Natural Products and Bioprospecting最新文献

Prostate cancer (PCa) remains one of the most common malignant tumors among men worldwide, typically relying on the androgen receptor (AR) signaling pathway. Inducing ferroptosis, a novel form of iron-dependent cell death, represents a promising strategy; however, its regulation by AR signaling is complex. The molecular chaperone heat shock protein 70 (HSP70) is critical for AR stability and function, yet its role as a therapeutic target in this context is underexplored. The anti-proliferative effect of the compound nidurufin (Nid) was assessed across PCa cell lines using MTT, clonogenic, and 3D spheroid assays. Ferroptosis was evaluated by transmission electron microscopy, reactive oxygen species (ROS) detection, and lipid peroxidation analysis. Mechanistic insights were gained through Western blot, qPCR, immunofluorescence, ChIP-qPCR, molecular docking, and cellular thermal shift assay (CETSA). In vivo efficacy was validated in a zebrafish xenograft model. Nid exhibited potent, selective anti-proliferative activity against AR-positive PCa cells, particularly 22Rv1 (IC₅₀ = 10.30 μM), and induced ferroptosis characterized by mitochondrial shrinkage and ROS accumulation. Mechanistically, Nid did not bind to AR, but it directly bound to HSP70, disrupting its chaperone function and leading to AR protein destabilization and transcriptional downregulation. This consequently suppressed the expression of the AR-target gene membrane-associated O-acyltransferase domain protein 2 (MBOAT2), a key ferroptosis suppressor enzyme. ChIP-qPCR confirmed AR directly binds the MBOAT2 promoter, and Nid treatment reduced this enrichment. In vivo, Nid significantly inhibited tumor growth and metastasis in a zebrafish xenograft model. Our study identifies Nid as a novel HSP70-targeted compound that triggers ferroptosis by disrupting the HSP70-AR-MBOAT2 axis. This work not only reveals a previously unrecognized connection between protein chaperone function and ferroptotic susceptibility but also positions HSP70 as a compelling therapeutic target for overcoming AR-pathway dependency in PCa.

Atopic dermatitis (AD) is a persistent, relapsing skin inflammatory disorder characterised by epidermal barrier dysfunction, immune system anomalies, and microbial dysbiosis. Current therapies encompass calcineurin inhibitors, topical corticosteroids, and synthetic drugs such as JAK inhibitors and biologics, which, despite their efficacy, have safety issues and constraints on prolonged use. Recently, natural bioactive compounds namely flavonoids, polyphenols, and terpenoids have garnered interest for their anti-inflammatory, antioxidant, and skin-barrier-repairing characteristics. Recent studies emphasise the incorporation of these bioactive compounds into hydrophilic/hydrophobic polymeric conjugates and nanocarrier systems to promote skin distribution, increase efficacy, and minimise systemic adverse effects. This study encapsulates traditional and innovative medicines, highlights the promise of polymer-conjugated herbal formulations, and examines recent developments in nanotechnology and delivery technologies for AD management. The increasing interest in bioactive ingredient formulations and polymeric nanocarriers indicates a favourable shift towards safer, more effective, and patient-compliant treatment methodologies.

The crisis of antimicrobial resistance (AMR) is escalating while the antibiotic pipeline remains stagnant. Our bibliometric analysis of eight decades of literature reveals a critical imbalance: research on AMR has grown, yet fundamental research on antibiotic discovery has declined. Most strikingly, research attention to Actinomycetota, the source of most clinical antibiotics, has sharply decreased since its mid-twentieth-century peak. This therapeutic disinvestment coincides with the intensifying AMR crisis. We argue for a strategic reinvestment in natural product discovery, now enabled by advances in genomics, artificial intelligence, and synthetic biology. These tools can unlock the vast, silent biosynthetic potential of actinobacteria, transforming discovery into a targeted and efficient endeavor. Rebalancing research priorities by coupling this historically proven source with modern technology is essential to revive the antibiotic pipeline. We urge funding agencies and industry to bridge the growing gap between a well characterized problem and a neglected solution.

