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The bioactive isoflavan glabridin of Glycyrrhiza glabra remains in the limelight because of its widespread pharmacological prospect. Here, a better and eco-friendly synthetic method to (±)-glabridin has been introduced, that relies on a six-step protocol, and that is more overall yielding, less dependent on chromatographic purification, and more operationally simpler than previously described and patented ones. The synthesized (±)-glabridin is very effective antioxidant, showing 87.46% the percentage of inhibition. Antibacterial assay indicates that there is a distinct strain-dependent reaction, with a significant response against Escherichia coli (MIC = 33.8 μM) and moderate efficacy against Staphylococcus aureus (MIC = 125 μM). Cytotoxicity assay and IC50 values show a dose-response profile, (±)-glabridin would not be cytotoxic until 62.5 μM and therefore, these concentrations would be more applicable to mechanistic or efficacy research which would need minimal viability decline and a good safety margin within the assayed concentration range. In addition, molecular docking experiments have been performed against the chosen biological targets, which are in agreement with the experimental findings. On the whole, this study holds a viable and green chemistry principles guided synthesis of (±)-glabridin that indicates how it could be used in multidrug functions and pertains to the future bioorganic and medicinal chemistry research.

Interleukin-4 (IL-4) and its cognate receptor subunit IL-4 receptor alpha (IL-4Rα) constitute a central cytokine-receptor recognition system in type 2 inflammation and represent a challenging therapeutic target at the protein-protein interaction level. The IL-4/IL-4Rα interface is broad, highly polar, and dynamically linked to higher-order receptor assembly, creating substantial barriers to direct small-molecule modulation while also offering a valuable framework for structure-guided ligand design. This review examines the molecular basis of IL-4 signaling with emphasis on receptor recognition, interfacial hotspot residues, heterodimerization with γc or IL-13Rα1, and the structural determinants that govern downstream pathway activation. Clinically validated antibodies targeting IL-4 or IL-4Rα are discussed as important examples of successful interface-directed modulation and as benchmarks for target validation. Particular attention is then given to emerging small-molecule strategies aimed at perturbing IL-4-centered signaling, including direct and indirect modulators, while macrocycles are briefly considered as complementary non-antibody modalities for difficult cytokine-receptor PPI surfaces. By positioning the IL-4/IL-4Rα system as a defined and chemically challenging bioorganic target, this review highlights how biomolecular recognition, interfacial topology, and druggability considerations can inform future efforts to develop next-generation modulators of cytokine-receptor signaling. The article therefore provides a chemistry-oriented perspective on therapeutic intervention at a biologically important immune interface.

In this study, we explore a new approach for the mild and selective activation of C(sp3)-F bonds in fluorinated azidoalkanes. Our approach utilizes electrophilic azide groups, which promote fluoride elimination and enable nucleophilic addition to newly formed electrophilic sites. This method achieves rapid, high-yield transformations of (per)fluoroalkyl azides into novel sulfur-containing azides, imines, and triazoles under mild conditions and using inexpensive reagents. The reaction proceeds without metal catalysts or external energy input and displays broad functional group tolerance, including toward thiol-sensitive motifs. Mechanistic studies supported by spectroscopy and x-ray crystallography, corroborated by ab initio calculations, reveal key azide intermediates and establish the denitrogenation pathway via α,α-disubstituted species. This transformation provides a practical and scalable route for the conversion of (per)fluoroalkyl azides into nitrogen- and sulfur-functionalized scaffolds, advancing C─F activation processes.

