Search Results (549)

Advanced glycation end products (AGEs) are implicated in the pathogenesis of chronic diseases. This study investigated the inhibitory effect of theaflavin (TA) on AGE formation in a human serum albumin (HSA)-fructose model system, both in the absence and presence of non-cytotoxic Mg²⁺ or Mn²⁺. The underlying mechanism was elucidated using multiple spectroscopic techniques and molecular docking. TA significantly inhibited AGE formation, with the enhancement by metal ions following the order: 1.5 mM Mn²⁺ > 1.5 mM Mg²⁺ > 1 mM Mg²⁺. This trend aligned with the binding affinity between HSA and TA derived from molecular interaction studies. Site marker competition and docking results revealed that TA binds preferentially within subdomain IIA of HSA. Furthermore, the conformational changes in HSA following glycation and inhibition were monitored, along with the influence of metal ions on the antioxidant activity of TA. By integrating the results, it was concluded that free radical scavenging contributes more significantly to AGE inhibition than does blocking the glycation sites on HSA. Overall, this study elucidates the influence of metal ions on the inhibitory effect of TA against AGE formation and the corresponding mechanism, providing insights for the prevention and management of chronic diseases. Full article

Digestive enzymes such as pancreatic lipase (PL), α-glucosidase (AG), and α-amylase (AA) play key roles in the hydrolysis of dietary lipids and carbohydrates and are therefore relevant biochemical targets for evaluating compounds with potential to modulate postprandial metabolic responses. Neurolaena lobata (L.) R. Br. ex Cass. (Asteraceae) is a neotropical medicinal species traditionally used for several health-related conditions, including metabolic complaints. This study evaluated the in vitro inhibitory activity of the hydroalcoholic extract, selected VLC fractions, and isolated metabolites from N. lobata leaves against PL, AG, and AA. Enzyme inhibition screening of the extract and VLC fractions was used to select fractions for phytochemical investigation, affording six known metabolites: the sesquiterpene lactones neurolenin B (C1) and lobatin A (C2), the benzoic acid derivatives p-hydroxybenzoic acid (C3) and 3,4-dihydroxybenzoic acid (C4), and the flavonoids 6-hydroxykaempferol 3,7-dimethyl ether (C5) and quercetagetin 3,7-dimethyl ether (C6). The hydroalcoholic extract and the MeOAc and iPrOH fractions inhibited PL, AG, and AA. Among the isolated compounds, C1, C2, C5 and C6 inhibited PL and AG, with IC₅₀ values ranging from 134 to 615 µM and from 170 to 639 µM, respectively, whereas all compounds showed weak AA inhibition. Exploratory kinetic analysis yielded apparent inhibition profiles mainly consistent with competitive behavior; C6 showed an apparent profile consistent with noncompetitive inhibition against AG under the assay conditions used. These findings expand the phytochemical and in vitro bioactivity profile of N. lobata and provide preliminary evidence of digestive enzyme modulation in isolated enzyme systems, without establishing therapeutic efficacy. Full article

Marine-associated polar fungi are promising sources of structurally diverse natural products. To investigate polyketide metabolites from the Antarctic moss-derived fungus Penicillium sp. OUCMDZ-4014, HSQC NMR combined with DeepSAT analysis was used to prioritize fractions enriched in cyclic and aromatic polyketides, and chromane-like metabolites. Chromatographic separation yielded ten resorcylic acid lactone-derived aromatic polyketides, including RAL macrolides, ring-opened esters, and isocoumarins, among which compounds 4–7 were new. Their planar structures were established by HRESIMS and 1D/2D NMR analyses. Their chemical structures including configurations were established by HRESIMS, 1D/2D NMR, ECD calculations, 13C NMR calculations, and DP4+ analysis. Isocoumarins 7–10 displayed diverse levels of α-glucosidase inhibition, with compound 9 being the most active (IC₅₀ = 47.0 ± 3.83 μM). Kinetic analysis indicated noncompetitive inhibition by 9 and mixed-type inhibition by 10. Genome mining revealed a putative res biosynthetic gene cluster containing HR-PKS, NR-PKS, and tailoring-enzyme genes. Compound 1 underwent nonenzymatic conversion into 9 under culture-medium conditions, while trace conversion was also observed during concentration, revealing a chemical link between the RAL macrolide and isocoumarin scaffolds, and highlighting the contribution of post-biosynthetic chemical transformation to fungal polyketide diversification. Full article

