Search Results (869)

Background/Objectives: Epilepsy is characterized by unpredictable seizures and drug resistance, along with rising antimicrobial resistance (AMR), highlighting the urgent need for innovative dual-action therapies. This study aimed to design, develop, and evaluate novel pyrazolone derivatives for a dual antimicrobial and antiepileptic potential. Methods: Novel pyrazolone derivatives were designed, synthesized (using 2,4-dinitrophenylhydrazine/semicarbazide condensation with ethyl acetoacetate), and evaluated through molecular docking against antimicrobial (4URM, 3FYV, 3FRA) and neuronal targets (4COF, 5TP9, 5L1F). The in vitro antimicrobial activity was assessed against Gram-positive (S. aureus) and in vitro Gram-negative (E. coli, P. aeruginosa) strains via agar cup plate assays, while in vivo antiepileptic efficacy was tested in a PTZ-induced seizure model in Swiss albino mice. Results: Compound IIa showed potent dual activity, inhibiting E. coli (9 mm zone at 80 μg/mL) and S. aureus (9.5 mm at 80 μg/mL), alongside a significantly delayed seizure onset in the PTZ-induced mouse model (100% survival rate, 45 sec delayed seizure onset, p < 0.001). Compounds Ia and Id showed selective activity against E. coli (6 mm at 80 μg/mL) and P. aeruginosa (7 mm at 80 μg/mL), respectively. Docking studies revealed that compound IIa has a superior binding affinity (−7.57 kcal/mol for 3FYV) compared to standards, driven by hydrogen bonds (SER X: 49) and hydrophobic interactions (LEU X: 20). Conclusions: This study presents a novel approach by proposing a rationally designed pyrazolone scaffold exhibiting both antimicrobial and antiepileptic activity, which integrates in silico modeling with experimental validation. Compound IIa emerged with preliminary dual biological activities, exhibiting strong antibacterial activity, a superior binding affinity toward both bacterial and neuronal targets, and notable seizure prevention in vivo. These findings show the potential of multifunctional pyrazolone derivatives as a new treatment strategy for addressing drug-resistant infections linked to epilepsy and support further optimization toward clinical development. Full article

To improve the gel quality of low-salt shrimp surimi gel (SSG) from Pacific white shrimp (Litopenaeus vannamei), L-arginine (L-Arg), L-lysine (L-Lys), and L-proline (L-Pro) were used as partial substitutes for NaCl. The effect of the three amino acids on gel properties, protein conformation, microstructure, and in vitro digestion of low-salt SSG were systematically analyzed. Macro-/microstructural analyses revealed that L-Arg, L-Lys, and L-Pro promoted denser three-dimensional networks in low-salt SSG with smaller pore sizes. Compared with the low-salt control (LC) group, the addition of L-Arg, L-Lys, and L-Pro significantly increased the gel strength of low-salt SSG. Cooking loss was significantly decreased from 10.80% (LC group) to 1.89–4.31%. Protein solubility and turbidity results demonstrated that all amino acids markedly enhanced protein solubilization and inhibited protein aggregation. L-Arg and L-Lys mainly promoted hydrogen and disulfide bonds, but reduced hydrophobic interactions and ionic bonds. L-Arg impaired digestibility only in the gastric phase, whereas L-Lys suppressed digestibility across both gastric and intestinal phases. Through molecular docking technology, ASN-238 and LYS-187 of myosin (the dominant gel-forming protein) are the key shared binding residues with three amino acids. These findings suggest that amino acids provide a feasible approach to specifically modulate the gel characteristics of low-salt surimi products. Full article

Promising approach for the expansion of the functional food sector is combining various ingredients with potential health benefits. The aim of this study was to create protein aggregates by freeze-drying encapsulation. Rice or pea proteins were used as carriers for encapsulation of chokeberry juice polyphenols. Additionally, disaccharides (sucrose and trehalose) were added to explore possible enhancement of encapsulation of polyphenols. Two methods were employed for complexation of ingredients prior to freeze-drying: one based on complexation of all ingredients at the same time and the other on complexation first of proteins with disaccharides and then with chokeberry juice. All parameters affected the binding of polyphenols on proteins. Total polyphenols, proanthocyanidins, individual polyphenols, and antioxidant potentials of created protein aggregates were determined. When rice protein was the main carrier, the addition of disaccharides caused a decrease in total polyphenols and proanthocyanindins contents (22.41–24.01 mg GAE/g and 6.36–7.28 mg PB2E/g, respectively) in comparison to aggregates without their addition (28.03 mg GAE/g and 8.57 mg PB2E/g, respectively). In the case of pea proteins, a different trend was observed. Aggregates without disaccharide addition had a lower amount of total polyphenols and proanthocyanindins (21.25 mg GAE/g and 5.56 mg PB2E/g, respectively) than those with disaccharide addition (21.42–26.44 mg GAE/g and 6.37–9.45 mg PB2E/g, respectively). Interactions between compounds were proven through IR spectra, and they included changes in amid structures, as well as hydrogen bonds and hydrophobic interactions. Such formulated plant-based protein aggregates can be used in the food industry for the enrichment of foods with polyphenols, incensement of antioxidant potential, and prolonging stability of products. Full article

