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Berberine, a natural alkaloid, is a substance widely used in natural medicine. However, there is a significant knowledge gap regarding the potential negative effects of higher environmental concentrations of berberine resulting from its use as a supplement. Therefore, the aim of this study was to assess its toxicity towards microorganisms and organisms from various trophic levels. The results indicate that berberine may influence the reorganization of bacterial membranes, thereby negatively impacting the environmental microbiome. However, oxidative cell damage, a phenomenon commonly described in the literature, was not demonstrated. At the concentrations used, berberine may even have a protective effect. The analysis of toxicity towards Tetrahymena, Selenastrum, and Heterocypris indicated a similar level of berberine toxicity across these organisms, suggesting that the toxic effect is not species-dependent and that the mechanism of toxicity is probably based on universal cellular mechanisms. Full article

Background/Objectives: Dendrobium officinale (D. officinale), an endangered ornamental and medicinal orchid, displays significant variability in its bioactive compounds depending on geographical and environmental factors. To decipher these influences, we investigated metabolic divergence across three cultivars (GN, LS, DX) cultivated in greenhouse and outdoor conditions using untargeted metabolomics. Methods: Metabolites extracted from stem and leaf tissues were analyzed via UHPLC-Q Exactive Orbitrap MS, and the raw data were processed using XCMS for peak alignment and quantification. Differentially abundant metabolites (DAMs) were identified by multivariate statistical analyses including PCA and OPLS-DA. Metabolic pathways were annotated using KEGG, HMDB, and LIPID Maps databases, with enrichment analysis and visualization performed via TBtools II and Hiplot. Results: Metabolite profiling and multivariate analysis revealed distinct chemotypes. The DX cultivar exhibited anthocyanin enrichment in its stems, correlating with a red pigmentation, while GN accumulated specific amino acid derivatives. Tissue-specific metabolic specialization was evident, with leaves displaying greater flavonoid diversity and stems prioritizing lipid and amino acid metabolism. Outdoor cultivation enhanced flavonoid biosynthesis, whereas greenhouse conditions favored alkaloid accumulation. Functional analysis identified both conserved pathways, like phenylpropanoid biosynthesis, and varietal-specific adaptations in amino acid and secondary metabolism. Notably, alkaloid levels declined sharply during plant defoliation. Conclusions: Our findings demonstrate that environmental factors and geographical origin synergistically shape the metabolic profiles of D. officinale. This provides a scientific basis for optimizing cultivation strategies—through targeted environmental adjustments and varietal selection—to enhance the yield of desired bioactive compounds. Full article

Datura species are valued ornamentals but contain toxic tropane alkaloids (TAs) like hyoscyamine and scopolamine, which restrict their safe horticultural use. To address this, we developed a genome editing platform in Datura inoxia for creating non-toxic varieties. We first established an efficient, auxin-independent shoot regeneration system using a novel cytokinin combination (thidiazuron and 6-benzylaminopurine) achieving over 7 shoots per explant. This system facilitated an Agrobacterium tumefaciens-mediated transformation protocol with a stable efficiency exceeding 50% (49 independent lines from 100 explants for LS; 36 lines from 70 explants for CYP80F1). Using this platform, we performed CRISPR/Cas9-mediated knockout of two key TA biosynthetic genes, LS (littorine synthase) and CYP80F1 (littorine mutase). Among the transgenic lines analyzed, 8 out of 15 (53%) carried mutations in LS, while all 12 (100%) lines carried mutations in CYP80F1. HPLC and high-resolution mass spectrometry confirmed the complete absence of hyoscyamine and scopolamine in the mutant leaves, with no detectable peaks at the corresponding retention times. Crucially, the edited plants grew normally and were morphologically indistinguishable from the wild type. This work establishes the first CRISPR/Cas9 platform for Datura and generates the first non-toxic germplasm, providing both a functional genomics tool and a foundation for breeding safe ornamental cultivars. Full article

