Search Results (1,805)

This study presents a comparative in vitro evaluation of 24 natural sesquiterpene γ-lactones and selected semisynthetic derivatives against three trypanosomatid parasites responsible for neglected tropical diseases: Trypanosoma brucei brucei, Trypanosoma cruzi, and Leishmania amazonensis. The compounds were screened for antiparasitic activity across different parasite life stages, and their cytotoxicity was assessed in mammalian cells. Several compounds demonstrated high inhibitory activity (>95%) at 10 µg/mL, including estafiatin (1), grossheimin (4), cynaropicrin (5), argolide (2) derivatives, and arglabin (23). However, a marked decrease in activity was observed at lower concentrations and in intracellular parasite models, particularly for T. cruzi and L. amazonensis amastigotes. Among the tested compounds, dihydroargolide (3) and pulchellin C (19) exhibited comparatively lower cytotoxicity and were further evaluated, yielding IC₅₀ values of 10.51 ± 1.72 µg/mL and 2.51 ± 1.13 µg/mL against T. b. brucei, respectively. Against L. amazonensis promastigotes, estafiatin (1), 8α-chloroacetoxygrossheimin (12), and arglabin (23) showed IC₅₀ values of 0.16 ± 0.13, 0.35 ± 0.18, and 0.58 ± 0.11 µg/mL, respectively, although their selectivity indices remained limited. Comparative analysis of the dataset indicates that specific structural elements, such as the α-methylene-γ-lactone moiety and selected substituents (e.g., epoxy and acetyl groups), may influence antiparasitic activity in a species-dependent manner. At the same time, the generally low selectivity indices and reduced activity in intracellular models highlight important limitations of these compounds as direct drug leads. Overall, this work provides a systematic comparative dataset and identifies preliminary structure–activity trends that may guide further chemical optimization of sesquiterpene γ-lactones as antiparasitic hit compounds. Full article

Background: Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are key nociceptive ion channels involved in chemosensation, pain signaling, and neurogenic inflammation. Several sesquiterpene lactones target TRPA1, but the activity profile of these secondary metabolites of the common ragweed (Ambrosia artemisiifolia) remains uncharacterized. Purpose: The purpose of this study was to explore the activity of five ragweed sesquiterpene lactones on TRPA1 and TRPV1, respectively. Methods: We investigated the effects of five ragweed-derived sesquiterpene lactones—acetoxydihydrodamsin, costunolide, isoalantolactone, peruvin, and psilostachyin—on TRPA1 and TRPV1 using ⁴⁵Ca²⁺ uptake in receptor-overexpressing CHO cells and covalent docking to human TRPA1. Results: Costunolide, isoalantolactone and acetoxydihydrodamsin induced TRPA1 activation (counts per minute of ⁴⁵Ca²⁺ uptake at 40 µM concentration: 5070 ± 346.5, 10,197 ± 1237, 3704 ± 1634, respectively) but not TRPV1 activation, as demonstrated by Ca²⁺ influx. Acetoxydihydrodamsin induced concentration-dependent TRPA1 activation that was significantly inhibited by 10 µM of the selective antagonist HC-030031. Docking studies demonstrated covalent interactions of costunolide, isoalantolactone, and acetoxydihydrodamsin (−47.3, −51.5, and −45.0 kcal/mol FITTED score) with the electrophile-sensitive binding region of TRPA1. Conclusions: Ragweed sesquiterpene lactones act as TRPA1 agonists without detectable TRPV1 activation. This study provides the first data identifying acetoxydihydrodamsin as a TRPA1 agonist, expanding the pharmacological map of ragweed sesquiterpene lactones. These results suggest that these metabolites may contribute to both the irritant properties and the pharmacological potentials of A. artemisiifolia. Full article