Tylorrhynchus heterochaetus is an aquatic food with both edible and medicinal value in China. With a protein-rich body wall, it has strong potential for producing bioactive peptides. To explore its potential as a source of immunomodulatory peptides, in this study, flavor enzymes were selected as the optimal hydrolases, and the hydrolyzed products were subjected to ultrafiltration fractionation. The <3000 Da portion exhibited the most effective immune-stimulating activity in RAW 264.7 macrophages, enhancing phagocytosis and promoting the secretion of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nitric oxide (NO) in a concentration dependent manner. Peptide omics analysis, combined with the activity and safety screened by bioinformatics, identified 43 candidate peptides. Molecular docking predicts that three novel peptides, LPWDPL, DDFVFLR and LPVGPLFN, exhibit strong binding affinity with toll-like receptor 4/myeloid differentiation factor-2 (TLR4/MD-2) receptors through hydrogen bonding and hydrophobic/π stacking interactions. Synthetic verification confirmed that these peptides were not only non-toxic to cells at concentrations ranging from 62.5 to 1000 µg/mL, but also effective in activating macrophages and stimulating the release of immune mediators. This study successfully identified the specific immunomodulatory peptides of the Tylorrhynchus heterochaetus, supporting its high-value utilization as a natural source of raw materials for immunomodulatory functional foods. Full article

The clinical durability of SARS-CoV-2 main protease (M^pro) inhibitors depends on their resilience to emerging resistance mutations. Recent genomic surveillance and functional reports have highlighted substitutions at positions 49, 165, and 301, raising questions about the robustness of the noncovalent inhibitor WU-04 in variant backgrounds. Here, we combined μs-scale, triplicate molecular dynamics simulations with end-state binding free energy estimates and a network-rewiring inference (NRI) framework that maps long-range dynamical communication across the full protease dimer. We evaluated wild type (WT), single mutants M49K, M165V, S301P, and selected double mutants (M49K & M165V, M49K & S301P). Relative to WT, single substitutions produced reductions in computed binding affinity of up to ~12kcal/mol, accompanied by loss or reshaping of the S2 subsite and altered ligand burial. Notably, the M49K/S301P double mutant partially restored WU-04 engagement, narrowing the ΔΔG_restore gap to within ΔΔG_restore of WT and re-establishing key hydrophobic and hydrogen-bond contacts. NRI analysis revealed that distal residue 301 participates in a communication corridor linking the C-terminal helical domain to the active-site cleft; its substitution rewires inter-domain coupling that can compensate for local disruptions at residue 49. Together, these results identify structural hotspots and network pathways that may inform the design of next-generation M^pro inhibitors with improved mutation tolerance—specifically by strengthening interactions that do not rely solely on the mutable S2 pocket and by engaging conserved backbone features near the 165–166 region. Full article

Despite their potential, alkali-treated konjac glucomannan (KGM) gels are limited by excessive brittleness and a lack of eco-friendly synthesis methods, creating an urgent need for more durable and ‘green’ alternatives. In this study, highly stable KGM gels were constructed under low-alkali conditions by adjusting the ethanol content. The results showed that intermolecular hydrogen bonding and hydrophobic interactions were enhanced with increasing ethanol concentration (0–20% v/v) under low-alkaline conditions. The physicochemical properties of KGM gels showed dynamic improvement, with denser micro-network morphology and simultaneous enhancement of thermal stability. However, the addition of a high ethanol concentration (20% v/v) tended to trigger local aggregation, disrupting the gel network structure. At an ethanol addition of 15%, the hydrogen bonding and hydrophobic interactions of KGM gels reached an optimal equilibrium, exhibiting the most compact gel network and excellent resistance to deformation. This study reveals the regulation of the microstructure and macroscopic properties of KGM gels by ethanol, which provides theoretical support for the construction of high-performance KGM gels under low-alkali conditions. Full article

