligence-assisted prioritization were evaluated according to their outputs, principal failure modes, validation requirements, and supported development decisions. Results: Current tools address distinct analytical tasks. Examples include VIBRANT and geNomad for viral identification, CheckV and PhageTerm for genome-quality and termini assessment, Pharokka, PHANOTATE, and PHROGs for gene prediction and annotation, PhageAI, BACPHLIP, and PhaTYP for lytic–temperate lifestyle prediction, iPHoP and CRISPR spacer matching for host prioritization, and PADLOC and DefenseFinder for bacterial defence profiling. Their outputs differ in taxonomic resolution, reference coverage, training-data dependence, and biological interpretation. The review maps these outputs to proportionate validation requirements while integrating formulation and PK/PD context, sequence-to-product traceability, intellectual-property documentation, minimum-information reporting, and resistance-responsive redesign. Conclusions: This review presents a practical sequence-to-product framework for interpreting contemporary phage-bioinformatics methods. By separating computational discovery from isolate-level activity, product quality, pharmacological evidence, and clinical monitoring, it clarifies the decisions supported at each stage and the additional evidence required before candidate progression, product use, or redesign. Full article

Objectives: Herpetrione (HPE) is a bioactive lignan recognized for its hepatoprotective properties; however, it exhibits limited oral bioavailability. This study aimed to classify HPE within the framework of the biopharmaceutics classification system (BCS) and to develop a nanoparticle formulation. Methods: To this end, a comprehensive investigation was conducted, encompassing computer prediction analysis, equilibrium solubility measurements across the gastrointestinal pH range, Caco-2 bidirectional transportation, in situ single-pass intestinal perfusion (SPIP), and molecular docking with P-glycoprotein (P-gp). Results: In silico analyses suggested that HPE possesses low solubility and low permeability characteristics. Experimental assays revealed pH-dependent solubility and inherently low aqueous dissolution. Unlike the computer prediction results, Caco-2 studies revealed moderate permeability but a high efflux ratio, suggestive of possible P-gp substrate activity for HPE, a finding further supported by molecular docking simulations. Conversely, SPIP studies demonstrated that the effective permeability (P_eff) of jejunal intestinal segments exceeded the high-permeability threshold, thereby classifying HPE as a high-permeability drug. Based on these findings, HPE was classified as a BCS class II compound. To overcome its solubility-limited absorption, a nanoparticle was developed, resulting in a marked enhancement of both solubility and dissolution rates. Conclusions: These findings underscore the importance of integrating experimental biopharmaceutical evaluations with computational tools when designing delivery systems for natural products. Full article

Intranasal drug delivery is noninvasive, rapid-acting, and well suited to self-administration, yet the real-world performance of nasal sprays depends on the interaction among formulation, device mechanics, nasal anatomy, and user technique rather than on the active ingredient alone. This narrative review examines how aerosol science, regional targeting, and human factors jointly shape intranasal performance, using GentleMist Technology™ as a representative example of emerging device-centered development. Computational fluid dynamics (CFD) and anatomically informed in vitro models indicate that device geometry, plume characteristics, and administration angle can significantly alter where a dose is deposited, while human factors research identifies priming, positioning, and angulation as key determinants of successful over-the-counter (OTC) use. We summarize early feasibility data suggesting that angle-optimized administration may increase posterior nasopharyngeal delivery and that essential tasks are feasible for lay users, with priming emerging as a specific usability vulnerability. We also review preliminary clinical evidence on a chlorpheniramine maleate (CPM)-based intranasal formulation in allergic rhinitis and viral upper respiratory illness. Although the strongest device-specific findings remain preliminary and require independent replication, they support an emerging shift from a formulation-centered model toward an integrated device–formulation–user paradigm. Full article

Sea rice harbors a diverse array of bioactive constituents, among which the efficient liberation of phytic acid is pivotal for unlocking its full functional potential. In this study, a co-fermentation system integrating yeast and lactic acid bacteria was established to generate a sea rice fermentation filtrate (SRF) with enhanced phytic acid (PA) content, aiming to broaden its application as a cosmeceutical ingredient and to facilitate the high-value utilization of sea rice. Response surface methodology was employed to optimize the inoculation ratios of the two microbial strains and the fermentation duration, and the PA levels were quantified using a commercial assay kit. The anti-melanogenic activity of SRF was assessed in murine B16 melanoma cells, and the underlying molecular mechanisms were elucidated with particular emphasis on the PI3K/AKT/GSK3β/MITF signaling cascade. Under the optimal conditions, specifically Saccharomyces cerevisiae (SC) inoculation at 4.5% and Lactobacillus plantarum (LP) at 6.0% with a fermentation time of 18 h, the PA concentration reached 576.61 μg/mL. Mechanistically, SRF treatment enhanced GSK3β phosphorylation, which was associated with reduced MITF phosphorylation and diminished the expression of downstream melanogenic enzymes, thereby effectively curtailing melanin synthesis, suggesting that SRF, as a complex fermentation product containing multiple bioactive constituents including PA, exhibits potent whitening efficacy. Collectively, these results provide novel perspectives for the valorization of sea rice and the development of natural skin-lightening agents, while also contributing to the extension of the sea rice industrial value chain. Full article