Machine learning has revolutionized protein structure and interaction prediction, yet its full potential for drug discovery is still emerging. In this study, we show that denoise diffusion-based co-folding methods-such as AlphaFold3 and Boltz-1/2-not only achieve highly accurate protein-ligand interaction predictions but can also separate active compounds from inactive ones. We introduce a simple and effective strategy, pairwise competitive docking, which ranks candidate molecules by directly comparing their relative binding to a protein's target site. Applied to 17 protein benchmark systems, the method generated rankings consistent with experimental trends, although the degree of agreement varied considerably by system, with concordance indices ranging from 0.52 (indicating no meaningful correlation) to 0.89 (indicating strong correlation). Notably, our rankings showed strong agreement with Boltz-2 affinity predictions, positioning our method as a practical alternative for inhibitor prioritization. Finally, we show how pairwise competitive docking can accelerate the identification of promising hits within a large chemical library and guide the de novo design of inhibitors with improved predicted potency. Collectively, these findings highlight how modern machine-learning models can make structure-based drug design faster, more reliable, and more cost-effective than relying solely on experimental workflows.

Specialized metabolites are often distributed sporadically across distantly related plant lineages, a pattern commonly attributed to convergent evolution, although the genomic processes enabling such innovation remain poorly understood. Here, we demonstrate that parasitic dodders (Cuscuta spp.) accumulate the lignan sesamin, a compound previously considered characteristic of sesame (Sesamum indicum) and related Lamiales species. We identified Cuscuta homologs of S. indicum CYP81Q1, which encodes piperitol/sesamin synthase (PSS), and demonstrated that these proteins retain catalytic PSS activity in vitro. Phylogenetic analyses indicate that CYP81Q was horizontally transferred from a Lamiales host to an ancestral Cuscuta lineage. Parasitism by C. campestris induces host CYP81Q expression and enhances interspecific transfer of genetic material across the haustorial interface, providing a mechanistic basis for horizontal gene transfer (HGT). Notably, comparative genomic analyses reveal that following horizontal acquisition, the transferred gene underwent extensive structural remodeling, characterized by sequential intron gains, while its enzymatic function was preserved. Many of the newly acquired introns exhibit hallmarks of insertion and excision of transposable elements, suggesting that mobile genetic elements contributed to post-transfer gene restructuring. The intron-rich architecture of Cuscuta CYP81Q was stably maintained throughout species diversification. Together, these findings suggest that parasitism-mediated HGT can be followed by intronization and transposon colonization, resulting in the generation of structurally complex yet functional genes. This process represents an underappreciated mechanism through which parasitic plants remodel horizontally acquired genes to facilitate metabolic innovation.

Reducing polysaccharide degradation through inhibition of α-amylases and α-glucosidases is one of the strategies for glycemic control in the treatment of diabetes mellitus. Here we report the identification and characterization of a new β-defensin-like miniprotein magnificamide-2 (Mgf-2), one of the most potent inhibitors of mammalian α-amylases with subnanomolar binding affinity (Ki of recombinant Mgf-2 is 0.029 nM against human pancreatic α-amylase, 0.057 nM against human salivary α-amylase, and 0.011 nM against porcine pancreatic α-amylase). Using nuclear magnetic resonance (NMR) spectroscopy, ensemble protein-protein docking, and molecular dynamics (MD) simulations, the key structural determinants responsible for this ultra-tight inhibition were identified, which was subsequently confirmed by site-directed mutagenesis experiments. The β1-β2 loop containing the inhibitory motif 7YIYH10 plays a crucial role in the inhibitor-enzyme interaction by forming an extensive hydrophobic interface with the hydrophobic "rim" around the α-amylase active site. The data obtained enhance our understanding of the molecular mechanisms underlying high-affinity α-amylase inhibition and provide valuable insights into the design of novel proteinaceous α-amylase inhibitors for the treatment and prevention of postprandial hyperglycemia.