Polycyclic aromatic hydrocarbons (PAHs), characterized by their high stability, are typical persistent organic pollutants that pose irreversible risks to human health. Conventional chemical oxidation methods exhibit limitations that hinder effective remediation in practice. In contrast, sulfate-radical-based advanced oxidation processes have emerged as promising alternatives, among which the heat-alkaline activation system for persulfate (PS) demonstrates distinct advantages. In this study, a heat-alkaline-activated PS system was established to investigate the degradation of PAHs in both simulated contaminated soils and coal chemical industrial site soils, as well as the modulatory effects of natural organic matter (NOM). Response surface methodology optimized critical experimental parameters to 12.53 mmol PS dosage, 60.31 °C reaction temperature, and a 1.55 CaO/PS molar ratio. Under these conditions, degradation efficiencies of 98.32% and 82.26% were achieved in simulated and field soils, respectively. Radical test experiments revealed a cooperative mechanism dominated by SO₄⁻• > •OH > O₂⁻• radicals, accompanied by auxiliary involvement of non-radical ¹O₂. Low concentrations of NOM plausibly facilitate degradation via a hypothesized electron transfer protective effect and boosted radical generation, whereas excessive NOM inhibits degradation through competitive consumption of reactive radicals. Density functional theory calculations identified preferred radical attack sites on the aromatic rings of PAHs and corroborated the degradation pathway involving aromatic ring oxidation, functional group addition, ring cleavage, and mineralization. QSAR-based theoretical toxicity predictions via T.E.S.T. suggested that the ultimate degradation products exhibit lower potential toxicity than parent PAHs. Experiments fill the knowledge gap regarding NOM-mediated regulation in heat-alkaline activated PS systems, and elucidate degradation mechanisms and toxicity evolution. Full article

Selective inhibition of MEK isoforms remains a central challenge in MAPK-targeted drug discovery, largely due to the structural similarity between MEK1 and MEK2. While MEK1 has been extensively characterized, the structural basis of MEK2-specific ligand recognition is not fully understood. Here, we present crystal structures of human MEK2 in complex with the noncompetitive inhibitor U0126 and the allosteric inhibitor refametinib at resolutions of 3.15 Å and 3.30 Å, respectively. Despite a conserved kinase fold, MEK2 exhibits isoform-specific features within the N-lobe β-sheet. Additional differences are observed in the relative orientation of the helix C and activation segment, and the helix F-supported regulatory spine. Structural differences are reflected in micromolar binding affinities for U0126 (K_d = 9.8 μM) and refametinib (K_d = 7.4 μM). Notably, a single N-lobe substitution (Thr87 in MEK2 versus Phe83 in MEK1) selectively enhanced U0126 binding. The MEK2 T87F mutant exhibited an approximately twofold increase in affinity, while refametinib binding remained largely unchanged. SEC–MALS analysis demonstrated that MEK2 predominantly exists as a monomer in solution, contrasting with the reported homodimeric behavior of MEK1. Molecular dynamics simulations supported these findings by revealing isoform-specific differences in oligomeric state-dependent flexibility and inhibitor-induced dynamics. Collectively, our findings define the structural basis underlying the differential inhibitor recognition of MEK2 and MEK1, providing mechanistic insight into isoform-selective MEK-targeted drug design. Full article