The emergence of seekRNA- and bridgeRNA-guided recombination has introduced a distinct paradigm in genome engineering by coupling programmable RNA-directed DNA recognition with recombinase-mediated insertion, excision, inversion, and genomic rearrangement without canonical double-strand breaks. Since their discovery in 2024, these systems have progressed rapidly from bacterial mobile genetic elements and mechanistic characterization to structural elucidation and programmable genome engineering in human cells. However, these advances remain distributed across foundational and rapidly emerging studies, creating a need for an integrated molecular perspective on their mechanisms, technological development, and position within contemporary genome engineering. This review synthesizes the molecular architecture, RNA-guided recognition, strand-exchange mechanisms, programmability, and engineering of seekRNA and bridgeRNA systems, with particular emphasis on complementary human-cell advances involving ISCro4 and engineered IS621. Whereas ISCro4 systems have enabled multikilobase DNA insertion, genomic excision, and near-megabase inversion, the enIS621–tebRNA platform has enabled scarless kilobase-scale integration across multiple human cell types, including proof-of-concept functional CD19 chimeric antigen receptor and factor IX gene insertion. The review further integrates recent genome-scale bacterial rewriting and Targetable Recombinase Assisted DNA Exchange (TRADE)-mediated DNA replacement, while benchmarking RNA-guided recombination against conventional site-specific recombination, clustered regularly interspaced short palindromic repeats (CRISPR)-based editing, Programmable Addition via Site-specific Targeting Elements (PASTE), CRISPR-associated transposases, and emerging large-payload genome-writing strategies, including kilobase-scale nickase-targeting (KNIT) editing, Prime Assembly, engineered R2 retrotransposons, and TransCRISTI. This comparative framework highlights a broader transition from programmable sequence modification toward direct engineering of genomic architecture, while identifying recognition-site constraints, mismatch-tolerant recombination, unintended recombination products, delivery, and genome-wide specificity as key translational barriers. By integrating foundational mechanisms with recent mammalian engineering, genome-scale bacterial rewriting, large-payload technologies, and emerging computational design strategies, this review provides a contemporary framework for defining the distinctive capabilities, current limitations, and future development of programmable RNA-guided DNA recombination. 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

Background/Objectives: Risdiplam is a low-molecular-weight small-molecule modifier of SMN2 pre-mRNA splicing that was developed for spinal muscular atrophy (SMA) therapy and approved for the treatment of SMA as Evrysdi^® (Roche, Basel, Switzerland). Vapromin^® is a generic drug produced by JSC GENERIUM. In order to evaluate its biological activity and compare different batches of the reference drug and generic risdiplam, we performed comprehensive in vitro procedures. It is important to emphasize that this study did not assess the bioequivalence of the medicinal products for the purpose of comparing the biopharmaceutical quality of the generic and reference products. Instead, this study was designed specifically to compare their biological activity using cells derived from SMA patients and a reporter cell line. Methods: The biological activity of generic risdiplam was compared with that of the reference drug by assessing increases in SMN protein production and the relative transcription level of SMN2 mRNA in fibroblasts from SMA donors. Additionally, Exon 7 inclusion efficiency was evaluated using a constructed reporter cell line. Results: Using primary dermal fibroblasts from SMA probands, we demonstrated a concentration-dependent relationship between risdiplam concentration and SMN2 FL and SMN2 Δ7 transcript levels. At a risdiplam concentration of 0.18 μM, the relative SMN2 full-length transcript levels reached a maximum, with a mean 2.5-fold increase observed for both Evrysdi^® (Roche, Basel, Switzerland) and Vapromin^®. In primary fibroblasts derived from three SMA patients, the 2 SD quality range for Evrysdi^® (Roche, Basel, Switzerland) was 98.0–106.7% (σ(log RP) = 0.0092), and the activities of all Vapromin^® batches fell within this range. Using the reporter cell line, the quality range for Evrysdi^® (Roche, Basel, Switzerland) was 88.32–117.3% (σ = 0.0309), and the Vapromin^® values also fell within this range. Conclusions: This study experimentally confirmed that the in vitro biological activity of the generic drug Vapromin^® is comparable to that of Evrysdi^® (Roche, Basel, Switzerland). Further research should be conducted to confirm bioequivalence between the two products. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) develops when hepatic lipid acquisition and synthesis exceed the capacity for oxidation and very-low-density lipoprotein export. Flavonoids act on several components of this network, yet their therapeutic development is constrained by poor aqueous solubility, extensive intestinal and first-pass metabolism, variable activity of circulating metabolites, and limited information on hepatic exposure. Experimental studies link representative flavonoids to AMPK–SREBP-1c and PPARα signaling, mitochondrial quality control, Nrf2-dependent redox defense, inflammatory pathways, and the gut–liver axis. By contrast, the available randomized trials of quercetin, hesperidin, anthocyanins, green-tea catechins, EGCG, and soy isoflavones show at most modest changes in liver fat or biochemical markers and do not demonstrate metabolic dysfunction-associated steatohepatitis (MASH) resolution or fibrosis regression. Liposomal, lipid-based, polymeric, and nanocrystal formulations have improved dissolution, systemic exposure, or liver distribution in preclinical models, but comparative pharmacokinetics, chronic safety, manufacturability, and clinical efficacy remain poorly defined. The evidence therefore supports viewing flavonoids as formulation-dependent investigational candidates rather than established MASLD therapies. Progress will depend on chemically standardized products, exposure–response studies, clinically relevant models, and adequately powered trials using validated imaging or histological endpoints. Full article

