This study led to the isolation of 17 triterpenoids, including two lanostane-type (1 and 2), two dammarane-type (3 and 7), ten tirucallane-type (4 and 8-16), and three oleanane-type (17-19) triterpenoids, as well as nine sterols (5, 6, and 20-26) from Cotinus coggygria var. cinereus Engl, which were first discovered from the genus Cotinus. Among them, coggygrenoids A-D (1-4), coggygrerol A (5), and coggygrerol B (6) are undescribed compounds. Additionally, seven flavonoids (27-33) were also isolated from this plant. Compound 15 displayed inhibitory activities in LPS-induced RAW 264.7 cells with an IC50 value 6.81 ± 0.15 μM. Molecular docking demonstrated that 15 exhibited favorable affinity for NLRP3 and iNOS. In vitro and in vivo antibacterial evaluations indicated that coggygrnoid C (3) exhibited significant inhibitory activity against methicillin-resistant Staphylococcus aureus ATCC BAA-1717 (USA300), with An MIC of 8 μg/mL. Further mechanistic investigations demonstrated that 3 exerted antibacterial activity by compromising the integrity of the cell wall and membrane. Notably, the combination of 3 with ampicillin exhibited an additive antibacterial effect. In the Galleria mellonella infection model, compound 3 exhibited comparable activity to that of the positive control at 20 mg/kg. These findings suggest that triterpenoids of C. coggygria are potential antibacterial lead agents.
Liver disease is a serious threat to human health, so its prevention and treatment have been the focus of medical research. In the past few years, natural products have proved to be promising and valuable in the treatment of liver diseases. The bioactive substance paeonol, extracted from the root bark of peony (Paeonia lactiflora) of the buttercup family, is a promising drug candidate because of its low toxicity and multifaceted pharmacological properties. This review comprehensively explored the therapeutic potential of paeonol in different liver pathologies as well as the regulatory mechanisms. Despite its promising potential, the poor solubility and rapid metabolism of paeonol hindered its clinical translation. To improve bioavailability and liver targeting, we highlighted the potential of paeonol as a next-generation therapy for liver diseases by integrating preclinical evidence and technological advances, while exploring key avenues for future research, such as metabolic regulation and smart nanocarrier design.
Natural products (NPs) and their analogues have long underpinned therapies in humans, animals, and plants health, yet, discovering truly novel scaffolds remains a formidable challenge, even with the enormous diversity offered. Over the last two decades, breakthroughs in bioinformatics, cheminformatics, advanced analytical methods, synthetic biology toolkits, and optimized microbial culture have surmounted many of the bottlenecks that stalled NP research in the 1990s and 2000s. Researchers now deploy innovative extraction and purification protocols alongside high-throughput dereplication tools to fish trace metabolites out of complex matrices. These combined approaches not only enable the discovery and rigorous characterization of biosynthesized metabolites, bio-transformed analogues and new chemical entities but also allow precise tuning of biosynthetic gene clusters (BGCs) and culture conditions- modulation and optimization, dramatically improving yield, scalability, and cost-efficiency. Several of these newly unearthed compounds exhibit unique bioactivities that directly inspire drug-development programs against metabolic disorders, cancer drug resistance, and infectious diseases. In this review, we present an up-to-date, concise roadmap of natural product discovery (NPD), majorly covering strategies for awakening silent BGCs, genome mining, and late-stage diversification systems, and we discuss the current limitations and perspectives of rational NPD.
Rhodomyrtus tomentosa fruits serve as both functional food and medicinal resources due to their rich bioactive constituents and manifold pharmacological effects. Phytochemical exploration of the R. tomentosa fruits led to the identification of eight new polymethylated phloroglucinols, designated as rhodotomentodione F (1) and rhodotomentodimers H-N (2-8), along with six previously described congeners (9-14). Based on the detailed inspection of comprehensive spectroscopic data, electronic circular dichroism (ECD) simulations, and nuclear magnetic resonance (NMR) calculations, and DP4+ analyses, the structures of phloroglucinols 1-8 were determined. Heterodimeric phloroglucinols 3-14 exhibited human acetylcholinesterase (hAChE) inhibitory activities, with 13 exhibiting the highest potency (IC50 = 1.04 μM). Moreover, molecular docking analysis clarified the potential binding interactions between the most active phloroglucinol 13 with hAChE. In addition, phloroglucinols 11 and 12 displayed significant anti-VRE (vancomycin-resistant Enterococci) activities, with MIC values reaching as low as 1 μg/mL.
