Natural Products and Bioprospecting最新文献

Purpose

Triple-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.

Methods

Pharmacological 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.

Results

Both 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.

Conclusion

This 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.

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.

Graphical Abstract

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.

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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.

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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.

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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.

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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.

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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.

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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.

Graphic Abstract

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.

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