The species Psychotria densicostata Müll.Arg. is a shrub belonging to the Rubiaceae family, endemic to Brazil. So far, there are reports neither of phytochemical work on nor of biological evaluation of it. This study investigated its alkaloid profile and evaluated the inhibitory effects of extracts, alkaloid-enriched fractions and one of its major constituents on human neutrophil elastase (HNE). The monoterpene indole alkaloids (MIAs) strictosidine (1), (3α,5α)-5-carboxystrictosidine (2), strictosidine lactam (3), lyaloside (4), lyalosidic acid (5), 5-carboxystrictosamide (6), 3,4-dehydrostrictosidinic acid (7), and N-glucopyranosyl vincosamide (8) were characterized in mixture, in its leaves, and/or stems by using an integrated approach combining nuclear magnetic resonance (NMR) techniques, high performance liquid chromatography coupled to a tandem mass spectrometer with an electrospray ionization source (HPLC-ESI-MS/MS), and molecular networks. The crude leaf extract and an alkaloid-enriched fraction derived from it showed inhibitory activity against HNE. These results contribute to the chemical knowledge of the species and suggest its potential biological property. Full article

Endophytic fungi (EF) inhabit internal plant tissue in a mutually beneficial symbiotic relationship with their host plant. EF synthesizes metabolites that are structurally similar or identical to those found in their host plants, which include alkaloids, flavonoids, terpenoids, phenolic compounds, polysaccharides, proteins, lipids, and organic acids. These molecules have promising therapeutic effects, such as antimicrobial, antioxidant, anti-inflammatory, and antitumor activities. Wound healing has earned attention in recent years because of its relation to chronic pathological diseases. This systematic review scanned the available scientific literature database about the wound-healing properties of EF biomolecules. Amongst 994 works, 24 were screened after abstract and full-text reading. The studies were published between 2014 and 2026, in twelve countries. In total, 16 studies presented in vivo assays, 11 studies presented in vitro assays, and 3 studies presented both assays. Most studies identified molecules, which include melanin, benzoic acid, terpenes, sesquiterpenes (purpurolide), extracellular polysaccharides, exopolysaccharides, carotenoids, fatty acids, proteins, pyrones, quinones, and hydrocarbon acids, among others. A meta-analysis was not conducted due to high heterogeneity across extracts, methodologies, and outcomes. All studies showed wound-healing properties from EF extracts. The findings suggest a positive effect of EF extracts on wound-healing properties and the need for standardized in vitro and in vivo protocols. Full article

Generally, forest trees with medicinal value present diverse chemotypes considered key determinants of efficacy, safety, and commercial valuation. Such heterogeneity varies among tissues, genotypes, and seasons, and stress exposure. This review summarizes how regulatory controls and genome architecture affect the stability and synthesis of secondary metabolites in woody medicinally important taxa. Detailed haplotypic and chromosomal analyses have recently identified diverse and repeatable architectural drivers. Among these, LTR/transposon-mediated revamping, neofunctionalization, biosynthetic gene clusters, and tandem duplication play a special role in reshaping pathway capacity. The enzymatic regulation of these drivers translates this “capacity” into harvest-pertinent chemistry by employing conserved TF modules, hormone crosstalk, and emergent chromatin/epigenetic layers. Nevertheless, major parameters pertaining to the tissue-specific storage, transport, and compartmentalization of these chemotypes are contextualized with certain limitations. In this review, the integration of GWAS/eQTL/TWAS with multi-tissue is explained in addition to the replacement of a single reference with pangenome/haplotype frameworks, and explicit modeling of G × E further strengthen genotype-to-chemotype mapping. Therefore, in this review we summarize practical workflows for chemotype discovery utilizing staged validation models of heterologous reconstitution, isotope/spatial evidence, and chemistry. These findings were supported by data on saponins, alkaloids, iridoids, and defense response. Such an integration links mechanistic understanding to authentication, standardization, and sustainable utilization strategies in woody medicinal trees. Full article

Wound healing involves the coordinated regulation of inflammation, angiogenesis, and extracellular matrix remodeling, processes modulated by natural bioactives. In this context, Chelidonium majus L. (C. majus), a plant rich in alkaloids and flavonoids, remains mechanistically underexplored. This study, therefore, investigates its metabolites using an integrated computational–experimental approach and evaluates their applicability in sericin-based wound-healing systems. A curated database of 83 C. majus bioactive compounds was analyzed using cheminformatics and molecular docking against key wound-healing targets (iNOS, VEGF, MMP-3, and tyrosinase), followed by ADMET and toxicity prediction (StopTox). Selected plant–sericin formulations were subsequently evaluated for wound-healing activity using an in vitro fibroblast scratch assay. Docking revealed strong binding affinities for several metabolites, particularly protopine, kaempferol-3-rutinoside, cynaroside, hesperidin, quercetin-3-rhamnosylrutinoside, and vitexin, indicating multi-target modulation across inflammatory, proliferative, and remodeling phases of tissue repair. ADMET and toxicity analyses predicted favorable dermal safety and pharmacokinetic profiles for most compounds. Consistently, in vitro assays demonstrated that C. majus–sericin systems had fibroblast migration and wound closure in a concentration- and ratio-dependent manner, with improved healing kinetics observed at 150 µg/mL and for formulations containing higher relative proportions of both components. The experimental outcomes supported the pro-angiogenic and matrix-stabilizing mechanisms predicted in silico. Overall, C. majus metabolites exhibit polypharmacological wound-healing activity, supporting their integration into sericin-based systems as a promising strategy for topical therapies. Full article