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound therapy resistance driven by lysosome-dependent nutrient recycling, metabolic adaptation, and stress tolerance. Current lysosome targeting agents such as chloroquine (CQ)/hydroxychloroquine (HCQ) show limited efficacy due to transient activity and dose-limiting-toxicities. To overcome these limitations, we developed lysostilbenes, a new class of hybrid small molecules combining the CQ pharmacophore with lysosome-disrupting stilbene analogs. Stilbene pharmacophore is the core structural component of resveratrol. Among the synthesized hybrids, lysostilbene-4 emerged as the lead candidate, demonstrating ~30-40-fold greater cytotoxicity against PDAC cells than parent compounds, while sparing nonmalignant cells. At nanomolar concentrations, lysostilbene-4 induced rapid, irreversible lysosomal membrane permeabilization (LMP), initiating a lysosome mitochondria apoptotic cascade via CTSB (cathepsin B) release, BID cleavage, BAX activation, and caspase-mediated apoptosis. In parallel, it abrogated lysosomal recovery by significantly reducing repair, lysophagy, autophagosome maturation, and uncoupling TFEB-driven transcriptional programs from effective lysosome biogenesis. Reduced TFEB mRNA expression correlated with poor overall-survival and disease-free-survival across multiple cancer patients, with a particularly strong association in pancreatic cancer patients. Using TFEB+/+ and TFEB-/- knockout pancreatic cancer cells we establish that lysostilbene-4 exerts severe cytotoxicity by inducing persistent lysosomal-damage and disrupting autophagosome-lysosome assembly, with vulnerability further amplified in TFEB-deficient cells. This finding underscores TFEB as a key determinant of lysosomal-resilience and a potential predictive biomarker. Importantly, lysostilbene-4 was well tolerated in preclinical mouse-models at supra-therapeutic doses without systemic-toxicity. These findings position lysostilbene-4 as a first-in-class lysosome-targeting therapeutic that enforces sustained lysosomal collapse while compromising adaptive recovery-mechanisms, providing a mechanistically precise and safe strategy against PDAC.Abbreviations: ALG: autophagy-lysosome genes; AMPK: AMP-activated protein kinase; CASM: conjugation of ATG8s to single membranes; CTSB: cathepsin B; LGALS3: galectin 3; LMP: lysosomal membrane permeabilization; LS: lysostilbene; MTOR: mechanistic target of rapamycin kinase; PDAC: pancreatic ductal adenocarcinoma; TCGA: The Cancer Genome Atlas; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.

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Eukaryotic genomes are pervasively transcribed, producing a vast repertoire of RNA molecules. In plants, diverse RNA species play pivotal roles in regulating growth, development, and responses to environmental stimuli. The activities of RNAs are determined not only by their nucleotide sequences but are also shaped by multiple regulatory mechanisms, including processing, turnover, chemical modifications, and higher-order structure formation-each contributing critically to phenotypic outcomes. Over the past decade, technological advances, particularly in high-throughput sequencing and genome editing, have substantially deepened our understanding of RNA regulation; concurrently, research in this field has expanded from foundational studies in Arabidopsis to encompass a broad range of crop species. Building upon this expanded knowledge, this review provides a comprehensive overview of the regulation and functions of RNAs in plants. Specifically, we discuss the roles and molecular mechanisms of diverse RNA types, the roles of RNA structures and modifications in regulatory processes, and the translational application of RNA-based strategies for improving agronomic traits. Finally, we outline future research directions and offer perspectives on harnessing RNA regulation to advance crop improvement.