Enantiomerically enriched vanillin-derived cis- and trans-β-aryl-δ-iodo-γ-lactones were synthesized using a chemoenzymatic pathway based on Candida antarctica lipase B (CALB)-catalyzed transesterification of racemic (E)-4-(4′-benzyloxy-3′-methoxyphenyl)but-3-en-2-ol, followed by Claisen rearrangement, hydrolysis, iodolactonization, and deprotection. The trans orientation of substituents on the γ-lactone ring of the target compounds was identified as the key structural feature enhancing cell-viability-reducing activity against selected human cancer cell lines. No statistically significant differences were observed between the enantiomerically enriched pairs of the studied lactones: the most active trans-δ-iodo-γ-lactones, 7b, exhibited similarly high potency (IC₅₀ = 3.98 ± 2.60 μM and 5.08 ± 1.30 μM) against the multidrug-resistant (MDR) gastric adenocarcinoma cell line EPG85-257RDB. Their IC₅₀ values were not significantly different from that determined for doxorubicin under the same experimental conditions (IC₅₀ = 5.48 ± 0.75 μM). Notably, both enantiomers exhibited high selectivity indices (SI = 9.22 and 10.19, respectively). TUNEL analysis demonstrated that enantiomer (4R,5S,6R)-7b induced concentration-dependent DNA fragmentation, increasing the percentage of TUNEL-positive cells from 8.30 ± 0.95% to 74.10 ± 4.26%. Flow cytometric analysis further revealed the pronounced accumulation of cells in the G2/M phase, with up to 55.25 ± 2.74% of cells detected at the highest tested concentration. The observed activity of enantiomerically enriched vanillin-derived trans-β-aryl-δ-iodo-γ-lactone 7b in the multidrug-resistant EPG85-257RDB cell line warrants its further investigation in additional drug-resistant cancer models. Full article

DNA methyltransferases (DNMTs) regulate gene expression and genome stability by transferring a methyl group from S-adenosylmethionine to cytosine through a catalytic mechanism involving a conserved cysteine. Dysregulated DNA methylation contributes to cancer, chronic inflammation and persistent metabolic phenotypes, encouraging the development of non-nucleoside DNMT modulators. This narrative review examines whether electrophilic reactivity, particularly Michael acceptor chemistry, provides a plausible mechanistic framework for the reported DNMT-modulatory effects of structurally diverse natural compounds, evaluated across polyphenols, isothiocyanates, sesquiterpene lactones, alkaloids, terpenoids, polyketides and endogenous electrophilic lipids according to experimental level, distinguishing direct enzymatic inhibition from docking predictions, altered DNMT expression and broader cellular effects. The literature was retrieved from PubMed, Scopus and Web of Science and appraised with an explicit grading scheme that separates cell-free enzyme inhibition, proposed engagement of the catalytic cysteine, cellular changes in DNMT expression or methylation, and downstream biological effects. Curcumin and parthenolide provide notable precedents for catalytic-cysteine-directed hypotheses, whereas direct covalent engagement remains insufficiently demonstrated for most other candidates. The review also considers reversibility, electrophile selectivity, bioavailability and interactions with histone modifications, inflammatory signalling and the NAD⁺/sirtuin axis. Michael acceptor chemistry offers a useful hypothesis for prioritising natural DNMT modulators, but biochemical, structural and chemoproteomic validation is required before covalent DNMT inhibition can be regarded as a general mechanism or translated into therapeutic recommendations. Full article

Glioblastoma (GBM) is the most aggressive primary brain malignancy in adults, which remains difficult to treat because of extensive intratumoral heterogeneity, intrinsic and acquired treatment resistance, a profoundly immunosuppressive tumor microenvironment (TME), and restricted drug delivery across the blood–brain barrier (BBB). Owing to their relatively low molecular mass, potential for BBB penetration, and ability to modulate multiple targets, natural and synthetic compounds have attracted increasing interest as candidates for GBM treatment. This narrative review summarizes the mechanisms by which naturally derived compounds—including saponins, flavonoids, and sesquiterpene lactones—and synthetic small molecules exert anti-GBM effects on tumor and the TME. Their reported actions include suppressing key prosurvival pathways, such as the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR), nuclear factor kappa B (NF-κB), and mutant p53 signaling; activating regulated cell-death processes, including apoptosis, pyroptosis, and parthanatos, as well as autophagy-associated cell death; and remodeling the tumor immune milieu to promote CD8⁺ T-cell infiltration. In preclinical models, some of these agents also overcome temozolomide (TMZ) resistance and resensitize glioma stem cells (GSCs) to chemotherapy or radiotherapy. Future studies should prioritize molecularly informed patient stratification, rational combination strategies, and advanced nanocarrier-mediated delivery platforms to facilitate the clinical translation of small-molecule therapeutics for GBM. Full article