Quercetin’s therapeutic potential is limited by its poor water solubility and rapid degradation. Natural clay minerals such as kaolinite present sustainable platforms for drug delivery, yet the molecular mechanisms of drug encapsulation are not fully understood. Specifically, the role of kaolinite’s structural polarity, its hydrophilic aluminol (001) and hydrophobic siloxane (00-1) basal surfaces, in selective drug adsorption remains unexplored. This study combines Monte Carlo sampling and Density Functional Theory (DFT) to provide the first quantitative, atomistic comparison of quercetin adsorption on both kaolinite surfaces. The results demonstrate a pronounced polarity-driven selectivity. Strong, exothermic adsorption (−206.65 kJ mol⁻¹) occurs on the hydrophilic (001) surface, stabilized by a network of five hydrogen bonds. In contrast, the hydrophobic (00-1) surface exhibits significantly weaker sorption (−147.16 kJ mol⁻¹), dominated by van der Waals interactions. Charge-transfer analysis shows that the hydrophilic (001) surface exhibits a net charge transfer of −0.198 e, approximately 2.4 times greater than that of the hydrophobic (00-1) surface (−0.083 e), consistent with differential electron density maps and partial density of states. By linking hydrogen bonding and charge transfer to adsorption energy, these results elucidate how surface polarity dictates drug encapsulation. This work establishes a predictive framework for designing kaolinite-based nanocarriers with optimized stability, bioavailability, and controlled release, guiding the development of sustainable drug delivery systems. It is noted that this DFT study models adsorption at 0 K using periodic slab models in a vacuum. Full article

Background/Objectives: Osteoporosis is a multifactorial skeletal disorder in which chronic inflammation, dysregulated cytokine signaling, and metabolic imbalance contribute to excessive bone resorption and impaired bone formation. Asiatic acid has demonstrated bone-protective effects, but its molecular mechanisms in osteoporosis remain incompletely understood. This study aimed to investigate the anti-osteoporotic mechanisms of asiatic acid using an integrative in silico strategy. Methods: Network pharmacology analysis was performed to identify osteoporosis-related molecular targets of asiatic acid. Molecular docking was used to predict the binding modes and affinities between asiatic acid and its target proteins. Molecular dynamics simulation was used to assess the structural stability and interaction persistence of the asiatic acid–protein complex. Results: Network pharmacology identified 135 overlapping targets between asiatic acid and osteoporosis, with IL-6, STAT3, PPARG, and NFKB1 emerging as key hubs. KEGG analysis indicated the PPAR signaling pathway as a potential mechanism underlying the anti-osteoporotic effect. Molecular docking showed strong binding energies of asiatic acid with all predicted target proteins, with the highest affinity observed for IL-6, involving key residues ASN61, LEU62, GLU172, LYS66, and ARG168. Consistently, molecular dynamics simulation confirmed stable binding of asiatic acid to IL-6, with persistent interactions with ASN61, LYS66, LEU62, LEU64, and GLN154 mediated by hydrogen bonds, water bridges, and hydrophobic interactions. Conclusions: This integrative in silico study provides mechanistic insight into the potential anti-osteoporotic actions of asiatic acid, implicating IL-6 as a plausible upstream molecular target. These results establish a robust mechanistic framework for future translational studies exploring asiatic acid as a natural therapeutic candidate for osteoporosis. Full article