As a dual-purpose medicinal and edible mushroom, Ganoderma species have garnered significant interest in both the food, cosmetics and pharmaceutical industries. To further substantiate its traditional and functional uses, we conducted a systematic phytochemical study of Ganoderma resinaceum fruiting bodies, isolating 43 lanostane-type triterpenoids. Among these, 16 were identified as new compounds (1-11, 15, 31, 35, 37, and 42). Compound 1 represents the first reported C29 lanostane triterpenoid featuring a 21,24-cyclo five membered carbon ring fraction. The spectroscopic (1D/2D NMR, ESIMS) and X-ray crystallographic analyses confirmed their structures. Among these, compounds 2-4, 13, 17, 35, 36, and 42 exhibited potent antioxidant activity by suppressing UV-induced ROS in skin keratinocytes. The most active compound, 42, reduced ROS and malondialdehyde (MDA) levels, enhanced antioxidant defenses (superoxide dismutase, SOD; hydroxyproline), and suppressed matrix metalloproteinases (MMPs) through activating Nrf2 pathway and suppressing MAPK signaling. These results position G. resinaceum triterpenoids, particularly compound 42, as multifunctional natural antioxidants with applications in functional foods for oxidative stress management or skin-protective formulations.
Seed water content affects wheat quality, storage, and food safety, influencing viability and fungal contamination risks. Grain moisture is influenced by both genetic and environmental factors, with agronomic practices aiming to optimize it. However, no genotype has been specifically developed for enhanced seed water properties, as the underlying biochemical and genetic mechanisms remain unclear. Using a durum wheat mutant (WM) with higher water affinity of leaves, compared to its wild-type cultivar, Trinakria (WT), this study investigates the biophysical and biochemical mechanisms affecting seed performance. Genotypic characterization of unaged seeds includes differential scanning calorimetry, metabolomic profiling, and functional analyses of water uptake rate, dehydration rate, and seed coat electrical resistance. Germination and Fusarium resistance were examined, too in both unaged and aged seeds. As for the leaves, WM seeds exhibit higher water-binding strength than WT. Metabolomic analysis revealed a higher polar/apolar ratio in WM (83 vs. 72 in WT), with significantly greater myo-inositol and raffinose content and lower levels of unsaturated fatty acids. No differences in seed imbibition velocity or dehydration velocity were observed, but WM showed lower seed coat electrical resistance, indicating greater free water retention on the seed surface. Under low Fusarium inoculum concentrations or in the absence of pathogens, aged WM seeds showed higher germination rates and vigor than WT. As an inherited trait, selecting for strong water-binding capacity, increased osmoprotective compounds, and lower unsaturated acid content could contribute sustainably improve seed longevity and Fusarium resistance.
Omicsynins are a group of pseudo-tetrapeptides produced by Streptomyces sp. 1647, which exhibited potent anti-influenza A virus and anti-coronavirus activities. However, its biosynthesis mechanism of C-terminus reduction remains unknown. In this work, we explored two short-chain dehydrogenase/reductase (SDR) superfamily encoding genes in the omicsynin biosynthetic gene cluster (BGC) and confirmed the necessity of omnF, rather than omnG, in the biosynthesis of omicsynins through gene deletion in vivo. Subsequently, Feature-Based Molecular Networking (FBMN) analysis revealed three pseudo-tetrapeptides with C-terminal carboxyl group and four unexpected analogues encoded by the omicsynin BGC in the omnF reductase (R) domain knockout mutant strain. This led to the isolation and structural characterization of a group of novel pseudo-tripeptide compounds. Compared to the known omicsynins, these pseudo-tripeptides lack the second amino acid unit and the C-terminal aldehyde group, and consequently lose their anti-coronavirus activity. In conclusion, our work highlights the effectiveness of FBMN in unveiling cryptic analogues and clearly underscores the essential role of the R domain of OmnF in the biosynthesis of the C-terminal aldehyde warhead.
