Natural product pseudolaric acid A (PAA), the main bioactive component from Traditional Chinese Medicine Pseudolarix cortex (“tujingpi”), is a promising anticancer agent. However, its potential molecular targets are not clear and this hinders its development. In this study, chemical proteomics approaches including activity-based protein profiling (ABPP) and drug affinity responsive target stability (DARTS) technology, followed by quantitative proteomics, were combined to reveal the target of PAA. Target validation was performed by NMR techniques and surface plasmon resonance. Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) was identified and further confirmed to be the target of PAA. The direct interaction and binding mode between MTHFD1L and PAA were elaborated. PAA induced the accumulation of the reactive oxygen species (ROS) which mediates the antitumor effect. Transcriptome and network pharmacology analysis reveals the effects of PAA on the gene expressions of the associated pathways. Taken together, our findings proposed a new target that could be used for structure-based rational design and modifications of PAA.

The use of natural products as antibiotic adjuvants to enhance efficacy and mitigate resistance is increasingly recognized as a promising strategy. This study explored five novel synergistic antimicrobial combinations (SACs) of carvacrol (CARV) and three already identified SACs of thymol (THY) with chloramphenicol, gentamicin, and streptomycin against Staphylococcus aureus and Acinetobacter baumannii, critical WHO-listed pathogens, and investigated their mechanisms of action and resistance-prevention capabilities. Despite being isomers, CARV and THY exhibited distinct synergistic effects and fractional inhibitory concentration index (FICI) values depending on the antibiotic and bacterial species. The SACs significantly reduced the required antibiotic dose by 4- to 16-fold, with FICI values ranging from 0.25 to 0.5. Growth kinetics revealed that SACs completely inhibited planktonic bacterial growth, outperforming antibiotics alone. Additionally, the SACs demonstrated efficacy in both inhibiting and eradicating biofilms of S. aureus and A. baumannii. Resistance development studies highlighted that neither THY nor CARV induced resistance in these pathogens. Moreover, SACs combining aminoglycosides with THY reduced the emergence of resistance in A. baumannii by up to 32-fold. In S. aureus, THY mitigated gentamicin resistance by 16-fold. CARV exhibited similar, albeit slightly less potent, effects.
Mechanistic investigations revealed that THY and CARV exert antimicrobial action by multiple mechanisms, including bacterial membrane depolarization and disruption, efflux pump inhibition, disrupting ATP metabolism and mitigating oxidative stress induced by antibiotics. These findings highlight the potential of SACs to enhance antibiotic efficacy while preventing resistance, positioning them as strong candidates for innovative antimicrobial therapies against multidrug-resistant pathogens.

Natural products (NPs) are invaluable resources for drug discovery, characterized by their intricate scaffolds and diverse bioactivities. AI drug discovery & design (AIDD) has emerged as a transformative approach for the rational structural modification of NPs. This review examines a variety of molecular generation models since 2020, focusing on their potential applications in two primary scenarios of NPs structure modification: modifications when the target is identified and when it remains unidentified. Most of the molecular generative models discussed herein are open-source, and their applicability across different domains and technical feasibility have been evaluated. This evaluation was accomplished by integrating a limited number of research cases and successful practices observed in the molecular optimization of synthetic compounds. Furthermore, the challenges and prospects of employing molecular generation modeling for the structural modification of NPs are discussed.

Two new together with 32 known compounds were isolated from the leaves of Lycium barbarum. Their structures were elucidated using 1D and 2D NMR, HRESIMS, and ECD spectroscopic techniques. Compounds 1–34 were evaluated for their anti-rheumatoid arthritis activities in a lipopolysaccharide (LPS)-induced MH7A cells inflammatory model. As a result, compounds 1–3, 6, 8, 10, 14, 17–19, 29 and 31 inhibited the activity of lactate dehydrogenase (LDH) and nitric oxide (NO) at concentrations 20 μM. Among them, compound 1 showed the best effectiveness, with inhibition rates of 46.7% for NO and 32.8% for LDH.

