Search Results (4,879)

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

The health benefits of jujubes are closely related to their active substances. In this study, the active substances in ‘huizao’ (HZ), ‘junzao’ (JZ), ‘hamidazao’ (HMDZ), ‘kashigerexiaozao’ (KSGEXZ) and ‘yuanlingzao’ (YLZ) jujube varieties were identified via ultrahigh-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS). After identification, a total of 1583 metabolites were found in jujube fruits, covering 13 major categories including alkaloids, amino acids and their derivatives. Pairwise comparisons revealed 518–755 differentially abundant metabolites across cultivars, and each variety had its main dominant metabolites. Through network pharmacology, 141 potential disease-related bioactive compounds were screened out, and key compounds were identified through molecular docking. These substances bind to the key target TP53 through hydrogen bonding and hydrophobic interactions. Among them, catechin, naringenin, and coniferin had the strongest binding affinities. These data increase our understanding of the active components of jujube and provide valuable information for the sustainable cultivation of jujubes for health applications. Full article

Neuroinflammation is determinant in the progression of neurodegenerative diseases. One of the main mechanisms underlying this process involves the persistent activation of glial cells. Persistent activation of glial cells induces proinflammatory transcription factors and the release of cytokines, chemokines, and reactive oxygen species that exacerbate cellular dysfunction. This neurotoxic environment promotes neuronal death, while the products of cellular damage feed back into glial activation, establishing a self-sustaining pathogenic cycle that drives neurodegeneration. Alkaloids present in Amaryllidaceae plants support the use of this resource in folk medicine, displaying potent effects as acetylcholinesterase inhibitors and allosteric modulators of nicotinic receptors (nAChR). In this study, a murine microglial cell (IMG) model of LPS-induced inflammation was used to evaluate the involvement of α7 and α4β2 nAChRs in glioprotection and neuroprotection of SH-SY5Y cells against 6-hydroxydopamine (OHDA). GC-MS analysis revealed differences in the alkaloid profile between in vitro cultures with fructose and wild-type Rhodophiala pratensis. Homolycorine-type, norbelladine-type and crinine-type alkaloids produced in vitro reduced LPS-induced inflammation (5 µg/mL), possibly via α7 and α4β2 nAChRs, and showed a protective effect against OHDA-induced oxidative stress (1–3 µg/mL) and inhibited AChE and BuChE (24–78 µg/mL). Full article

Introduction: Neisseria gonorrhoeae, a bacterium responsible for gonorrhea, can spread through oral sex, causing pharyngeal gonorrhea, which is also a leading cause of urethritis in outpatient clinics. This study investigated whether tea tree oil (TTO) alone or in combination with other natural products could serve as an effective alternative to chlorhexidine in preventing the spread of oral gonorrhea. Methods: An in vitro model was developed using T84 epithelial cells as a mucosal layer and Neisseria gonorrhoeae strain MS11. The study assessed the minimal inhibitory concentration (MIC), bacterial adherence, invasion, and transmigration across the mucosal barrier. Berberine (BB), a major and bioactive alkaloid derived from Coptis chinensis, was tested with and without TTO in MIC assays and epithelial cell viability tests. Ceftriaxone was used as a positive control. Results: The MIC values for TTO, BB, and ceftriaxone against the MS11 strain were determined to be 0.2%, 5 μg/mL, and 0.0125 μg/mL, respectively. Notably, the combination of TTO with BB demonstrated a synergistic effect, reducing the MIC to 0.000625% TTO + 1.25 μg/mL BB. This combination provided the strongest protective effect. No cytotoxicity was observed in the epithelial cell viability tests for 0.2% diluted TTO, 5 μg/mL BB, or the combination of 0.000625% TTO + 1.25 μg/mL BB. Conclusions: BB, when combined with TTO, exhibited a synergistic antimicrobial effect against Neisseria gonorrhoeae strain MS11 in the T84 mucosal model. These findings highlight the potential of this combination as a natural alternative to chlorhexidine gluconate for managing oral gonorrhea. Full article

Papaya (Carica papaya L.) is a widely cultivated tropical and subtropical fruit crop valued for its rich nutritional content, diverse food industry applications, and the medicinal use of papain. However, bitterness in papaya fruit, particularly in fibrous strands, negatively affects fruit quality and consumer acceptance; therefore, the development of papaya cultivars with stable and desirable quality is of great importance. To identify the bitter compounds in papaya fruit fibrous strands and elucidate the molecular mechanisms underlying their biosynthesis, we performed transcriptomic and metabolomic analyses of fibrous strands from two papaya cultivars at three developmental stages. We identified carpaine, dehydrocarpaine II, and their derivative alkaloids. Furthermore, we identified two key regulatory genes, CpNAC82 and CpHD-Zip ANT2, associated with alkaloid biosynthesis. Finally, using single-nucleus RNA sequencing technology, we constructed a comprehensive gene expression atlas of papaya fibrous strands and stems, successfully identifying multiple cell types, including epidermal cells, guard cells, parenchyma cells, and phloem cells. Epidermal and phloem cells serve as the primary sites of alkaloid metabolism in papaya. These findings provide new insights into the molecular mechanisms of bitterness in papaya’s fibrous strands and yield genomic resources for improving fruit quality in papaya. Full article