Inula helenium L. (elecampane) is a traditional medicinal plant whose roots contain both hydrophilic polyphenols and lipophilic sesquiterpene lactones. However, the influence of the raw material origin and the extraction solvent on its combined bioactivity profile remains unclear. Moreover, although isolated sesquiterpene lactones from I. helenium have been extensively investigated for their anticancer properties, the bioactivity of whole root extracts against human melanoma cells has remained largely underexplored. This study aimed to systematically compare the phytochemical characteristics and biological activity of I. helenium root extracts obtained from three distinct raw material sources and three solvents of increasing polarity, and to identify the main factors associated with the observed bioactivity through multivariate integration. In this study, I. helenium roots from three distinct sources—commercially available dried roots, wild-collected roots, and cultivated roots collected from the Botanical Garden of Vilnius University—were extracted with three solvents of increasing polarity (n-hexane, ethyl acetate, and 70% ethanol). Each extract was characterized by total phenolic content, four antioxidant assays (DPPH, ABTS, FRAP, CUPRAC), UV–Vis fingerprinting, antimicrobial testing against Staphylococcus aureus, Klebsiella pneumoniae, and Candida albicans, and a CCK-8 assay on SK-MEL-28 human melanoma and HEK293 non-cancerous cells. Multivariate integration (PCA, HCA, Spearman rank correlation) identified solvent polarity as the dominant driver of both the phytochemical and the biological profile (PC1 and PC2 together explained 87.9% of the total variance). Ethanolic extracts combined the highest phenolic content (up to 38.6 mg GAE/g dry extract) and the strongest antioxidant capacity across all four assays, with maximum values of 177.3 (DPPH), 328.9 (ABTS), 174.1 (FRAP), and 541.6 (CUPRAC) µmol TE/g DE (p ≤ 0.004). In the preliminary antimicrobial screening, ethanolic extracts showed near-complete to complete inhibition of S. aureus and C. albicans at 25 mg/mL, with MIC₉₀ values as low as 12.5 mg/mL against S. aureus and 6.25 mg/mL against C. albicans, whereas K. pneumoniae showed only marginal growth inhibition (median values below 20% across the entire tested concentration range). Strikingly, n-hexane and ethyl acetate extracts—despite negligible antioxidant activity—produced concentration-dependent cytotoxic effects. Six of the nine extracts reduced SK-MEL-28 viability while sparing HEK293 cells, with the cultivated Botanical Garden n-hexane extract showing the greatest difference across the tested cell models (SI > 1.50, p = 0.0003). Targeted solvent selection thus enables a single plant material to yield two functionally distinct bioactive fractions: more polar extracts with pronounced antioxidant and antimicrobial activities and less polar extracts with preferential activity against SK-MEL-28 within the cell models tested. Full article

Xueshan Jinluohan Pain-Relief Liniment (XJPL) is a Tibetan topical compound preparation composed of 11 medicinal materials. Its current quality standard relies mainly on thin-layer chromatographic identification, which is insufficient to comprehensively characterize its complex chemical composition, marker constituents from key medicinal materials, and batch-to-batch quality consistency. In this study, 17 batches of XJPL were analyzed by ultra-performance liquid chromatography coupled with quadrupole-Exactive Orbitrap high-resolution mass spectrometry (UPLC-Q-Exactive Orbitrap MS) for systematic chemical profiling. An integrated quality evaluation method was further developed by combining high-performance liquid chromatography (HPLC) fingerprinting, similarity evaluation, chemometric analysis, and multicomponent quantification. A total of 139 chemical constituents were confirmed by reference standards or putatively characterized, including alkaloids, flavonoids, phenolics, terpenoids, organic acids, lactones, and other compounds, indicating the coexistence of multiple medicinal-material-derived and structurally diverse constituents in XJPL. The HPLC fingerprint established for the 17 batches contained 23 common peaks, among which 10 representative constituents were assigned, and similarity evaluation indicated a high degree of overall chemical consistency among batches. Hierarchical cluster analysis (HCA), principal component analysis (PCA), and orthogonal partial least squares-discriminant analysis (OPLS-DA) further revealed batch-related differences and suggested that common peaks corresponding to gentiopicroside, loganic acid, and related constituents contributed substantially to sample differentiation. On this basis, quantitative methods were established for representative constituents covering phenolic acids, iridoid glycosides, carotenoid glycosides, and Corydalis-derived alkaloids. Overall, this study improves the quality evaluation framework for XJPL by integrating chemical profiling, holistic fingerprint assessment, batch-difference characterization, and multicomponent quantitative control, providing experimental support for quality standard improvement and manufacturing quality control. Full article