Inflammatory bowel disease (IBD), particularly ulcerative colitis, involves disruption of the intestinal mucosal barrier due to ecological and metabolic imbalances in the gut as its underlying pathology. Current therapies for Ulcerative colitis (UC) exhibit limited efficacy and adverse effects, necessitating the development of novel treatment strategies. Naringin and osthole are natural herbal compounds that show therapeutic potential in various inflammatory models due to their excellent anti-inflammatory activity. However, their combined therapeutic effects and precise mechanisms in UC remain unreported. This study aimed to explore the therapeutic effectiveness and mechanism of naringin combined with osthole in addressing dextran sodium sulfate (DSS)-induced colitis. The investigation centered on their impact on the disruption of the intestinal epithelial cell barrier, modulation of intestinal flora composition, alteration of metabolites, and inflammation model in vitro. Modal assessment encompassed body weight, disease activity index (DAI) score, colon length, and histopathological examination. Intestinal barrier integrity was evaluated through Quantitative Real-Time PCR, western blotting, and immunofluorescence staining. Microbiota abundance and metabolic levels were assessed using 16S ribosomal RNA gene sequencing and metabolomics analysis. Protein expression levels of pertinent pathways and associated receptors were tested through network pharmacology prediction and western blot analysis. Naringin and osthole synergistically relieved colitis symptoms in mice compared with either drug alone or 5-aminosalicylic acid, as evidenced by weight loss recovery, DAI scores, and colon length preservation. Mechanistically, naringin combined with osthole down-regulated the expression level of JNK/NF-κB signaling pathway related proteins and repaired intestinal barrier. Furthermore, the combination regulates the composition of the microflora and promotes the restoration of a steady state of the microflora. Metabolomic revealed amino acid-tryptophan metabolism as a key metabolic pathway. It also reveals the microbiota-tryptophan pathway as a potential therapeutic strategy. Naringin combined with osthole can alleviate DSS-induced colitis more effectively by JNK/NF-κB signaling pathway, repairing barrier function and regulating intestinal microbiota and metabolites. These findings provide a theoretical basis for the combination therapy strategy to enhance the efficacy of potential functional food in treating ulcerative colitis.

Hippophae rhamnoides L. (Elaeagnaceae), commonly known as sea buckthorn, is a medicinal plant valued for its diverse bioactive constituents and broad therapeutic potential. Phytochemical investigation of its roots led to the isolation of three new 14-noreudesmane-type sesquiterpenoids (1-3), together with sixteen known compounds (4-19). Their structures and absolute configurations were determined using comprehensive spectroscopic analyses and quantum chemical computations of electronic circular dichroism (ECD) spectra and ¹³C NMR shifts. Three new sesquiterpenoids (1-3) were tested for their antioxidant, anti-inflammatory, antibacterial, and α-glucosidase inhibitory activities. Unfortunately, none exhibited significant activity under the tested conditions. Among the isolated known compounds, all those displaying α-glucosidase inhibitory and antibacterial activities are pentacyclic triterpenoids. Hippophamide (17) showed significant DPPH and ABTS radical-scavenging activity. These results enriched the chemical profile of H. rhamnoides roots.

Nitrogen-containing core structure pyrimidine has long been regarded as one of the privileged scaffolds for novel drug development. Natural products embedded with pyrimidine motifs are distinguished by their exceptional scaffold diversity and vast structural complexity, which endow them with versatile biological activities, including anticancer, antiviral, antifungal and anti-inflammatory activities. This review is dedicated to surveying a series of structurally distinctive naturally occurring compounds characterized by the presence of an aromatic heterocyclic pyrimidine moiety covering from 2004 to early 2025. Multiple key aspects of these 156 pyrimidine-containing compounds, including natural sources, features of chemical structure, biological activities, as well as biosynthetic studies are summarized. The review emphasizes the enduring potential of natural products, highlighting their inherent capacity for medication and optimization to fuel the pipeline of lead compound targeting major disease and providing new window for overview of these pyrimidine-containing natural products. Overall, this review aims to unlocking the potential of these isolates. It thus offers a fresh reference for the exploitation of pyrimidine-containing natural products, with the ultimate goal of realizing their therapeutic potential.