Valerian (Valeriana officinalis L.), passionflower (Passiflora incarnata L.), and ginkgo (Ginkgo biloba L.) are among the most widely used medicinal plants in European phytotherapy, with well-documented traditional use for anxiety, insomnia, cognitive decline, attention-deficit/hyperactivity disorder (ADHD), and Parkinson’s disease. This narrative review critically analyses available clinical, pharmacological, toxicological, and regulatory data on these three species in the context of central nervous system (CNS) disorders. A comprehensive literature search was conducted in PubMed, Scopus, and the Cochrane Library; regulatory documents from the European Medicines Agency (EMA), the European Scientific Cooperative on Phytotherapy (ESCOP), and the World Health Organization (WHO) were also included. Valerian showed the most consistent clinical evidence for an improvement in sleep quality and reduction in anxiety. Passionflower demonstrated anxiolytic and mild sedative effects in several controlled trials. Ginkgo showed clinically relevant benefits in mild cognitive impairment, dementia, and vertigo. All three plants exhibited acceptable safety profiles at the recommended doses; however, significant drug interactions were identified, notably ginkgo’s inhibition of CYP2C19 and antiplatelet effects, and valerian’s potentiation of CNS depressants. Regulatory frameworks across EU member states remain inconsistent. Further high-quality randomized controlled trials with standardized extract characterization are needed. Full article

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the management of inflammatory disorders, pain, and fever due to their significant anti-inflammatory and antipyretic properties. However, their long-term use is often associated with multiple adverse effects, including gastric erosion, hemorrhage, and perforation, as well as cardiovascular, hepatic, and renal complications. Indomethacin is a potent NSAID commonly used in the treatment of pain and rheumatoid arthritis. Its poor water solubility, Biopharmaceutics Classification System (BCS) Class II, results in low aqueous solubility and high membrane permeability, and conventional dosage forms often fail to overcome pharmacokinetic limitations and gastrointestinal irritation. To address these drawbacks, alternative indomethacin-loaded drug delivery systems have been developed, which enable controlled release, enhanced solubility, and targeted delivery for improving therapeutic efficacy and safety profile. Nature provides a diverse reservoir of bioactive compounds with significant anti-inflammatory potential, making them promising alternatives or complementary agents to indomethacin. Representative examples include the alkaloids piperine and berberine; the flavonoids oleocanthal and apigenin; and the terpenoids thymoquinone, kahweol, and cafestol; as well as anthraquinones and iridoids. This review summarizes the current evidence on plant-derived anti-inflammatory compounds that may “replace” or act synergistically with indomethacin. In addition, we discuss the pharmacological properties of indomethacin and recent advances in drug delivery systems designed to improve its topical and systemic therapeutic applications. Full article

Alliance network embeddedness provides firms with access to external knowledge and resources, yet its innovation implications vary across firms and network contexts. This study examines how network structure and combinations of embedding characteristics are associated with corporate innovation performance. Based on 335 firm-level observations from Chinese listed biopharmaceutical manufacturing firms, the study first identifies heterogeneous alliance network environments through community detection and K-Means clustering. Four network types are identified: dyadic, ringlike, star, and complex alliances. Classification and regression trees (CART) are then employed to extract interpretable, threshold-based decision rules linking network embedding characteristics to high and non-high innovation performance. The results show that no single network characteristic is consistently associated with innovation performance across alliance types. In dyadic alliances, moderate cooperation intensity is associated with high innovation performance, whereas ringlike alliances exhibit conditional associations involving cooperation intensity and partner centrality. Star alliances are characterized by configurations involving cooperation breadth and network position, while complex alliances exhibit more multidimensional combinations of structural and relational conditions. The findings indicate that the innovation relevance of alliance network embeddedness is network-type-specific and configuration-dependent. As a complementary robustness analysis, fuzzy-set qualitative comparative analysis broadly supports several core configurational patterns identified by CART, while also revealing alternative configurations, particularly in complex alliances. The study demonstrates that understanding alliance network embeddedness requires attention to network context, empirical thresholds, and combinations of network characteristics rather than isolated network attributes. Full article