Enhydrin, a melampolide-type sesquiterpene lactone abundant in the leaves of yacon (Smallanthus sonchifolius), has not previously been investigated for its anti-prostate cancer activity. This study investigated the antiproliferative effects of enhydrin in human prostate cancer cells, its regulatory effects on apoptosis-related molecules, and its impact on the PI3K/AKT and NF-κB signaling pathways. Three prostate cancer cell lines (PC3, DU145, and LNCaP) were treated with enhydrin, and its effects were analyzed using cell viability assays, morphological observation, flow cytometry, apoptosis-focused TaqMan qPCR array, qRT-PCR, and Western blotting. In vivo antitumor activity was assessed in a PC3 xenograft mouse model. Enhydrin reduced cell viability in a dose- and time-dependent manner, induced morphological changes associated with cytotoxicity, and caused G1 cell-cycle arrest. Gene expression analysis revealed downregulation of PI3K/AKT- and NF-κB-related genes and modulation of BCL2 family genes toward a pro-apoptotic profile, which was confirmed at both mRNA and protein levels. In vivo, enhydrin suppressed tumor growth without significant body-weight loss. These findings suggest that enhydrin exerts antitumor effects in prostate cancer by reducing the expression of PI3K/AKT and NF-κB related molecules and modulating apoptosis-related proteins. Although additional studies are required to determine pathway activity, directly confirm apoptosis, and evaluate normal-cell cytotoxicity and the therapeutic window, these findings provide preliminary biological evidence of the effects of enhydrin in prostate cancer models. Full article

Thermochromic wood coatings hold promising application prospects, yet conventional thermochromic microcapsules are limited by monotonous color transitions and non-environmentally friendly wall materials. In this study, two formaldehyde-free thermochromic microcapsules were prepared via spray drying using crystal violet lactone (CVL) and bisphenol A (BPA) as the core system, with chitosan–syringaldehyde (SA-MCs, decyl alcohol as solvent, Schiff base crosslinking) and chitosan–gum Arabic (GA-MCs, lauryl alcohol as solvent, electrostatic complex coacervation) as the wall materials, respectively. These microcapsules were incorporated into basswood ultraviolet (UV) coatings at mass fractions of 1%, 3%, 5%, 7%, and 9%. With increasing microcapsule content, the gloss of both coatings decreased progressively, roughness increased gradually, and the color-changing amplitude, expressed as the color difference (ΔE), was continuously enhanced. At 9% addition, the SA-MC coating exhibited a moderate transition from light yellow to yellow-green (ΔE = 7.2), while the GA-MC coating displayed a dramatic reversible change from deep blue to light gray (ΔE = 42.4), both with good reversibility. In terms of mechanical properties, SA-MCs exhibited higher hardness, both systems achieved an impact resistance grade of 3, and GA-MCs demonstrated superior adhesion. After 24 h of short-term UV accelerated aging, GA-MCs still maintained a higher thermochromic response, albeit with more severe gloss loss. In summary, GA-MCs are superior in color-changing amplitude and adhesion, while SA-MCs offer advantages in gloss retention and hardness, providing a reference for material selection in the application of smart wood finishing. Full article

Mycotoxin contamination remains a persistent threat to food and feed safety owing to the chemical stability of many mycotoxins, frequent co-occurrence, and matrix-dependent risks. Enzymatic detoxification enables structure-targeted transformation of toxicity-determining motifs, such as epoxide rings, reactive double bonds, amide linkages, and lactone structures. However, free mycotoxin-degrading enzymes are often constrained by poor operational stability, difficult recovery, and limited adaptability to complex matrices. Metal–organic frameworks (MOFs) provide programmable microenvironments for enzyme immobilization through tunable pore structures, interfacial chemistry, and confinement effects. This review links toxic structural motifs with enzymatic transformation targets, discusses MOF–enzyme interface engineering and representative host–enzyme compatibility, and evaluates application modes including single-enzyme systems, multi-enzyme co-immobilization or cascade systems, adsorption–degradation coupling, and detection–degradation integration. Key bottlenecks involving enzyme leakage, mass-transfer limitation, real-matrix stability, scalable preparation, and biosafety are critically discussed. Rather than treating MOFs as passive enzyme carriers, this review proposes an application-oriented framework that integrates toxin structure, enzyme function, MOF interface regulation, matrix compatibility, and safety validation to guide the development of MOF-immobilized degrading enzymes for practical mycotoxin detoxification. Full article

Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins, widely contaminating agricultural products and posing a serious threat to food safety and human health. Enzymatic degradation is considered a promising detoxification strategy due to its high efficiency, strong specificity, and lack of secondary pollution. AKR13B3, a member of the aldo-keto reductase family, possesses intrinsic catalytic activity for AFB1 degradation; however, its low natural activity severely limits practical application. In this study, the binding mode of the AKR13B3-NADPH complex with AFB1 was first determined using AlphaFold 3.0 and AutoDock Vina. Through interaction analysis, Trp102 and Asp41 were identified as key targets for enhancing catalytic activity. Following site-directed mutagenesis screening, two mutants, D41H and D41T, with significantly improved catalytic activity were obtained, exhibiting 52.32% and 46.44% higher activity than the wild-type enzyme, respectively. Three-dimensional structural simulation revealed that D41H and D41T form stable interactions with the carbonyl group on the lactone ring of AFB1, thereby polarizing the carbonyl group and reducing the activation energy of the reaction, ultimately enhancing catalytic activity. Substrate channel analysis demonstrated that, compared with the wild-type, the D41H and D41T mutants significantly increased the bottleneck radius of the substrate channel (by 25% and 22%, respectively) and shortened the channel length (by 23% and 33%, respectively), thereby partially relieving steric hindrance and diffusion limitations and improving catalytic efficiency. In summary, this study elucidates the molecular basis by which D41H and D41T enhance the catalytic activity of AKR13B3 toward AFB1 through the dual mechanisms of external/hydrogen bond catalysis and channel remodeling, providing an important theoretical foundation for the rational design and directed engineering of AFB1-degrading enzymes. Full article