Background: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors demonstrated amyloid-lowering efficacy but failed in phase II/III clinical trials due to adverse effects and limited disease-modifying outcomes. This study employed an integrated network pharmacology and molecular docking approach to quantitatively elucidate the multitarget mechanisms of 4 (phase II/III) discontinued BACE1 inhibitors (Verubecestat, Lanabecestat, Elenbecestat, and Umibecestat) and the preclinical compound AM-6494 in Alzheimer’s disease (AD). Methods: Drug-associated targets were intersected with AD-related genes to construct a protein–protein interaction (PPI) network, followed by topological analysis to identify hub proteins. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed using statistically significant thresholds (p < 0.05, FDR-adjusted). Molecular docking was conducted using AutoDock Vina to quantify binding affinities and interaction modes between the selected compounds and the identified hub proteins. Results: Network analysis identified 10 hub proteins (CASP3, STAT3, BCL2, AKT1, MTOR, BCL2L1, HSP90AA1, HSP90AB1, TNF, and MDM2). GO enrichment highlighted key biological processes, including the negative regulation of autophagy, regulation of apoptotic signalling, protein folding, and inflammatory responses. KEGG pathway analysis revealed significant enrichment in the PI3K–AKT–MTOR signalling, apoptosis, and TNF signalling pathways. Molecular docking demonstrated strong multitarget binding, with binding affinities ranging from approximately −6.6 to −11.4 kcal/mol across the hub proteins. Umibecestat exhibited the strongest binding toward AKT1 (−11.4 kcal/mol), HSP90AB1 (−9.5 kcal/mol), STAT3 (−8.9 kcal/mol), HSP90AA1 (−8.5 kcal/mol), and MTOR (−8.3 kcal/mol), while Lanabecestat showed high affinity for AKT1 (−10.6 kcal/mol), HSP90AA1 (−9.9 kcal/mol), BCL2L1 (−9.2 kcal/mol), and CASP3 (−8.5 kcal/mol), respectively. These interactions were stabilized by conserved hydrogen bonding, hydrophobic contacts, and π–alkyl interactions within key regulatory domains of the target proteins, supporting their multitarget engagement beyond BACE1 inhibition. Conclusions: This study demonstrates that clinically failed BACE1 inhibitors engage multiple non-structural regulatory proteins that are central to AD pathogenesis, particularly those governing autophagy, apoptosis, proteostasis, and neuroinflammation. The identified ligand–hub protein complexes provide a mechanistic rationale for repurposing and optimization strategies targeting network-level dysregulation in Alzheimer’s disease, warranting further in silico refinement and experimental validation. Full article

The purpose of the study was to characterize the basic structure of nanoparticles (Zein-CS-Cur-Que) embedded in curcumin and quercetin, realize the synergistic antioxidant of dietary polyphenols, and improve the transmembrane transport rate and bioavailability of curcumin. The oral delivery system Zein-CS-Cur-Que developed based on the synergistic encapsulation of curcumin and quercetin using the anti-solvent method with corn alkyd-soluble proteins and sodium caseinate possessed varying nanoparticle sizes (173.96–191.03 nm) and good dispersibility (PDI < 0.17), and relied on electrostatic interactions, hydrogen bonding, and hydrophobic interactions to successfully encapsulate curcumin (94.62%) and quercetin (73.75%). The results showed that Zein-CS-Cur-Que enhanced the stability and antioxidant activity of curcumin, and increased the bioaccessibility (nearly 2-fold) and rate of translocation (nearly 2-fold) of curcumin in the gastrointestinal tract significantly. Therefore, the nanocomposite system developed in this study is crucial for the development of functional foods and dietary supplements, providing effective insights into the synergy of polyphenol interactions. Full article

Type 2 diabetes mellitus (T2DM) poses a critical global health burden, necessitating safer multi-target therapies. We pioneer the exploration of novel bioactive peptides from Tenebrio molitor larvae—an underexplored, sustainable, and edible insect protein—through proteomics-guided screening and bioassays. Six unique peptides (DK-7, WK-6, GR-7, FK-8, SK-6, and DK-8) demonstrated significant α-glucosidase and dipeptidyl-peptidase IV (DPP-IV) inhibitory effects, and significant glucose consumption enhancement in insulin-resistant HepG2 cells. Molecular docking revealed a binding topology where peptides interacted with α-glucosidase at its active sites (Glu271, Arg643, Arg647, Arg653, Tyr733, Lys765, and Glu767) and with DPP-IV at active residues (Phe357, Tyr547, Trp629, Asp729, and Gln731) through dual hydrogen-bond networks and hydrophobic interactions, establishing a novel inhibition mechanism. We wish to propose that insect-derived biopeptides have potential value as next-generation therapeutics, simultaneously advancing sustainable drug discovery and approximating functional food bioresources to biomedicine. Full article