This study investigated the anti-obesity potential of Panax ginseng-derived exosomes (PGE) by evaluating their influence on energy metabolism, adipogenesis, and lipid accumulation. PGEs were isolated using a tangential flow filtration system, yielding particles with an average diameter of 159.5 nm and a concentration of 3.9 × 1012 particles/mL. In 3T3-L1 preadipocytes, PGE treatment resulted in a 72.1% reduction in lipid accumulation, as demonstrated by Oil Red O staining, indicating significant inhibition of adipogenic differentiation. Elevated expression of surface markers TET-8 (147.2%) verified the exosomal nature of the isolated vesicles. To determine their role in adipocyte differentiation, we analyzed gene and protein expression of key adipogenic markers-peroxisome proliferator-activated receptor gamma (PPAR-γ), CCAAT/enhancer-binding protein alpha and beta, and fatty acid-binding protein 4-revealing reductions of 23.6-35.6% and 26.7-35.2%, respectively. These results indicate downregulation of transcriptional and translational pathways driving adipogenesis. Lipogenic regulators, including sterol regulatory element-binding protein 1c, acetyl-CoA carboxylase, and fatty acid synthase, were also suppressed by 24.9-41.0% (gene) and 22.8-24.5% (protein), indicating impaired fatty acid synthesis. Conversely, AMP-activated protein kinase (AMPK) expression increased by up to 53.8% (gene) and 47.9% (protein), implying activation of energy homeostasis signaling. Immunofluorescence analysis showed a reduction in the MitoTracker/DAPI ratio (57.7-60.0%) and an increase in the F-actin/DAPI ratio (39.5-60.8%), indicating decreased mitochondrial activity and enhanced cytoskeletal integrity. These molecular changes were accompanied by AMPK activation and PPAR-γ inhibition. Collectively, these findings underscore the potential of PGEs as bioactive agents for obesity management by concurrently inhibiting adipogenesis and lipogenesis, providing a strong basis for their application in anti-obesity functional foods and pharmaceutical products.
A chemical constituent study on the fermented rice substrate of basidiomycetous fungus Panus rudis led to the isolation of four previously undescribed prenylhydroquinone derivatives compounds (1-4) and eight known compounds (5-12). Among them, compound 3 featured a rare benzothiazole derivative with hydroxy substituted 3-methyl-1-butenyl substitution on the benzene ring, and the absolute configurations of 7 and 12 were elucidated as unreported ones. Their structures were identified by the interpretation of 1D and 2D NMR spectroscopy, HRESIMS data, X-ray single-crystal diffraction, and comparison of calculated and experimental ECD spectra. The plausible biosynthetic pathways for 1-7 are proposed. Cytotoxicity evaluation was conducted on 1 and 3-12 against two cancer cell lines (A-549 and HepG2). The results demonstrated that 1, 3-6, 8, 9, and 12 exhibited weak cytotoxicity against both two cell lines. Among them, 8 and 12 showed dose-dependent inhibitory effects, and their IC50 values at 72 h were obtained.
Three unprecedented triterpenoids (1-2, 8), seven novel diterpenoids (13-16, 19-21), and 12 known compounds (3-7, 9-12, 17-18, 22) were isolated from the tender branches and leaves of Aglaia odorata Lour. Structural elucidation was achieved through integrated spectroscopic analysis, quantum chemical calculations (NMR/ECD), and single-crystal X-ray diffraction. All isolates were evaluated for neuroprotective effects. Compounds 3, 9-11, 13, 17, and 18 showed significant protective effects against oxygen-glucose deprivation/reperfusion (OGD/R)-mediated nerve injury in PC12 cells at 10 μM, while compounds 3 and 19 exhibited potent anti-excitotoxicity activity in the L-glutamate-induced HT22 cells at 20 μM. Strikingly, triterpenoids 1, 2, and 11 displayed remarkable activity against RSL3-induced PC12 cell death with EC50 values ranging from 1.16 to 1.74 μM. Compound 22 exhibited the most significant inhibitory activity among the isolates against nitric oxide (NO) release in lipopolysaccharide (LPS)-activated BV2 cells with an IC50 value of 22.41 μM.