The microbial production of pantothenic acid (d-PA) is critically limited by feedback inhibition and low activity of the key enzyme ketopantoate hydroxymethyltransferase (KPHMT). To overcome this, rational enzyme mining based on computational prediction was established. Following sequence conservation analysis, molecular dynamics simulations, and binding free energy (ΔG) calculations, five representative native KPHMT enzymes were selected for experimental validation: EcKPHMT from Escherichia coli, CgKPHMT from Corynebacterium glutamicum, MpKPHMT from Mangrovibacter plantisponsor, EpKPHMT from Enterovibrio pacificus, and BsKPHMT from Bacillus subtilis. EpKPHMT and BsKPHMT exhibited 4.25- and 4.60-fold times that of EcKPHMT, respectively, with relieved pantoate feedback inhibition (IC50: 14.07 and 19.86 mM vs. 1.08 mM) and virtually no inhibition by d-PA. The strain expressing BsKPHMT enhanced d-PA and pantoate titers by 74.30% (3.12 g/L) and 140.0% (0.84 g/L) in shake flasks, and further increased d-PA production by 55.4% in a 5 L bioreactor, over the control. This work established a predictive framework for mining superior enzymes based on in silico prediction, offering a valuable strategy for metabolic engineering of high-value chemicals.IMPORTANCEThe industrial-scale biosynthesis of pantothenic acid (d-PA) is often bottlenecked by the strict feedback inhibition of its key biosynthetic enzyme, ketopantoate hydroxymethyltransferase (KPHMT). This study describes a computational strategy for the mining and selection of naturally occurring KPHMTs with reduced feedback inhibition, providing superior genetic parts for metabolic applications. This approach provides a novel and rational framework for mining allostery-free enzymes, successfully delivering two highly efficient biocatalysts, BsKPHMT and EpKPHMT. These biocatalysts exhibit immediate potential for industrial applications, offering a direct solution to enhance the production of both pantoate and d-PA. Collectively, the integrated methodology demonstrates effective translation from fundamental discovery to practical application, presenting a generalizable model for overcoming similar metabolic bottlenecks.

Toll-like receptors (TLRs) are participants of the innate immune system that perceive the presence of pathogens, initiating the inflammation. The key event of their activation is dimerization upon ligand recognition. Signal transduction through the membrane is mediated by transmembrane and juxtamembrane regions. However, nothing is known about the structure of the transmembrane and intracellular parts of the receptors in the activated dimeric state. Here, we investigate the dimerization of transmembrane and juxtamembrane parts (TMJMs) of TLR1 and TLR2 in lipid bilayer-containing particles using NMR spectroscopy. We found that transmembrane domains of TLR1 and TLR2 both homo- and heterodimerize, with heterodimerization being tenfold stronger compared to homotypic interaction. The heterodimer is formed via an extensive interaction interface leading to local changes in the hinge and juxtamembrane region preceding the TIR domain. We believe that TMJMs of TLR1 and TLR2 could facilitate signalosome formation affecting the TIR domain.

Organic memristors have emerged as promising candidates for neuromorphic computing and secure information processing. However, challenges remain in developing sustainable active materials, establishing experimentally accessible parameter-performance relationships, and connecting device characteristics to application-oriented circuit functions. Herein, we report a sustainable bio-organic memristor using a zeaxanthin/PVP composite as the functional layer, with Ag and FTO as the top and bottom electrodes. The device exhibits stable bipolar resistive switching, and its memory window can be tuned by the bias range, scan rate, and zeaxanthin concentration. Under ±1.5 V, 1.0 V s-1, and 10 mg mL-1, the device shows a stable resistive switching behavior over 100 cycles with a larger HRS/LRS ratio. In addition, the linearized fitting suggests a segmented conduction behavior involving Fowler-Nordheim tunneling, hopping conduction, ohmic transport, Poole-Frenkel emission, and Schottky emission. Based on the experimentally identified switching window and logic threshold, we further construct logic gates, a 2:1 multiplexer, flip-flops, and a 16-bit LFSR-based encryption architecture, and demonstrate XOR-based encryption/decryption of medical CT images at the system level. Therefore, this work provides a sustainable and tunable proof-of-concept platform for linking bio-organic resistive switching materials with logic-oriented secure information processing.

The title compound, C4H4N6S5, consists of two 1,3,4-thia-diazol-2-amine moieties bridged by a tris-ulfanediyl group [S-S-S = 107.98 (6)°]. The conformation is supported by an intra-molecular π-π stacking inter-action. In the crystal, N-H⋯N hydrogen bonds link the mol-ecules, enclosing R 2 2(8) and R 5 5(31) ring motifs, into infinite channels/tubes propagating along the b-axis direction. Hirshfeld surface analysis revealed that the most important contributions for the crystal packing are from S⋯S (33.6%) and H⋯N/N⋯H (32.8%) inter-actions.