Five new α-pyrones, diaporpyrones G-K (1-5) and three new γ-butenolide derivatives, porbutenolides A-C (6-8), along with seven known compounds (9-15), were isolated from the culture extract of the endophytic fungus Diaporthe sp. CCY4. Their structures were elucidated by comprehensive spectroscopic analysis, including 1D/2D NMR and HRESIMS data. The absolute configurations of 7 and 8 were assigned using electronic circular dichroism (ECD) calculations. All compounds were evaluated for inhibitory activity against ubiquitin-specific peptidase 4 (USP4). Compounds 2, 5, 9, and 13 exhibited significant anti-ubiquitination effects at 40 μM, with 13 showing the most potent inhibition (IC₅₀ = 20.85 μM).

The Tiger Milk mushrooms (Lignosus spp.) have long been used as traditional folk medicines throughout Southeast Asia. However, the chemical constituents of these species remain largely unexplored. In this study, four type I sesquiterpene synthases (LrhTS1-LrhTS4) from Lignosus rhinocerus TM02^® were functionally characterized through genome mining, in vitro enzymatic assays, and heterologous expression in an Escherichia coli host engineered to overexpress an exogenous mevalonate pathway. The enzyme products were analyzed by GC-MS and further purified and structurally elucidated by NMR spectroscopy. A total of 11 sesquiterpenes (1-11) were identified, among which two were unstable and converted to stable derivatives (2 to 2a and 7 to 7a). Notably, compounds 1-10 are reported from the genus Lignosus for the first time. LrhTS1 and LrhTS3 exhibited high catalytic specificity, whereas LrhTS2 and LrhTS4 displayed product promiscuity. This work expands the knowledge of terpene synthase from mushroom, and advances the understanding of the chemical basis underlying the bioactivity of the Lignosus rhinocerus TM02®.

In course of investigating the endophytic and nematode-associated fungus Polydomus karssenii for the production of secondary metabolites, seven previously undescribed natural products were isolated from liquid and solid-state fermentations. 1D and 2D NMR spectroscopy, together with HR-ESI-MS data, enabled the elucidation of the planar structures of 3-decalinoyltetramic acids polydosetins A-E (1-5) and cyclodepsipeptides pullularins G and H (6 and 7). The relative configurations of the decalin moiety of 1-5 were determined based on ROESY correlations and ¹H-¹H coupling constants. The configuration of the side chains was established through a detailed J-resolved analysis (Murata's method) in combination with chemical shift comparison to model compounds. Absolute stereochemistry of 1-5 was assigned based on ECD data, and confirmed by Mosher's method utilizing 3. Finally, the absolute configuration of amino acid residues in 6 and 7 was determined through advanced Marfey's method. Bioassays revealed that compounds 1, 3, 5, and 7 were active against Gram-positive bacteria, 3 and 5 exhibited antifungal activity, and 1 and 2 showed nematicidal effects. These results underscore the untapped chemical potential of P. karssenii and highlight the importance of exploring nematode-associated fungi as sources of new natural products with potential antimicrobial and nematicidal properties.

Thrombotic disorders remain a global health burden, necessitating novel antiplatelet agents with improved safety and efficacy. This study investigates the molecular mechanisms of two lignans, 6'-Hydroxyjusticidin B (6'-HJB) and Neojusticin A (Neo-A), isolated from Justicia procumbens L., through an innovative target-driven strategy integrating LC/MS, proteomics, network pharmacology, and biophysical validation. For the first time, integrin β₃ (ITGB3) was identified as their direct molecular target, with microscale thermophoresis (MST) confirming high-affinity binding, the dissociation constant (Kd) = 0.0642 ± 0.005 μM for 6'-HJB; 0.0097 ± 0.001 μM for Neo-A. This study not only elucidates the structural basis of their activity-C-6 hydroxylation in 6'-HJB enhances ITGB3 specificity, whereas Neo-A's fused furan ring optimizes COX-1 interaction, but also establishes a paradigm shift from phenotypic screening to target-validated natural product research. The findings position 6'-HJB and Neo-A as promising candidates for the development of safer, ITGB3-mediated antithrombotic therapies, with future efforts directed toward structural optimization and preclinical validation.