Search Results (308)

Neurodegenerative disorders and epilepsy remain major clinical challenges, due to complex etiologies involving protein misfolding, excitotoxicity, metabolic dysregulation, and impaired cellular resilience. These unmet medical needs have stimulated interest in small-molecule modulators capable of targeting multiple pathogenic pathways. Cyclitols, a diverse family of inositol stereoisomers, play essential roles in cellular signaling and brain metabolism; among them, scyllo-inositol (SCI) has gained attention due to its distinct stereochemistry, capacity to cross the blood–brain barrier, and emerging neuroactive properties. Current pharmacokinetic data indicate that SCI exhibits dose-dependent systemic exposure, and good penetration into the central nervous system. Moreover, its supplementation seems to be well-tolerated. In experimental studies both on animals and humans, SCI has been shown to modulate amyloid-β aggregation, stabilize neuronal homeostatic pathways, and reduce network hyperexcitability, suggesting relevance for both neurodegenerative and epileptic phenotypes. Despite promising results, there is still a need for further analyses to define dosing, transporter involvement, and brain exposure thresholds. Collectively, the available data position SCI as a compelling candidate for translational development, warranting further investigation into its therapeutic window and disease-modifying potential across neurological disorders. Full article

Ferrocenium-catalyzed transformations provide a practical and sustainable approach to propargylic substitution reactions. Herein, we investigate the ring-opening of cyclopropyl-substituted propargylic alcohols with alcohol nucleophiles, catalyzed by ferrocenium tetrafluoroborate ([FeCp₂][BF₄]) to afford synthetically valuable enyne ethers. Mechanistic studies using GC and NMR spectroscopy reveal that the reaction proceeds via initial formation of a ring-closed propargylic ether intermediate, which subsequently undergoes ring opening to the enyne ether. Experimental evidence supports a carbocationic pathway in which the ferrocenium cation promotes ionization to a stabilized cyclopropyl ether intermediate, followed by intramolecular, ferrocenium-assisted cyclopropyl ring opening to the enyne product. Reaction rates and product distributions are strongly influenced by temperature and solvent polarity, with polar solvents and elevated temperatures favoring ring opening. At room temperature, the ring-closed substitution product predominates, whereas efficient formation of enynes occurs at 65 °C. The reaction progresses faster in a polar solvent, indicating an ionic mechanism. Studies employing substrates containing substituted cyclopropyl rings demonstrated pronounced regioselectivity during nucleophilic ring opening with alcohols, with preferential cleavage of the bond between the two substituted carbon atoms. This selectivity is consistent with partial positive-charge stabilization in the transition state. The corresponding enyne ether products were isolated in 98–31% isolated yields, in most cases as a single regio- and E/Z stereoisomer (5 h at 45 °C, 5 mol% [FeCp₂][BF₄] catalyst load, six equivalents alcohol nucleophile). The ferrocenium-catalyzed cyclopropyl ring opening establishes a convenient method for accessing enyne motifs, which are important structural units in organic synthesis and medicinal chemistry. Full article

The selective detection of small, highly hydrophilic metabolites differing only in stereochemistry represents a major challenge in biosensor development. Here, we present a computational investigation to elucidate the molecular basis of the experimentally observed selectivity of a protein-based electrochemical biosensor toward myo-inositol over D-chiro-inositol. Although the two stereoisomers differ only in the orientation of a single hydroxyl group, they induce distinct dynamic effects on the protein recognition element. Molecular docking revealed comparable binding regions and similar affinity scores, indicating that selectivity does not arise from differences in binding site or docking energy. To investigate dynamic contributions, all-atom molecular dynamics simulations were performed in triplicate (3 × 100 ns) using the AMBER99SB force field and explicit TIP3P water. Trajectory analyses showed that myo-inositol forms a more persistent hydrogen bond network, resulting in reduced residue-level flexibility, more stable ligand–protein interactions, and enhanced local structural stabilization. Overall, these findings support a dynamic model of stereoselective recognition in which ligand-induced modulation of protein conformational ensembles, rather than static affinity, governs biosensor performance. This work highlights the value of molecular dynamics simulations in the rational design of biosensors targeting structurally similar analytes. Full article