The title hydrated salt, C16H19FN3O3 +·C2H3O2 -·1.5H2O, crystallizes with two cations, two anions and three water mol-ecules of crystallization in the asymmetric unit. The protonation of the piperazine secondary amine group of norfloxacin occurs via proton transfer from acetic acid. In the extended structure, the components are linked into chains propagating along the a-axis direction through numerous N-H⋯O and O-H⋯O hydrogen bonds. Hirshfeld surface analysis and two-dimensional fingerprint plots confirm the significant contribution of H⋯O inter-actions to the consolidation of the crystal structure.

Dittrichia viscosa (L.) is widely recognized in alternative medicine in the Mediterranean area for its therapeutic purposes. This study evaluates the acute and subacute toxicity of polar and non-polar extracts of D. viscosa when administered orally or applied topically. Toxicity tests were conducted at a dose of 2000 mg/kg on Wistar rats over 14 days for acute toxicity and 28 days for subacute toxicity. Parameters assessed included body weight, behavioral observations, hematological analysis, serum biochemistry, and histopathological examinations. No significant toxic effects were observed after a single administration of 2000 mg/kg of D. viscosa extracts. Furthermore, during the 28-day sub-acute toxicity study, daily doses of 2000 mg/kg were well-tolerated without inducing mortality, clinical signs of toxicity, or significant changes in behavior, body weight, or physiological status in either male or female rats. Hematological parameters remained stable, and there were no disruptions in liver function enzymes, glucose, or creatinine levels, confirming normal hepatic and renal function. These findings suggest that D. viscosa extracts are non-toxic and safe for oral and dermal use.

d-Tagatose is a rare hexose sugar with excellent properties, and its synthesis catalyzed by d-tagatose 4-epimerase (T4E) represents a competitive novel pathway. In this study, EbT4E derived from the Eubacteriales bacterium was screened and systematically characterized. By reshaping the microenvironment of the active pocket, mutant M3(S131D/H410W/T279S) was constructed, which showed a 3.89-fold higher conversion rate compared with the wild-type (WT) enzyme. Kinetic parameter analysis and molecular dynamics (MD) simulations revealed that M3 had enhanced substrate affinity, hydrogen bond network, charge properties, and channel accessibility. Finally, the conversion rates of d-fructose to d-tagatose catalyzed by the purified M3 enzyme and M3 whole-cell catalysts reached 29.46% and 26.2%, respectively. Additionally, the dual-enzyme cascade reaction of M3 with glucose isomerase (GI) TEGI-M-L38M-V137L was constructed, achieving a 13.16% yield of d-tagatose from d-glucose. This study demonstrates that EbT4E-M3 is a promising biocatalyst for d-tagatose production, laying the foundation for its subsequent industrial application.

Acid-sensing ion channels (ASICs) are proton-gated sodium channels encoded by four genes in mammals. The ASIC3 isoform is widely expressed and plays a critical role in pain signaling and inflammatory responses. Despite a high degree of sequence homology between rat and human ASIC3 orthologs, they exhibit pronounced functional differences. Notably, rat ASIC3 undergoes steady-state desensitization (SSD) at extracellular pH values of 7.1-7.0, whereas human ASIC3 is largely desensitized at physiological pH (7.4-7.3), underscoring substantial interspecies divergence with important translational implications. In this study, we systematically investigated the functional properties of rat and human ASIC3 channels using concatemeric constructs that enable precise control over subunit stoichiometry and gene order within engineered trimeric assemblies. Using whole-cell electrophysiology, we show that homomeric concatemeric channels (r-r-r and h-h-h) closely recapitulate the biophysical properties of their respective wild-type channels. Substitution of a single subunit at the N-terminal position of the concatemer with an ASIC3 ortholog produced minimal functional perturbations and yielded channel properties most similar to those of the corresponding homomeric channel. In contrast, replacement of the C-terminal subunit resulted in the most pronounced shifts in pH50SSD values and significant alterations in activation kinetics and current characteristics, indicating that functional properties of ASIC3 concatemers are strongly influenced by subunit position within the construct. Together, these findings demonstrate that both subunit composition and positional arrangement contribute to the functional behavior of engineered ASIC3 concatemers and provide a useful experimental framework for analyzing interspecies differences between rat and human ASIC3 channels. The results also highlight important limitations of concatemeric approaches, including the potential emergence of non-native channel properties in certain construct configurations.