Thrombosis pathogenesis is closely linked to dysregulated lipid metabolism and inflammatory processes. However, the direct regulatory role of mevalonate pathway within the coagulation cascade is still not well understood. This study aimed to elucidate the regulatory effects of mevalonic acid (MVA) on the coagulation system. The effects of MVA on coagulation were measured by recalcification. Enzymatic kinetic analysis and natural substrate hydrolysis assays were performed to identify the coagulation target of MVA. Mice bleeding and thrombosis models were applied to evaluate the effects of MVA administration on hemostasis and thrombosis. Our current study reveals that MVA significantly accelerates plasma coagulation through potentiating the procoagulant activity of FXa, without influencing the platelet aggregation. Studies showed that MVA administration substantially shortened activated partial thromboplastin time, prothrombin time, and reduced bleeding time in both tail bleeding and saphenous vein injury models. Furthermore, using ferric chloride-induced thrombosis, deep vein thrombosis and cerebral infarction models, we observed that MVA markedly potentiated thrombus formation and stroke. Our findings establish for the first time that MVA directly regulates FXa procoagulant activity, while also suggesting potential crosstalk between lipid metabolic pathways and inflammatory signaling in coagulation modulation. These results provide novel mechanistic insights into coagulation abnormalities associated with metabolic disorders such as atherosclerosis and diabetes, highlighting the mevalonate pathway as a potential therapeutic target for thrombotic complications.
Microorganisms represent Earth's most abundant biological resource, producing metabolites of immense value across medicine, agriculture, and industry. Conventional cultivation and screening techniques, however, suffer from inefficiency and fail to meet contemporary demands. Providing a comprehensive overview, this review details how the One Strain Many Compounds (OSMAC) strategy—addressing cultivation bottlenecks—and genomics-driven mining approaches are revolutionizing the discovery of novel microbial metabolites. Crucially, it underscores the broad adoption of innovative technologies like machine learning to enable faster, more effective gene and structure targeting. Synthesizing case studies from 2019 to 2025, the review catalogs newly identified compounds and their bioactivities, while outlining future research directions to establish a theoretical framework for efficient microbial natural product exploration. These advanced discovery strategies are significantly accelerating the identification of structurally diverse lead compounds with novel mechanisms of action, thereby revitalizing pipelines for new antibiotic, anticancer, and therapeutic drug development.
In this study, a diabetic nephropathy (DN) rat model was established using 2% Streptozocin (STZ) solution, and an in vitro DN model was constructed by stimulating HK-2 cells with 30 mM glucose to investigate the mechanism of Phellodendron amurense Rupr. Polysaccharides (PAP) in ameliorating DN. Results demonstrated that PAP, a neutral homogeneous polysaccharide with molecular weight of 1.98 × 105 Da composed of Rha, GalA, Gal, and D-Xyl, exerted renal protective effects through multiple pathways. It enhanced renal antioxidant capacity and alleviated oxidative damage in DN by upregulating PI3K/AKT pathway-related protein expression. Simultaneously, PAP activated the TGF-β/Smad pathway via Nrf2 to mitigate renal fibrosis symptoms in DN, while inhibiting cellular apoptosis. Furthermore, PAP suppressed renal inflammation through gut microbiota reduction, thereby protecting against renal injury in DN rats. This study reveals that PAP alleviates DN symptoms by modulating gut microbiota, enhancing antioxidant and anti-fibrotic capacities, and inhibiting apoptotic pathways, comprehensively elucidating its multifaceted therapeutic mechanisms against DN.