Phellodendri amurensis Cortex is the dried bark of the cork tree (Phellodendron amurense Rupr.) from the Rutaceae family, and possesses traditional efficacy in clearing heat, drying dampness, purging fire, relieving steaming sensations, detoxifying, and healing sores. Clinically, it is commonly used for treating symptoms such as damp-heat diarrhea and dysentery, jaundice with reddish urine, leukorrhea with vaginal itching, painful and difficult urination due to heat strangury, flaccidity and weakness of the lower limbs, bone-steaming and consumptive fever, night sweats and seminal emission, sores, ulcers, swellings, and toxins, eczema, damp sores, and urinary tract infections. Modern pharmacological studies have further revealed its diverse bioactivities, including antioxidant, antibacterial, anti-inflammatory, immunosuppressive, and anticancer effects. To provide an updated and comprehensive review of the research into Phellodendri amurensis Cortex, this study conducted a thorough literature search and analysis based on databases such as SciFinder, Web of Science, and China National Knowledge Infrastructure. The review integrates information on the plant’s botanical characteristics, geographical distribution, traditional applications, chemical components, quality control methods, and pharmacological effects to present a current and holistic overview of its research status. To date, approximately 170 compounds have been isolated and identified from Phellodendri amurensis Cortex, primarily including alkaloids, phenolics, terpenoids, sterols, lignans, flavonoids, and others. Among these, alkaloids exhibit significant antioxidant and anti-inflammatory activities and demonstrate potential pharmacological value in antibacterial, anticancer, hypoglycemic, and multi-organ protective effects. Although substantial foundational research exists, the mechanisms of action and quality control of Phellodendri amurensis Cortex require further in-depth exploration. Future efforts should focus on clarifying its pharmacodynamic material basis, uncovering new targets and pathways, and improving analytical methods for component analysis and quality control to advance the scientific development and rational utilization of this medicinal material. Full article

Neuroinflammation mediated by astrocyte–microglia interactions plays a critical role in the progression of neurodegenerative disorders. Celastrus paniculatus (CP) seeds have long been associated with cognitive benefits; however, the chemical composition and anti-inflammatory potential of their high-polarity fractions remain poorly characterized. In this study, thin-layer chromatography (TLC)-derived high-polarity fractions (F6 and F7) from CP seeds were analyzed using untargeted LC–MS/MS metabolite profiling. After quality filtering, 99 metabolites were retained for classification, with enrichment of alkaloids and terpenoid-related compounds, including 41 structurally complex metabolites. To evaluate biological relevance, BV2 microglia were exposed to astrocyte-conditioned medium derived from H₂O₂-treated astrocytes (ACM-H), modeling sterile inflammatory signaling. ACM-H stimulation induced microglial activation characterized by morphological transformation, increased CD40 and inducible nitric oxide synthase (iNOS) expression, and elevated production of pro-inflammatory cytokines TNF-α and IL-6. Co-treatment with CP fractions attenuated ACM-H-induced inflammatory responses, with fraction F7 showing stronger effects than F6. Fraction F7 showed stronger inhibitory effects on CD40 and iNOS expression, suppressed TNF-α and IL-6 production, and partially restored ramified microglial morphology, whereas F6 exhibited comparable anti-inflammatory activity and showed a stronger effect on microglial phagocytic responses. Metabolomic analysis further indicated a higher relative abundance of terpenoid-related metabolites in F7. Collectively, these findings indicate that CP seed fractions, particularly F7, attenuate astrocyte-driven microglial activation in an in vitro sterile neuroinflammatory model. Full article