Excitatory–inhibitory (E-I) local circuits play a central role in synaptic plasticity and neural coding, yet their multilayer learning dynamics remain poorly understood. We constructed a multilayer feedforward spiking neural network with intra-layer E-I connectivity, using Izhikevich neurons to model regular spiking (RS) and fast spiking (FS) cells, and examined cooperative learning under excitatory and inhibitory spike-timing-dependent plasticity (eSTDP and iSTDP). FS-mediated lateral inhibition alleviates the long-term depression bias arising from RS firing rate adaptation via winner-take-all competition, promoting heterogeneous E→E weight differentiation while preserving mean synaptic strength. A $12\times 12$ parameter grid scan shows that iSTDP expands the stable learning region in the E-I parameter space and reveals a sustained cooperative co-evolution of eSTDP and iSTDP during training. For sparse coding, RS adaptation is the primary driver of Lifetime Sparseness, with FS inhibition acting as a cooperative enhancer; the network exhibits low sparseness at the input layer, a rapid increase at the second layer, and a stable plateau in deeper layers. For temporal pattern learning, the selectivity index $d^{\prime }$ improved substantially after training, reaching approximately 1.90 times that of the FS-absent condition; both interval sensitivity and pattern generalization tests confirmed that this advantage is robust across biologically plausible inter-group delays and preserved under small temporal jitter. Mutual information analysis reveals a consistent tendency for intra-layer FS circuits to maintain higher stimulus-related information across deep layers, consistent with FS-mediated suppression of non-specific responses. These findings provide computational evidence, within the scope of the present model, for understanding cortical E-I cooperative plasticity and inform design principles for neuromorphic systems with adaptive inhibitory regulation. Full article

Interleukin-22 binding protein (IL-22BP) is a soluble decoy receptor that competitively inhibits IL-22 by preventing its interaction with the IL-22 receptor. Although the IL-22 receptor is primarily expressed on non-hematopoietic cells, such as airway epithelial cells, the role of IL-22BP in the pathogenesis of asthma remains uncertain. We observed that IL-22BP was upregulated in the airways of wild-type (WT) mice intranasally sensitized and challenged with house dust mite (HDM) extract. To directly elucidate the function of IL-22BP in allergic airway responses, IL-22BP-deficient (IL-22BP−/−) and WT mice were sensitized and challenged with HDM, and airway responses were systematically assessed. IL-22BP−/− mice exhibited significantly lower airway hyperresponsiveness (AHR) compared to WT mice following sensitization and challenge with HDM. In contrast, eosinophil counts in bronchoalveolar lavage (BAL) fluid did not differ significantly between the two groups. Similarly, levels of interleukin (IL)-4, IL-5, IL-6, IL-13, IL-17A, and keratinocyte chemoattractant (KC) in BAL fluid were comparable between WT and IL-22BP−/− mice. Notably, IL-22 levels in lung homogenates were significantly higher in IL-22BP−/− mice than in WT mice after sensitization and challenge with HDM. These findings suggest that inhibition of IL-22BP attenuates the development of allergen-induced AHR, an effect likely mediated through enhanced IL-22 activity rather than alterations in airway inflammation or type 2 cytokine production. Full article

Human milk is widely recognised as the optimal source of nutrition for newborns and infants, providing not only an ideal macronutrient composition but also a range of bioactive components that exert important non-nutritional functions, and as such it represents the first functional food consumed in early life. Among these bioactive components, the human milk oligosaccharides (HMOs)—a structurally diverse family of glycans present in human milk at concentrations 100- to 1000-fold higher than in the milk of other mammalian species—have emerged as multifunctional contributors to the establishment of the intestinal microbiome, immune development, anti-infective defence, and epithelial barrier integrity during a developmental window characterised by immune immaturity. The aim of the present narrative review is to synthesise current evidence on the anti-infective properties of HMOs in infancy and to integrate, within a single framework, five interconnected mechanisms through which HMOs protect the infant against infection: glycan-mimicry-based competitive inhibition of pathogen adhesion, direct antimicrobial and antibiofilm activity, selective prebiotic shaping of the gut microbiome, modulation of innate and adaptive immune responses, and reinforcement of mucosal barrier integrity in the gut and lungs. Breastfeeding constitutes a natural strategy for anti-infective protection in early childhood, while infant formulas supplemented with biotechnologically produced HMOs that are structurally identical to those in human milk provide measurable benefits for non-breastfed infants. Full article