EpOMEs suppress excessive and unnecessary immune responses at late infection stage in insects. This immune resolvin activity of EpOMEs includes the cell lysis of hemocytes by causing apoptosis. This cytolytic toxicity of EpOMEs suggests a potential insecticidal activity of their stable analogs. In fact, a propoxy derivative of 12,13-EpOME called AS56 mimicked EpOME activity by suppressing immune responses and exhibited insecticidal activity against a lepidopteran insect, Spodoptera exigua. This study evaluated the potency of the EpOME analogs by modifying their functional groups. PD28 is a racemic mixture of propoxy analog at the twelfth carbon. FD25 is a racemic butoxy mixture at the twelfth carbon of AS56. AS61 is saturated at the ninth carbon of AS56. The effects of the EpOME analogs were assessed on two cellular immune responses: hemocyte-spreading and nodule formation. All four analogs inhibited the cellular immune responses; however, AS56 was the most potent in inhibiting the immune responses. FD25 and AS61 were significantly less potent compared to AS56, suggesting crucial roles of the double bond at the ninth carbon and the propoxy chain at the twelfth carbon. The stronger inhibitory activity of AS56 compared to PD28 also suggests the functional role of the stereoisomeric form in physiological functions. The cytotoxicity of AS56 was also the most potent among the analogs, suggesting its insecticidal activity. Subsequent insecticidal bioassays on AS56 toxicity were performed against different insect species. These EpOME analogs were potent against lepidopteran insects (S. exigua and Plutella xylostella) but not against coleopteran (Tenebrio molitor) or thysanopteran (Frankliniella occidentalis) species. Among the EpOME analogs, AS56 was the most toxic against the lepidopteran insects. Spraying AS56 in cabbage fields infested by lepidopteran insects led to acute and high control efficacy against two lepidopteran pests, similar to that of a chemical insecticide, fluxametamide. The AS56-intoxicated larvae exhibited over-excitation in their behavior around 12 h post-treatment. This study indicates that AS56 exhibits an oral toxicity against lepidopteran insects with its cytotoxicity and behavioral over-excitation. Full article

Sustainable phosphorus (P) management in agriculture requires a circular economy approach through the use of so-called bio-based fertilizers (BBFs). The properties of BBFs vary widely depending on raw materials and production processes. However, it is still unknown how these properties, and particularly the dominant P compounds determine not only the efficiency of BBFs in supplying P to crops, but also their effects on soil functioning and crop quality. This study aimed to evaluate the efficiency of a representative set of BBFs, and relate this efficiency to their composition and dominant P compounds. To this end, 14 BBFs were studied: four from water purification (struvite, vivianite, and sewage sludge with and without composting), four composts (municipal solid waste (MSW), vineyard residues, and two using olive husks), three vermicomposts (two homemade and one commercial), fish meal, digestate, and a commercial organic fertilizer. Phosphorus forms in BBFs were determined using ³¹P nuclear magnetic resonance spectroscopy (P-NMR). The BBFs were compared to a single superphosphate (SSP) in a pot experiment growing wheat in two different alkaline soils, one rich in iron (Fe) oxides and one rich in carbonates. The effects on critical elements in grain [magnesium, Fe, zinc (Zn), manganese, and copper] and enzyme activities related to soil functioning and P cycling were also assessed. The dominant P compound in the BBFs was orthophosphate (73.8–89.5% of the total P in the NaOH–EDTA extracts). The MSW had the highest polyphosphate content (4.1%), a complex inorganic P compound. The organic P content ranged from 9.2% (fish meal) to 25.5% (Moge). Sewage sludge and composted sludge contributed high levels of phosphonates (4.1 and 5.6% of extracted P). The most abundant organic P compound class was inositol hexakisphosphates (IHPs), and myo-IHP (phytate) was the dominant IHP stereoisomer (1.2–6.4%) followed by D-chiro-IHP and scyllo-IHP. Plant dry matter and grain yield with most BBFs were not significantly different from that of SSP in both soils, likely due to the high concentrations of phosphate in relatively soluble forms in most of the BBFs. Vivianite and sewage sludge resulted in significantly higher grain yield than SSP (43% and 40%, respectively) in the carbonate-rich soil, likely due to progressive phosphate dissolution, which decreased the precipitation rate of insoluble calcium (Ca) phosphates. The highest P recoveries were obtained with horse manure vermicompost (65% and 15% higher than SSP in the Fe oxide-rich and in the carbonate-rich soil, respectively), partially attributed to the decreased precipitation rate of insoluble Ca phosphates with the added organic matter. Some BBFs increased micronutrient concentrations in grains and most decreased the P-to-Zn ratio relative to SSP. Overall, phosphatase and β-glucosidase activities increased with carbon-rich BBFs. Most of the studied BBFs could effectively replace fertilizers from non-renewable sources, in some cases with better crop P recoveries. Furthermore, some BBFs could provide additional benefits to grain quality, in terms of micronutrient supply for humans, and soil functioning. Full article