Pseudomonas plecoglossicida causes bacterial hemorrhagic ascites in ayu (Plecoglossus altivelis), a lethal disease characterized by abdominal distension with hemorrhagic ascites, multifocal organ hemorrhages, and histopathologically evident hepatocellular necrosis and inflammatory infiltration. The lack of effective treatments exacerbates mass mortalities, posing a significant threat to aquaculture. Given the severe pathogenesis of P. plecoglossicida infection—which involves bacterial colonization, tissue necrosis, and host immune dysregulation—effective therapeutic strategies are urgently needed. Through a screen of traditional Chinese medicine monomers, we identified harmine, an indole alkaloid derived from Peganum harmala seeds, as a potent agent against this pathogen. In vivo, harmine exhibited direct bactericidal activity by disrupting membrane integrity, as evidenced by increasing membrane permeability, and inhibiting biofilm formation. In an ayu infection model, harmine significantly increased host survival, reduced tissue bacterial load, and enhanced innate immunity by augmenting monocyte/macrophage phagocytosis and bactericidal capacity while suppressing pro-inflammatory cytokine release and apoptosis. Mechanistically, the Drug Affinity Responsive Target Stability assay was used to identify the molecular target of harmine, followed by functional validation through PRDX6−knockdown experiments. Harmine exhibited direct bactericidal activity by disrupting membrane integrity and inhibiting biofilm formation. In the ayu infection model, harmine significantly increased host survival, reduced tissue bacteria1 load, and enhanced innate immunity by augmenting monocyte/macrophage system and bactericidal capacity while suppressing pro-inflammatory cytokine release and apoptosis, the latter likely through modulation of PRDX6−mediated oxidative stress and downstream caspase signaling. Mechanistically, DARTS revealed that harmine binds to peroxiredoxin 6 (PRDX6), a multifunctional enzyme possessing peroxidase, phospholipase A₂, and lysophosphatidylcholine acyltransferase activities. This binding liberates TNF receptor-associated factor 6 (TRAF6), facilitating its mitochondrial translocation and association with the ECSIT signaling integrator complex, thereby amplifying mitochondrial reactive oxygen species (mROS) production and potentiating macrophage-mediated bacterial killing. These findings establish harmine as a promising therapeutic candidate for controlling P. plecoglossicida infections and underscore the value of host-directed immunomodulation derived from natural products in aquaculture medicine. Full article

Periodontitis represents a primary etiological factor in tooth mobility, with oxidative stress contributing critically to periodontal tissue destruction. Evodiamine (EVO), a quinazolinocarboline alkaloid, exhibits multiple biological activities; however, its antioxidant effects and mechanism in periodontitis have not been elucidated. The aim of this study was to investigate the regulatory effect of EVO on oxidative stress in periodontitis and to explore the associated molecular mechanism. The results indicate that EVO exhibits potent antimicrobial activity against key periodontal pathogens and suppresses pathogen-induced ROS generation as well as the release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) under periodontitis conditions. EVO binds specifically to the Kelch domain of KEAP1 with a strong binding energy (−11.67 kcal/mol), inhibits KEAP1–NRF2 interaction, and consequently upregulates the expression of antioxidant enzymes (HO-1, NQO1, GCLC, and SOD2), while downregulating the expression of iNOS, COX2, and NOX2. Furthermore, EVO inhibits the pro-apoptotic effect of the JAK2/STAT3 signaling axis and mitigates inflammation, alleviates cell cycle arrest, and promotes the migration and repair of periodontal ligament cells. Collectively, these findings suggest that EVO acts as a potential binder of KEAP1 that alleviates periodontal inflammation through modulation of oxidative stress and regulation of the JAK2/STAT3 pathway. Full article

Plant-derived antimicrobial compounds are emerging as promising alternatives to synthetic preservatives in the food industry due to their efficacy against a broad spectrum of pathogenic and spoilage microorganisms, as well as their consumer acceptance. This review critically examines the main classes of bioactive phytochemicals, including essential oils, polyphenols, alkaloids, terpenoids, and saponins, comparing their relative antimicrobial effectiveness and highlighting representative examples. Notably, essential oils rich in thymol or carvacrol have shown strong inhibitory activity against Listeria monocytogenes and Salmonella spp., while polyphenols and alkaloids exhibit moderate to strong activity depending on concentration and food matrix. Their mechanisms of action include cell membrane disruption, inhibition of key enzymes, and interference with DNA or protein synthesis. Applications in food systems (i.e., incorporation into coatings, emulsions, or controlled-release formulations) demonstrate potential for extending shelf life and enhancing safety. However, practical implementation is challenged by matrix-dependent efficacy, compound stability, sensory impact, and regulatory and toxicological considerations. By synthesizing current knowledge, identifying the most promising compound classes, and highlighting key limitations, this review provides a critical framework to guide future research and the development of effective, sustainable natural preservatives in the food industry. Full article

Today, interest in natural remedies for biocontrol of crop pests is paramount. Punica granatum L. (pomegranate) is studied worldwide to obtain interesting bioactive compounds. Its anti-parasitic activity is associated with the presence of alkaloids in its roots. In this work, we explored the possibility of obtaining from P. granatum roots pelletierine-like alkaloids, which were extracted, characterized, isolated and used for the biocontrol of pests such as Spodoptera littoralis, Myzus persicae, Rhopalosiphum padi and Meloidogyne javanica. Two different extracts were obtained, characterised and quantified by GC-MS and LC-ESI-HRMS. In vitro assays of nematicidal activity were performed comparing the extracts with isopelletierine and pseudopelletierine as pure molecules. The results of these assays showed a difference in activity between iso- and pseudopelletierine, especially in terms of the nematocidal effect against M. javanica with isopelletierine being more active than pseudopelletierine. This leads us to conclude that only extracts from P. granatum roots with a high concentration of isopelletierine alkaloid can be used in effective pest control products. Full article