Plant-derived bioactive peptides have garnered widespread interest for their functions in managing obesity and associated metabolic disorders. This study investigated the lipid-lowering activity and underlying mechanisms of VPIIMH, a hexapeptide derived from Chlorella pyrenoids, using in vitro enzymatic assays, Caenorhabditis elegans models, and network pharmacology. In vitro, VPIIMH acted as a reversible non-competitive inhibitor of pancreatic lipase, achieving an inhibition rate of 43.17 ± 1.47% at 8.0 mg/mL. Molecular docking revealed that this inhibition likely occurs through ionic bonds between VPIIMH and PL (1LPB) at Arg256. In a high-fat C. elegans model, treatment with 0.5 mg/mL VPIIMH significantly reduced fat accumulation by 37.2% and triglyceride levels by 26.9%. Furthermore, VPIIMH extended the lifespan of C. elegans under oxidant stress by 40.3% and under heat stress by 17.5%. Network pharmacology predicted that VPIIMH targets nine core proteins, which were classified into three synergistic modules: the SIRT1-PPAR for core regulation, the RAS for systemic coordination, and the inflammatory target (CCR5, MMP9, EGFR) for microenvironment support. This study elucidates the multi-target and multi-pathway mechanism of VPIIMH, suggesting its potential application in combating obesity and related lipid metabolism disorders. These findings provide a scientific basis for the development of VPIIMH as a functional food ingredient targeting metabolic health. Full article

A new series of isoxazole-fused thiazole–oxazole derivatives (11a–n) was rationally designed and synthesised with the aim of developing potent carbonic anhydrase (CA) I and II inhibitors. The synthesis was achieved in five steps starting from 4-bromoacetophenone, involving key intermediates such as hydroxylamine hydrochloride, hydrazine hydrate, thioisocyanate, and various phenacyl bromide derivatives, using ethanol, triethylamine, tetrahydrofuran (THF), and dimethylformamide (DMF) as solvents. The synthetic route included the formation of a β-ketoester, isoxazole ester, hydrazine adduct, thiourea derivative, and, ultimately, a thiazole ring. The structures of the final compounds were confirmed by ¹H-NMR, ¹³C-NMR, IR spectroscopy, and elemental analysis. All compounds were examined as inhibitors of human carbonic anhydrase (hCA) I and II, and all of them inhibited hCA I and hCA II. Kinetic investigation results revealed that these compounds inhibited hCA I and hCA II in a non-competitive manner. To further explore the molecular basis of their inhibitory activity, in silico studies, including molecular docking and 300 ns molecular dynamics (MD) simulations, were carried out against both CA I and CA II isoforms. These simulations provided detailed insights into the dynamic behaviour, stability, and key binding interactions of the compounds within the enzyme active sites, supporting their potential as promising carbonic anhydrase inhibitors. Full article