Floridoside (2-(α-D-galactosyl)glycerol) is a compatible solute synthesized in red algae, known for its antioxidant, immunostimulatory, anti-inflammatory, and antimicrobial properties. However, the lack of target validation has limited mechanistic insights into its bioactivity. Mitogen-activated protein kinase 13 (MAPK13), a member of the p38 mitogen-activated protein kinase (p38 MAPK) family with unique structural and functional characteristics, plays an important role in respiratory tissue remodeling, tumor progression, and immune responses, making it an attractive therapeutic target. This study identifies MAPK13 as a high-affinity target of floridoside. In vitro kinase assays validated that floridoside effectively inhibits MAPK13 with a nanomolar inhibitory concentration (IC50 = 13.59 nM), significantly outperforming the classical inhibitor BIRB-796. Unbiased molecular dynamics simulations and steered molecular dynamics simulations reveal that floridoside binds within the MAPK13 hinge region via an ATP-competitive mechanism. Binding free energy analysis combined with computational alanine scanning highlight Asp-113 as a primary interaction hotspot, stabilized by persistent hydrogen bonds with Pro-108 and Met-110. Despite stable complex formation, the flexibility of the glycosidic bond and glycerol tail may limit binding persistence. Comparative simulations with 2-α-glucosylglycerol (2αGG), a stereoisomer of floridoside, demonstrate the sensitivity of MAPK13 binding to subtle structural variations. These findings elucidate the atomistic basis for floridoside’s bioactivity and establish it as a candidate natural scaffold for the design of isoform-selective p38 inhibitors. Full article

Background: Anxiety is a frequent clinical problem that becomes disabling when excessive or persistent. Cyclitols are naturally occurring polyhydroxy compounds, and inositols are the most abundant cyclitols in eukaryotic cells; several stereoisomers have been proposed as candidates for CNS-relevant effects. Methods: A narrative review was conducted using a structured search of biomedical bibliographic databases. The search was centered on myo-inositol, scyllo-inositol, and D-chiro-inositol in relation to anxiety-related outcomes. Results: The retrieved literature suggests some biological plausibility for anxiolytic effects of selected inositol stereoisomers through pathways related to intracellular signaling and neurotransmission. However, the available evidence is uneven and remains limited. The most informative findings concern myo-inositol and include both preclinical and clinical studies, whereas data on scyllo-inositol and D-chiro-inositol are scarce, particularly in relation to anxiety-related outcomes. Conclusions: Current evidence suggests a possible anxiolytic role of selected inositol stereoisomers; however, the existing data are limited and heterogeneous, and do not allow for definitive clinical conclusions. Further research is required. Full article

Background/Objectives: The clinical management of bladder cancer is severely impeded by high recurrence rates and the rapid emergence of chemoresistance, necessitating the discovery of novel therapeutic agents with distinct mechanisms of action. Dehydrodiisoeugenol (DHE), a bioactive neolignan, exhibits potent anti-tumor efficacy, yet its direct molecular targets and mode of action remain elusive. Methods: To deconvolute the mechanism of DHE, we integrated a phenotypic screening approach using 2D cell lines and 3D patient-derived organoids with a chemoproteomics-based activity-based protein profiling (ABPP) strategy. We synthesized a functionalized photoaffinity probe to capture the specific interactome of DHE under physiological conditions and validated targets via cellular thermal shift assays (CETSA), quantitative mass spectrometry, and 100 ns molecular dynamics (MD) simulations. Results: DHE exhibited potent dose-dependent cytotoxicity in bladder cancer cells, with IC50 values of 39.23 μM in T24 and 34.58 μM in 5637 cells. In 3D patient-derived organoids, DHE significantly reduced viability (p < 0.0001). Using a dual-filtering ABPP strategy, we identified 65 high-confidence candidate targets, prioritizing PTPN1 (PTP1B) as the primary functional interactor. Comparative molecular docking and 100 ns MD analyses showed that multiple stereoisomers of DHE could adopt plausible PTPN1-binding modes. Mechanistically, organoid proteomics indicated that DHE engagement with PTPN1 disrupts ER membrane homeostasis, thereby modulating the PI3K-Akt signaling axes. Conclusions: These findings establish PTPN1 as a critical druggable vulnerability in bladder cancer and define the molecular basis for the therapeutic potential of DHE. This study highlights the power of combining chemoproteomics with physiological 3D models to accelerate the translation of natural products into precision cancer therapies. Full article