Janus kinase 2 (JAK2) is a key mediator of oncogenic signaling and a promising therapeutic target in cervical cancer. This study employed a combination of in silico and in vitro approach to discover sesquiterpene lactone (SL) derivatives with JAK2 inhibitory activity. Molecular docking of forty SL derivatives, followed by drug-likeness and toxicity prediction, led to the selection of six candidates for synthesis and biological evaluation. Among these, SL10 (12.7 nM) and SL35 (21.7 nM) demonstrated potent JAK2 inhibition and exhibited selective cytotoxicity toward HeLa cervical cancer cells, outperforming ruxolitinib. Flow cytometry confirmed apoptosis induction and ROS elevation, suggesting ROS-mediated cytotoxic mechanisms. The 1 µs MD simulations demonstrated that both hydrogen bonding and hydrophobic interactions are critical determinants in stabilizing potent SLs–JAK2 complexes. These findings support SL10 and SL35 as promising scaffolds for further development of JAK2-targeted therapies in cervical cancer. Full article

Functionalized edible coatings represent a promising strategy to mitigate postharvest losses in fresh and fresh-cut fruits. This study developed a novel, ternary active coating by integrating pectin with a cationic antimicrobial polypeptide (ε-polylysine) and a hydrophobic plant flavonoid (luteolin). The resulting composite film demonstrated transformative improvements in hydrophobicity, antioxidant, and antimicrobial activities as compared with conventional pectin-based films. Specially, the ternary composite film exhibited enhanced barrier performance, reducing water vapor, oxygen and carbon dioxide permeability by 49.1%, 68.6%, and 26.5%, respectively. When applied to fresh-cut apples, the coating effectively suppressed the browning and microbial proliferation while maintaining the hardness, total phenols and flavonoids, total soluble solids, and titratable acids over a 12-day refrigerated storage period. Comprehensive characterization via Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and molecular docking simulations revealed that these superior functionalities originate from synergistic electrostatic interactions and hydrogen-bonding networks within the ternary matrix. This work provides a practical strategy for designing high-performance, plant-based coatings to reduce food waste and improve the quality of fresh-cut produce. Full article

This study investigates the adsorption/desorption behaviour of the widely used fungicide cymoxanil in twelve acidic agricultural soils, providing the first comprehensive assessment of its retention dynamics. Cymoxanil exhibited low adsorption, with K_d(ads) values ranging from 0.57 to 4.40 L kg⁻¹ and adsorption percentages between 18.7 and 65.9% at the highest tested concentration, suggesting high mobility and bioavailability in soils and, consequently, a potential environmental and human health risk. Hysteresis was observed, with desorption percentages for the highest initial concentration ranging from 2.4% to 32.6%, indicating that part of the adsorbed compound remained relatively strongly retained. Adsorption was positively correlated with desorption parameters, reflecting a statistical association whereby soils with higher adsorption tended to exhibit lower desorption. Among soil physicochemical properties, pH appeared to play a key role in controlling cymoxanil retention, as higher pH was associated with greater adsorption and lower desorption in the studied soils. Organic matter, clay content, and exchangeable base cations also appeared to influence cymoxanil behaviour, although to a lesser extent than pH. In this regard, soils richer in organic matter and clay, and with higher effective cation exchange capacity (eCEC), tended to display greater retention. Overall, cymoxanil adsorption appears to be largely governed by physisorption mechanisms—electrostatic interactions, cation exchange, and hydrophobic partitioning—while the observed hysteresis suggests that specific interactions, such as hydrogen bonding and π-π interactions, may also contribute to retention without implying irreversible chemisorption. Full article

The environmental behavior of biodegradable plastics under long-term hydrodynamic aging processes in seawater remains poorly understood, although plastic pollution has attracted global concern. This study obtained poly(butylene adipate-co-terephthalate) (PBAT) and poly(butylene succinate) (PBS) microplastics that endured 36-month hydrodynamic aging in seawater to elucidate their physicochemical transformations and interactions with benzo(a)pyrene (BaP). Hydrodynamic aging markedly altered surface morphology, generated cracks and pores, and enriched -C=O and -OH groups, indicating oxidative degradation. Adsorption experiments showed that BaP adsorption capacity of virgin PBAT/PBS reached 213.3/235.3 μg g⁻¹, while it increased to 233.3/258.2 μg g⁻¹ after hydrodynamic aging in seawater. Elevated salinity and alkaline conditions reduced BaP adsorption on microplastics. Notably, hydrodynamic aging mitigated the risk of BaP desorption from PBAT in ectothermic organisms. Gibbs free energy calculations indicated that the adsorption process was primarily driven by hydrophobic effects, hydrogen bonding, and van der Waals forces. These findings highlight that long-term hydrodynamic aging substantially modifies the interfacial properties of biodegradable plastics to alter their capacity for mediating the environmental fate of hydrophobic organic pollutants in marine ecosystems. Full article