Oxidative stress and inflammation play a key role in many diseases. This study evaluated the potential of bioactive compounds from Red-belted Bracket and Artist’s Bracket mushrooms to mitigate these processes. Multistep extraction yielded fractions with diversified composition (triterpenoids, polysaccharides) and bioactivities, including antioxidant properties and inhibition of pro-inflammatory enzymes. Both species were rich in triterpenoids: ethanolic extracts from Artist’s Bracket contained mainly ganoderenic and ganoderic acids (≈31 μg/g d.w.), while Red-belted Bracket extracts contained phenolic acids (≈20 μg/g d.w., mainly vanillic and chebulic acids) and triterpenoids (≈73 μg/g d.w., mainly forpinic and formipinic acids). The alkaline and ethanolic extracts exhibited the highest radical scavenging and reducing activities. Lipoxygenase was inhibited only by ethanolic extracts, with IC₅₀ values of 0.93 mg d.w./mL for Artist’s Bracket (mixed inhibition) and 0.62 mg d.w./mL for Red-belted Bracket (noncompetitive). Artist’s Bracket was also a potent source of xanthine oxidase inhibitors acting uncompetitively (IC₅₀ = 0.71, 1.39, and 2.06 mg d.w./mL for ethanolic, methanolic, and aqueous extracts, respectively). In contrast, Red-belted Bracket was less active (IC₅₀ = 3.84 mg d.w./mL, noncompetitive). In conclusion, these mushrooms, particularly their ethanolic extracts, are promising sources of compounds with antioxidant and anti-inflammatory activities, acting as effective inhibitors of lipoxygenase and xanthine oxidase. Full article

Mycotoxins are one of the biggest threats to global food safety, public health, and economic stability. More than 400 mycotoxins have been found to be secondary metabolites of toxigenic fungi, mostly from the genera Aspergillus, Fusarium, Penicillium, and Alternaria. Aflatoxins (AFs), ochratoxin A (OTA), deoxynivalenol (DON), zearalenone (ZEA), fumonisins (FBs), patulin (PAT), and T-2/HT-2 toxins are the most dangerous to the health of people and animals. Conventional physical and chemical decontamination methods are only partially effective and can reduce food quality, leave toxic residues, or be too expensive for smallholder food systems. Recent studies have shown that the application of lactic acid bacteria (LAB) as a biological detoxification method is a safe, cost-effective, and environmentally friendly option, and has a long history of safe use in fermented foods. Selected strains or taxonomic units have been granted GRAS status by the FDA or QPS (Qualified Presumption of Safety) status by EFSA. However, their use for mycotoxin detoxification still requires strain-level safety assessment and efficacy validation in the intended food matrix. There are several mechanisms by which LAB employ to reduce the bioavailability of mycotoxins in food systems: (i) physical adsorption via cell wall components such as peptidoglycan, teichoic acids, and exopolysaccharides; (ii) enzymatic biotransformation that may produce non-toxic or less-toxic metabolites, though the safety of degradation products requires case-by-case toxicological assessment; (iii) antifungal metabolite production that inhibits fungal growth and mycotoxin biosynthesis; and (iv) competitive exclusion of toxigenic fungi during fermentation. This comprehensive review examines the existing evidence on the detoxification of major food mycotoxins by LAB, with an emphasis on mechanisms, strain-specific efficacy, food-matrix applications, and factors that affect detoxification efficacy. Discussion has also been made of translating in vitro findings to in vivo settings and food-scale applications, alongside regulatory frameworks, current challenges, and future research directions. The review also suggests ways to combine LAB with new technologies, such as encapsulation, genetic engineering, and fermentation optimization, to make food systems safer by synergistically controlling mycotoxins. Full article

Background/Objectives: Gold(I) complexes are promising bioactive agents with anticancer and anti-inflammatory potential. This study evaluated cytochrome P450 (CYP) interactions and in vitro pharmacokinetic properties of two Au(I)–triphenylphosphine complexes bearing 6-alkoxy-9-deazapurine ligands. Methods: Complexes [Au(HL_1,2)(PPh₃)] (HL₁ = 6-isopropyloxy-9-deazapurine, complex 1; HL₂ = 6-benzyloxy-9-deazapurine, complex 2) were investigated. Inhibition of nine human CYP isoforms was assessed in liver microsomes, and kinetics were analyzed using Dixon and Lineweaver–Burk plots. CYP binding was evaluated by UV–Vis difference spectroscopy. ADME properties (chemical/plasma stability, microsomal stability, plasma protein binding, and PAMPA permeability) were determined. Binding thermodynamics were analyzed by ITC. Results: Both complexes weakly inhibited most CYP isoforms, with stronger effects on CYP2C9 and CYP3A4/5. A non-competitive inhibition mechanism was observed, which may be related to the binding of the complexes to the substrate channels of CYP2C9 and CYP3A4, thereby limiting the active site’s accessibility to the substrate, as supported by molecular docking studies. UV–Vis spectra showed type I binding with Kd values of 9.32 µM (1) and 12.64 µM (2). Both compounds showed high chemical and plasma stability (>90%), moderate microsomal stability (~60% after 60 min), high plasma protein binding (~80%), and low passive permeability. Conclusions: Au(I)–triphenylphosphine complexes with 6-alkoxy-9-deazapurine ligands exhibit moderate CYP affinity and defined pharmacokinetic profiles, supporting further preclinical evaluation. Full article