A mild, visible-light-driven protocol has been developed for the regioselective ortho-C(sp2)-H mono-halogenation (Cl, Br, and I) of 3-aryl-2H-benzo[b][1,4]oxazin-2-ones via a synergistic metallaphotoredox strategy. The transformation employs Pd(OAc)2 (20 mol %) in combination with the organic photocatalyst eosin Y (WS, 10 mol %) under irradiation with a 24 W blue LED, using bench-stable N-halo-5,5-dimethylhydantoins (DCDMH, DBDMH, and DIDMH) as sustainable halogen sources. Conducted in 1,2-dichloroethane (DCE) with p-toluenesulfonic acid (1.0 equiv.) as an essential additive, the reaction proceeds under oxidant-free and thermally mild conditions to afford ortho-halogenated products in high isolated yields (75%-97%) with excellent regioselectivity. A broad range of substituents on the 3-aryl ring, including electron-donating, electron-withdrawing, and extended aromatic groups, are well tolerated. Mechanistic investigations-including radical trapping experiments (TEMPO, BHT), light on/off studies, and control reactions-support a cooperative pathway involving Pd(II)-directed C─H activation and photoredox-mediated generation of halogen radicals, followed by radical capture and reductive elimination from high-valent palladium intermediates. This operationally simple dual catalytic approach provides an efficient platform for late-stage diversification of pharmaceutically relevant 2H-benzo[b][1,4]oxazin-2-one scaffolds and advances sustainable strategies in photocatalytic C─H halogenation.

There exist two pathways in the cleavage of ester bonds, R-(O═)C-O-C-R', which are central to polyester recycling and organic synthesis. Traditional views emphasize electronic effects, where the more positively charged carbon is considered the preferred site for nucleophilic attack, resulting in the breaking of Cacyl-O bond. However, halide based ionic liquids were found to selectively cleave the Calkoxy-O bond of polyesters, a finding that cannot be rationalized by charge considerations alone. In this work, we propose that it is the presence of clusters in solutions that leverages the accessibility of reactants and thus determines the reaction pathways. The idea has been demonstrated in the study of a model binary system of methyl benzoate (MB) and 1-butyl-3-methylimidazolium bromide ([BMIm]Br) using excess infrared spectroscopy, molecular dynamics simulations, and density functional theory calculations. Excess infrared spectroscopy reveals seven distinct aggregate species in solution, including ionic liquid-ester clusters and MB self-aggregates, providing direct experimental evidence that the solution is microheterogeneous and that cluster formation dictates the local reaction environment. In the catalytically relevant cluster, [BMIm]Br(MB)3, DFT optimized geometries show that the Br-···Calkoxy distance (3.56 Å) is significantly shorter than the Br-···Cacyl distance (5.53 Å). Molecular dynamics simulations confirm the preferential solvation of Calkoxy around Br-. A potential energy surface scan with respect to the Br-···C distance identifies a critical distance of approximately 3.5 Å where the alkoxy C-O bond begins to deviate from equilibrium, marking the incipient stage of partial bonding. At 2.34 Å, the Calkoxy-O bond undergoes abrupt elongation, corresponding to an energy maximum, showing a pattern of the transition state in classic SN2 reactions. These findings establish the proximity effect, through cluster mediated spatial preorganization, as the governing principle of C-O bond cleavage selectivity in ionic liquid-ester systems.