Sesquiterpene lactones (SLs) are privileged medicinal scaffolds, offering potent bioactivities driven by their reactive α-methylene-γ-lactone motif. This review highlights the literature published up to the first half of 2026, detailing the synthetic methodologies utilized to optimize SLs via Michael addition. We critically evaluate how these structural transformations translate into biological and pharmacokinetic improvements. Specifically, the resulting Michael adducts achieve significantly enhanced solubility in aqueous media and highly refined drug–target interactions. Addressing a clear literature gap unaddressed since earlier foundational reviews, this focus review highlights the literature published up to the first half of 2026. By explicitly correlating synthetic strategies with pharmacological outcomes, such as enhanced efficacy and target specificity, this review provides medicinal chemists with a robust framework to accelerate the development of next-generation SL-based therapeutics. Full article

The bacterial Quorum Sensing system refers to the recognition of signaling molecules called autoinducers produced by bacteria when a certain cell density is reached in the environment. Those cell-density-dependent autoinducers regulate and coordinate diverse functional processes, such as bioluminescence, biofilm production, sporulation, and even the expression of some virulence factors, among others. There is a wide variety of autoinducers, and for Gram-negative bacteria, the canonical autoinducers are the N-acyl-homoserine lactones (AI-1). Presently, the production of autoinducers in Leptospira has not been described; therefore, the objective of this study was to detect and identify autoinducers in this bacterial genus. We report here the expression of AI-1 in cultures ≥2.4 × 10⁸ of Leptospira meyeri. Ethyl acetate extracts of Leptospira culture supernatants were capable of activating the β-galactosidase system in the biosensor Agrobacterium tumefaciens strain NTL4. Partial identification of the leptospiral supernatant extracts was done by thin-layer chromatography (TLC), showing a similar retention factor to the synthetic standard N-Octanoyl-DL-homoserine lactone (C8-AHL) in the Leptospira supernatant extracts. In addition, infrared spectroscopy (IR) analysis showed peaks corresponding to the lactone and amide groups in both the C8-AHL standard and the Leptospira meyeri culture extracts. Moreover, High-Performance Liquid Chromatography–Mass Spectrometry (HPLC-MS/MS) confirmed the same retention time (10.7 ± 0.1 min) in both the Leptospira meyeri supernatant extracts and the C8-AHL standard. These results show that Leptospira meyeri synthesizes N-acyl homoserine lactone family autoinducers, particularly the N-Octanoyl-DL-homoserine lactone, and lay the groundwork for future research on Quorum Sensing systems in Leptospira. Full article

The Turkistan Region of southern Kazakhstan lies within the Mountains of Central Asia biodiversity hotspot and harbors a flora of beneficial plants whose traditional use is well documented but whose chemistry and conservation status remain, for most species, formally unassessed. Following the PRISMA extension for Scoping Reviews (PRISMA-ScR), with accepted names verified against Plants of the World Online, this scoping review maps—for the first time as a single co-occurring assemblage rather than isolated single-taxon surveys—the evidence for nine regionally important species across the Nitrariaceae, Fabaceae, Apiaceae and Asteraceae. From 4362 records, 82 were charted by structured per-species extraction. The species span a broad chemical space: β-carboline alkaloids, furanocoumarins, sesquiterpene coumarins, sesquiterpene lactones and flavonoid-rich essential oils, sharing a recurring antioxidant and antimicrobial profile overlaid with species-specific effects such as the anthelmintic santonin of Artemisia cina. For most species the underlying data derive from non-Central Asian populations, limiting regional transferability, and safety evidence is sparse: no acute or repeated-dose toxicity study on regionally collected material was identified, although several species contain monoamine oxidase inhibitors, phototoxic furanocoumarins or thujone-rich oils. We propose a tiered, conservation-aware framework and a prioritized research agenda. Provenance was charted for all 82 records, and the country of origin could be established for 35. Full article