The epicuticle of Cataglyphis niger is endowed with hydrocarbons comprising both linear and branched alkanes. For linear alkane, it is hypothesized that the primary driving force for their evolution was acquiring means for attaining cuticular impermeability that protects the ants from desiccation, and, secondarily, was co-opted as cues and signals. For example, being more abundant in foragers, they signal colony foraging intensity and, accordingly, adjust task allocation. Branched alkanes serve mostly in communication, but their evolution is less clear. Studies of the biosynthesis of both classes of hydrocarbons revealed disparate pathways, which suggests an independent evolution. The biosynthesis of branched alkanes hints at their possible evolution. They are derived from branched fatty acids, which have evolved as protective means due to their bactericidal activity. It is hypothesized that their biosynthetic pathway was secondarily co-opted for producing branched alkanes as signals and cues. Branched alkanes blend within the linear alkane layer to evenly cover the ants’ body surface and enhance the ants’ communicative capacity by conveying larger informational content due to their numerous positional and stereoisomers. The present study presents the occurrence of substantial amounts of branched fatty acids with branching position that matches that of the branched alkanes. The disparate biosynthesis pathways and the postulated differences in their evolutionary roots lend credence to the hypothesis of their independent evolution. Full article

Dihydroquercetin (DHQ) is a promising object for the development of a treatment for patients with obesity and prediabetes requiring a moderate therapeutic effect. This paper reports a clinical case of DHQ application in a 30-year-old Caucasian male and proposes a molecular mechanism of its anti-obesity effect. DHQ was administrated as a dietary supplement at a dose of 100–200 mg/day during 3 months with treatment interruption for 1 month. The data collected one month before the treatment were used as a control. The molecular aspects were studied via molecular docking with β₃-adrenoceptor (ADRB3, PDB ID: 9IJE) and peroxisome proliferator-activated receptor γ (PPARG, PDB ID: 2ZNO) and molecular dynamic simulation under conditions mimicking a human cellular environment. A pronounced weight decrease up to 0.73 kg/week was observed during DHQ administration. The highest affinity to ADRB3 was observed for the non-ionized H2aH3e-conformation of 2S,3R-DHQ (–8.846 kcal/mol). Molecules with 2S-configuration demonstrate 0.332 kcal/mol higher affinity to PPARG compared to 2R-stereoisomers. The intermolecular complex with cis-DHQ demonstrated higher stability in molecular dynamics simulation. The insights gained from this study may contribute to our understanding of flavonoids not merely as antioxidants but also as active ingredients that selectively interact with receptors. If future investigations confirm these results, they may serve as a foundation for developing a new class of anti-obesity remedies that act via ADRB3. Full article

The photocycloaddition (PCA) of chalcones represents an important reaction pathway for accessing substituted cyclobutanes, which is a molecular framework with utility in synthetic chemistry, materials science, and medicine. In the past, our group has demonstrated the utility of the large cavity of γ-CD as a container for encapsulating two photo reactants for directing the PCA of several classes of aryl alkenes with high stereo- and regioselectivity: the cavitand-mediated photodimerization (CMP) approach. The CMP of chalcones reported in this work further demonstrates the effectiveness of this approach as high yields of dimers were observed in the photoreactions, while they were non-reactive in the solid state and yielded only the isomerization product in homogeneous media. The γ-CD CMP of chalcones yielded predominantly dimerized products in very good to high yields (>70%), composed of a mixture of three dimers in different proportions with syn HH as the major product. Computational analysis of the ground state complex structures revealed a strong correlation between the stability of the complex and predominance of the stereoisomer in the mixture. Further insights were deduced from temperature-dependence studies, which showed a shift in dimer selectivity tending towards a single stereoisomer. Full article