The alarming increase of multidrug-resistant (MDR) bacteria presents a serious global health crisis, reducing the effectivenessof traditional antibiotics and requiring alternative therapeutic strategies. Among the most promising innovations are bacteriophages—viruses that specifically infect bacteria—and CRISPR-Cas systems, molecular tools enabling precise genome editing. These technologies individually offer targeted antibacterial activity with minimal disturbance to the host microbiota. When combined, they forma synergistic platform capable of overcoming many limitations of conventional antibiotics, including broad-spectrum activity, resistance development, and limited adaptability. This review examinesmechanisms of bacterial resistance, the biological foundation of bacteriophages and CRISPR-Cas systems, and their application in fighting MDR pathogens. However, significant challenges remain, including delivery barriers, off-target effects, regulatory uncertainty, and public acceptance of gene-editing tools. Antimicrobial resistance now tanks among the top threats to global health, with an estimated burden exceeding one million deaths annually, surpassing many other infectious diseases. The article concludes with a discussion of the clinical prospects of phage-CRISPR therapies and highlights key areas for future research. By merging the specificity of phages with the programmable strength of CRISPR, these biotechnological advances provide a powerful and approach to address the growing threat of antibiotic resistance.
PurposeTriple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, remains clinically challenging due to the lack of effective targeted therapies. This investigation revealed the anti-TNBC potential of Trichoderma viride ethyl acetate extract (TVEAE) from the endophytic fungus Trichoderma viride isolated from Coreopsis basalis. MethodsPharmacological validation of TVEAE's anti-TNBC efficacy was conducted through in vitro and in vivo pharmacological models. The cell death mechanisms were systematically investigated using Hoechst staining, reactive oxygen species (ROS) detection, and lipid peroxidation assays. Potential therapeutic targets and signaling pathways were identified by integrating network pharmacology, transcriptomics, and weighted gene co-expression network analysis (WGCNA). Furthermore, this study validated key tumor-related proteins involved in tumor progression and cell death pathways via Western blotting. Finally, chemical constituents were characterized through molecular network coupled with Global Natural Products Social Molecular Networking (GNPS) analysis. ResultsBoth in vitro and in vivo models established TVEAE's significant anti-TNBC efficacy. Mechanistic interrogation established TVEAE-mediated ferroptosis induction via selective modulation of leukocyte transendothelial migration (TEM) signaling cascades. Integrative analysis combining transcriptomics, WGCNA, and network pharmacology identified IL-6/TNF-α/HSP90AA1 as core therapeutic targets regulating TEM pathway dynamics. GNPS-assisted molecular networking uncovered six structurally novel anti-TNBC metabolites, including N-lauryldiethanolamine, erucamide, and Gliotoxin. ConclusionThis study provides the first evidence of TVEAE's anti-TNBC activity through multi-target engagement along the leukocyte TEM signaling axis, effectively triggering ferroptosis. The mechanistic elucidation advances TNBC therapeutic development, offering a multi-dimensional targeting strategy against this recalcitrant malignancy.
Metabolomics provides powerful means to analyze metabolite profiles in biological samples, enabling insights into biochemical changes under genetic, environmental, or pathological conditions. Nuclear Magnetic Resonance (NMR) spectroscopy is central to metabolomics, but its utility is often constrained by the strong and overlapping resonances of abundant components, such as sugars in plant- and food-derived materials, which obscure signals of lower-abundance metabolites. Here, we introduce a modified NMR acquisition method that increases sensitivity and specificity by selectively suppressing dominant signals, while enhancing weaker metabolite signals across the spectrum. The method integrates water presaturation with excitation sculpting (ES), yielding a robust 1D presat-1H-ES pulse sequence. Validation on a range of sugar-rich samples demonstrated 2-fourfold signal enhancement for low-abundance metabolites compared with conventional 1H-ES. Multivariate analyses show the method improves reproducibility and discrimination, enabling detection and comparison of low-abundance metabolites not accessible with conventional approaches’. Beyond sugar-rich systems, the method is broadly applicable to other spectral regions where dominant metabolite classes obscure lower-concentration compounds, including primary metabolites and structurally diverse natural products. Overall, the 1D presat-1H-ES significantly enhances resolution and sensitivity of NMR-based metabolomics, shortens analysis time, and supports more precise profiling for both fundamental studies and translational applications in metabolomics and natural-products discovery.