The distinctive bitter profile of Castanopsis fissa honey (LSZH) has not yet been clearly characterized at the chemical and molecular levels. Based on the LSZH samples (n = 6), this study investigated bitterness-associated compounds and their potential receptor interactions by integrating sensory evaluation, machine learning, untargeted metabolomics, electronic tongue analysis, targeted UPLC-QQQ-MS/MS quantification, and molecular docking. A Random Forest model combined with untargeted metabolomics screened 71 candidate bitter compounds, among which alkaloid-related metabolites were prominently represented. Electronic tongue analysis showed that several compounds exhibited higher bitterness-related sensor responses than quinine under the tested conditions. Targeted UPLC-QQQ-MS/MS analysis identified and quantified five key compounds, among which kynurenic acid was the most abundant, reaching approximately 4500 ppm (mg/kg). Molecular docking suggested that these compounds could favorably interact with the human bitter taste receptor TAS2R46, with binding affinities ranging from −5.4 to −6.5 kcal/mol, mainly through hydrogen bonding, hydrophobic interactions, and π-related interactions. Overall, this study provides chemical evidence and mechanistic clues for understanding the bitterness of LSZH and offers an integrated analytical framework for screening bitterness-associated compounds in complex food systems. Full article

In the treatment of atopic dermatitis (AD), synergistic activation of the aryl hydrocarbon receptor (AHR)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways represents a promising strategy. However, known dual agonists are limited, and traditional screening methods are inefficient. Therefore, this study developed machine learning models to predict AHR/NRF2 dual agonists using molecular descriptors and fingerprints. All models achieved area under the receiver operating characteristic curve (AUC) values above 0.86, indicating good classification performance. The optimal AHR model showed an accuracy (ACC) of 0.811 and an AUC of 0.878, while the best NRF2 model yielded an ACC of 0.839 and an AUC of 0.907. Based on this model, compounds with a low fraction of sp³-hybridized carbons, moderate hydrophobicity, limited alkyl chains, and highly conjugated structures tend to act as AHR/NRF2 dual agonists. Finally, this study screened 1011 potential natural AHR/NRF2 dual agonists suitable for drug development. Among these, 2-arylbenzofurans, alkaloids, phenanthrenes, flavones, and furocoumarins demonstrated particular advantages. For validation, Indirubin, imperatorin and 3′-O-Methylbutastatin III were first discovered as AHR/NRF2 dual agonists in HaCaT cells. This work provides a robust predictive tool, clarifies key molecular features of dual agonists, and may support the discovery of anti-AD agents. Full article

Myocardial ischemia–reperfusion injury (MIRI) significantly limits the clinical benefits of reperfusion therapy, underscoring a pressing need for effective interventions. This study examines the cardioprotective effects and underlying mechanisms of the natural amide alkaloid N-p-trans-Coumaroyltyramine (p-CT). Using hypoxia/reoxygenation (H/R) models in neonatal rat cardiomyocytes and in vivo rat MIRI models, we assessed p-CT pretreatment on cell viability, cardiac function, serum injury markers (lactate dehydrogenase, creatine kinase-MB, cardiac troponin T, and myoglobin), myocardial histopathology, ultrastructural alterations, and infarct size. The systematic screening and validation of potential targets were conducted via label-free quantitative proteomics, molecular docking, and Western blot. The results demonstrated that p-CT pretreatment dose-dependently mitigated H/R-induced cellular injury, improved cardiac function in MIRI rats, reduced serum markers of myocardial damage, alleviated pathological and ultrastructural injury in myocardial tissue, and significantly diminished infarct size. Proteomic analysis revealed 19 differentially expressed proteins specifically reversed by p-CT, with Titin-cap (Tcap) exhibiting the most pronounced downregulation in the MIRI model—a change effectively restored by p-CT pretreatment. Molecular docking indicated strong binding affinity between p-CT and Tcap protein. In summary, p-CT represents a promising cardioprotective agent, likely exerting its effects by targeting Tcap protein and upregulating its expression, thereby helping preserve cardiomyocyte structural and functional integrity. Full article