Background: Stroke is a major global risk to human health due to its high incidence, mortality, and prevalence of associated long-term disabilities. Recent studies have highlighted a significant impact of the gut–brain axis and metabolites derived from intestinal microbiota on modulating neurological disorders, including stroke. Methods: In this study, we investigated the effects of pre- and post-treatment with D-lactate, a lactate stereoisomer mainly produced by certain gut bacteria, on stroke outcome using a transient middle cerebral artery occlusion (MCAO) mouse model. For this purpose, male C57BL/6J mice received a single administration of D-lactate or vehicle (PBS) via the tail vein either before the MCAO surgery, as a preventive approach, or upon reperfusion, as a therapeutic paradigm. Functional outcome was assessed daily using a standard neuroscore and the adhesive removal test until day three post-surgery, when mice were sacrificed. Results: Our results indicated no significant difference in infarct size, measured using cresyl violet staining, between the D-lactate and PBS groups in both pre- and post-treatment experiments. In addition, evaluation of neurological deficits and sensorimotor function showed no statistically significant differences between the interventions throughout the experiment. Conclusions: The present data suggest that treatment with D-lactate does not show a beneficial effect in our C57BL/6J mouse MCAO model. Full article

Myo-inositol, the most common stereoisomer of inositol, plays an important role in many physiological processes, such as cell signaling, regulation of glucose and lipid metabolism, and protection of cells against oxidative stress. The main focus has been on pharmacokinetics, and it has been studied in both animal models (Wistar rats, mice, and Danio rerio) and humans. It is characterized by high oral bioavailability and is primarily eliminated via the kidneys. Preclinical studies have shown that myo-inositol has hepatoprotective potential, reducing oxidative stress, inflammation, and lipid accumulation in hepatocytes, as well as stabilizing liver cell membranes. Animal models make it possible to assess mechanisms of action, toxicity, and efficacy, thereby laying the groundwork for clinical research. In clinical practice, myo-inositol is currently used mainly in the treatment of polycystic ovary syndrome, gestational diabetes, fertility disorders, and certain affective disorders. Based on the results of preclinical studies, its potential application in liver diseases and drug-induced injury has been suggested. Despite promising findings, further translational research and randomized clinical trials are necessary to evaluate the therapeutic efficacy and safety of myo-inositol in hepatology. In summary, myo-inositol is a natural, well-tolerated compound with a multidirectional mechanism of action that may represent a promising element of supportive therapy for liver diseases. Full article

The Mediterranean fruit fly (Ceratitis capitata) is a globally invasive pest that affects a wide range of fruit and vegetable crops. Identifying cost-effective attractants is essential for sustainable integrated pest management (IPM). This study explored whether molecular docking, combined with electrophysiological recordings, can help prioritize structurally diverse compounds with potential relevance to medfly olfaction. We assessed the predicted interactions of more than 100 attractant-related and semiochemical compounds, including multiple stereoisomers, with 14 odorant-binding proteins (OBPs) and four odorant receptors (ORs). Trimedlure served as a benchmark ligand. Docking suggested that several sesquiterpenes may interact favorably with subsets of OBPs and ORs, although these predictions require biochemical validation. A small set of compounds with high predicted affinity, readily available in the laboratory, was further examined using electroantennography (EAG), which confirmed that selected sesquiterpenes elicited peripheral antennal activation in irradiated males. Overall, our results demonstrate the utility of computational screening as an exploratory tool for prioritizing candidate ligands and generating hypotheses about chemosensory processing in C. capitata. Integrating molecular modeling with biochemical and behavioral validation is a promising approach to developing next-generation IPM attractants. Full article

In contrast to bactericides, elicitors induce plant immune systems to defend against pathogen attack and avoid potential damage to the environment. However, the energy cost caused by the continuous activation of immunity leads to the inhibition of plant growth, which has limited the agricultural application of a large number of elicitors. Here, we identified a natural elicitor 3,4-dihydroxy-3-methyl-2-pentanone (DMPN) that can induce disease resistance in plants. DMPN contains four stereoisomers (3R,4S), (3S,4R), (3R,4R) and (3S,4S), which exhibit different induced resistance activities in Arabidopsis thaliana but do not inhibit plant growth. B1 is different from the other three isomers in that it only induces disease resistance to the necrotrophic pathogen Erwinia carotovora instead of the biotrophic pathogen Pseudomonas syringae, and the remaining isomers is effective for both pathogens. When it comes to threo-isomers B1 (3R,4S) and B2 (3S,4R), transcriptomic and gene expression analysis reveal that both B1 and B2 activated the jasmonic acid (JA)/ethylene (ET) and chitin-mediated signalling pathways. B2 also activated the salicylic acid (SA) pathway and upregulated a wider range of defence-related genes. These findings indicate that stereoconfiguration critically influences elicitor bioactivity. In summary, we reported a natural stereoisomeric elicitor, DMPN, which can elicit the plant defence response in Arabidopsis thaliana without inhibiting plant growth and revealed the differential inducing effects on the plant immune system of its four isomers. Full article