Proton pump inhibitors (PPIs) serve as the primary treatment for acid-related disorders, such as gastroesophageal reflux disease and peptic ulcer disease. Although PPIs are regarded as the first-line medication for acid suppression, they have notable limitations, including the need for acid-mediated activation, a short half-life and duration of action, and metabolic variability. Zastaprazan is a newly developed potassium-competitive acid blocker (P-CAB) that competitively and reversibly inhibits acid production and secretion. Like other P-CABs, zastaprazan exhibits pharmacodynamic and pharmacokinetic properties that differs significantly from those of PPIs. These differences offer potential advantages, such as rapid, robust, and long-standing acid suppression, the lack of CYP2C19 metabolism, and no need for conversion into an active form. Completed clinical trials of zastaprazan have demonstrated comparable or superior efficacy to that of PPIs for the healing of erosive esophagitis and gastric ulcers without concerning safety signals. Notably, in erosive esophagitis, zastaprazan 20 mg demonstrated faster healing at week 4 compared to esomeprazole 40 mg, whereas in gastric ulcers, zastaprazan 20 mg achieved a 100% healing rate at 8 weeks compared to 97.1% with lansoprazole 30 mg. Zastaprazan is approved in the Republic of Korea for the treatment of erosive esophagitis and gastric ulcer and is undergoing phase III clinical trials for the prevention of non-steroidal anti-inflammatory drug-induced peptic ulcer and the treatment of non-erosive reflux disease. In this review, we summarize and discuss the pharmacology, efficacy, and safety of zastaprazan in acid-related disorders. Full article

The increasing demand for premium-quality meat has intensified interest in the molecular regulators that govern lipid deposition and sensory quality. Lipid metabolism, encompassing synthesis, oxidation, and storage, represents a key biological process affecting intramuscular fat content, tenderness, and flavor. G0/G1 Switch Gene 2 (G0S2) is widely recognized as an endogenous, non-competitive inhibitor of adipose triglyceride lipase. By inhibiting this key lipase, G0S2 restrains triglyceride hydrolysis and helps preserve lipid storage. Recent studies further suggest that G0S2 participates in adipocyte differentiation, mitochondrial regulation, apoptosis, and inflammatory signaling. Together, these findings indicate that G0S2 functions not only in lipolysis control but also as a multifunctional regulator of energy metabolism and cellular homeostasis. Despite its pleiotropic roles, which position G0S2 as a key integrator of lipid metabolism and cellular signaling networks, the specific roles and regulatory mechanisms by which G0S2 influences lipid metabolism and meat quality remain incompletely understood. This review summarized recent advances in G0S2-mediated lipid metabolism with emphasis on its regulatory network in livestock species. The physiological mechanisms by which G0S2 modulated lipolysis, lipid deposition, and intramuscular adipogenesis were discussed, along with nutritional, hormonal, and epigenetic factors controlling its expression. Moreover, its functional implications for meat quality improvement, marbling formation, and feed efficiency were highlighted. Understanding the molecular and regulatory features of G0S2 provided a foundation for developing genetic and nutritional strategies to optimize lipid utilization and enhance meat quality in modern animal production systems. Full article