The emergence of antimicrobial resistance and the increasing incidence of cancer have highlighted the urgent need to develop new drugs; therefore, the discovery of new bioactive molecules is an important goal for future research. In this study, freshwater fungi isolated from submerged Phragmites australis from Egypt were screened for antimicrobial and cytotoxic activities. Using ITS1 and ITS4 primers, eight frequently occurring Sordariomycetes taxa were identified and were then selected for further evaluation of bioactivity. Ethyl acetate crude extracts (A–H) were evaluated for antimicrobial activity using the agar disk-diffusion method. Extracts A and E, derived from Chaetomium globosum SCUF0000404 (PX596738) and Chaetomium madrasense SCUF0000401 (PX596735), respectively, showed broad-spectrum activity at 100 mg/mL against bacterial pathogens, including Staphylococcus aureus ATCC 29213 (15.33 and 18.00 mm), Streptococcus pyogenes ATCC 19615 (11.00 mm), Escherichia coli ATCC 35218 (10.33 and 10.67 mm), Klebsiella pneumoniae ATCC 700603 (14.00 and 16.67 mm), and Pseudomonas aeruginosa ATCC 27853 (13.33 and 16.33 mm), and show antifungal activity against Candida albicans ATCC 14053 (20.33 mm), Candida krusei ATCC 6258 (15.67 and 15.33 mm), Trichosporon asahii AMS 187 (17.00 and 17.67 mm), Exserohilum rostratum AMS 1077 (34.00 and 33.67 mm), and Trichophyton indotineae AMS 180 (38.33 and 34.00 mm). Selective cytotoxic effects on the breast cancer cell line MDA-MB-231 were observed by extracts A and E at IC₅₀ = 309 and 277 μg/mL, while non-selective cytotoxic effects on the normal HUVEC cell line were found with IC₅₀ = 919 and 796 μg/mL, respectively. Characterization of the most effective extracts A and E by high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) shows that they have a wide range of secondary metabolites, including cytochalasans, azaphilone alkaloids, steroids, terpenoids, flavonoids, and phenols. These findings underscore the chemical diversity and therapeutic potential of freshwater fungi from Egypt. Full article

Natural products represent an important reservoir for GPCR ligand discovery. In this study, we established an integrated workflow combining virtual screening, biophysical validation, functional signaling assays, and transcriptomic profiling to identify reticuline, a dopamine-derived intermediate from the genus of Stephania, as a potential agonist of dopamine D5 receptor (D5R). Molecular docking revealed that most dopamine-derived compounds along the BIA synthetic pathway exhibit predicted binding affinities for the D5R that are lower than that of dopamine. As expected, the reticuline–D5R complex has a favorable predicted binding affinity of −7.9 kcal/mol. As for binding validation, direct interaction between reticuline and D5R was experimentally confirmed using cell membrane chromatography (CMC) and bio-layer interferometry (BLI), yielding a dissociation constant of 1.07 μM. cAMP assay demonstrated that reticuline activates D5R-mediated Gs-cAMP increasement in a concentration-responsive manner, which exhibits agonist-like activity with an EC₅₀ value of 0.07 μM. The transcriptomic profiling further revealed that reticuline treatment induces transcriptional reprogramming in D5R-overexpressing cells, with enrichment of pathways related to ribosome biogenesis, mitochondrial oxidative phosphorylation, and neurodegenerative diseases. In summary, this study demonstrates that reticuline acts as a potential D5R agonist and highlights a systematic natural product-GPCR discovery strategy integrating computational prediction, experimental validation, and transcriptome-level mechanistic exploration. Full article

Nalca (Gunnera tinctoria Mol.) is traditionally consumed for its edible petioles and valued for medicinal properties associated with its bioactive compounds. In this study, natural deep eutectic solvents (NADESs) were synthesized and applied for the ultrasound-assisted extraction of phenolic compounds and alkaloids from Nalca leaves. NADES synthesis was confirmed using ¹H NMR, and their physicochemical properties were evaluated to assess their influence on extraction efficiency. The extracts showed total phenolic contents ranging from 6.8 to 142.6 mg GAE/g DW and total alkaloid contents ranging from 0.2 to 3.2 mg OXIE/g DW, depending on solvent composition. Antioxidant activity, evaluated using DPPH and FRAP assays, confirmed that most NADES extracts exhibited significant radical-scavenging and ferric-reducing capacities, generally correlating with phenolic content. The extraction yields obtained with specific NADES formulations were comparable or superior to those achieved with conventional solvents, demonstrating their efficiency. These results demonstrate that NADESs are effective and environmentally friendly alternatives to conventional solvents for extracting bioactive compounds from Nalca leaves. The physicochemical properties of NADESs enable the selective extraction of different metabolite classes, highlighting their potential for green extraction processes in food, nutraceutical, and pharmaceutical applications. Full article