Otteacumienes G–K (1–5), five pairs of enantiomeric diarylheptanoids, along with one undescribed diarylheptanoid glycoside and one new lignan, were isolated from Ottelia acuminata var. acuminata. Compounds 1–5 were identified as five pairs of enantiomers and their structural configurations were determined through a combination of spectroscopic analysis, X-ray crystallography, and ECD calculation. Notably, compound 6 was the first diarylheptanoid glycoside isolated from this aquatic species, and its absolute configuration was unequivocally established through semi-synthesis. Biological evaluation demonstrated that compound 1 exhibited α-glucosidase inhibitory activity, with an inhibition ratio of 38.97% (acarbose as the positive control, inhibition ratio = 13.52%).

The activation of conventional (α) and novel (δ) protein kinase C (PKC) isoforms promotes lysosomal biogenesis, a critical process for clearance of pathogenic protein aggregates including β-amyloid (Aβ) and phosphorylated Tau (p-Tau) in neurodegenerative disorders. Notably, PKC activators HEP14/15, characterized by 20-methyl moiety, fail to establish classical C1B domain pharmacophore interactions, suggesting a non-canonical activation mechanism. In this study, structural diversification of 20-deoxyingenol through esterification and acetonide protection yielded 18 new derivatives (2–19). Systematic screening revealed their lysosome-promoting activities, with structure–activity relationship analysis identifying compounds 4 and 18 as superior autophagy inducers. At 20 μM, these derivatives enhanced autophagic flux by 2.45-fold and 2.31-fold versus vehicle control. Moreover, compounds 4 and 18 exhibited a dose-dependent increase in lysosome numbers, promoted TFEB nuclear translocation, and enhanced lysosome-mediated lipid droplet clearance. Western blot analysis further revealed that compounds 4/18 upregulated proteins associated with the autophagy-lysosome system, suggesting their potential as promising autophagy inducers. Mechanistically, molecular docking simulations indicated thier high-affinity binding to PKCδ, which may explain their autophagy-enhancing properties.

Our continuous study of the fruits of Garcinia xanthochymus and Garcinia subelliptica led to the isolation and structural characterization of six new polyprenylated acylphloroglucinols, xanthochymusones N and O (1 and 2), (–)-garciyunnanin L (3), and garsubelones C–E (4–6), together with two known analogues. Their structures were elucidated by interpretation of NMR and MS spectroscopic data. It was found that the Grossman-Jacobs rule is no longer applicable to determination of the C-7 configuration of compounds 1–3, as they possess a complex 6/6/6/6/6 fused ring system. The inhibitory activities of all the compounds against two human hepatocellular carcinoma cell lines Huh-7 and HepG2 were evaluated, and compound 1 exhibited moderate cytotoxic activities against HepG2 cells with IC₅₀ value 7.3 μM. Furthermore, the previous assignments of some polyprenylated acylphloroglucinols have been proved to be incorrect in this study, and analysis of NMR data enabled the structural revision of seven analogues: hyperselancins A and B, garcinielliptones F and G, garxanthochins A and B, and 13,14-didehydroxygarcicowin C. The revised structures of garcinielliptone F and garxanthochin A were shown to have the same structures of garsubelone B and xanthochymusone K, respectively, and the revised structures of other five compounds have not been reported.

Four previously undescribed polyprenylated acylphloroglucinols, hyperisenins A–D (1–4), along with two known analogues (5 and 6), were obtained from the aerial part of Hypericum seniawinii Maxim. Compounds 1 and 2 were two highly degraded polyprenylated acylphloroglucinols with a cyclohexanone-monocyclic skeleton, while compound 3 was the first example of O-prenylated acylphloroglucinols with a 6/6/6 ring system. Their structures were identified by analyzing NMR, HRESIMS data, and quantum chemical calculations. The biosynthetic pathway of 1 and 2 might originate from bicyclic polyprenylated acylphloroglucinols via a series of complex retro-Claisen, keto-enol tautomerism, and intramolecular cyclization. The bioassay results showed that 4 exhibited quorum sensing inhibitory activity against Pseudomonas aeruginosa, which could decrease the activation of the rhl system, and significantly reduce rhamnolipid levels at a concentration of 100 μM, and the mechanism might be the ability to bind 4 to lasR and pqsR.

Qingfei Paidu decoction (QFPDD) has been extensively used in clinical treatments during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic. SARS-CoV-2 primarily invades host cells via its spike (S) protein binding to the angiotensin-converting enzyme 2 (ACE2) on the cell membrane, mediating viral-host membrane fusion. Blocking viral entry is a crucial step in preventing infection, with the interaction between the S receptor binding domain (S-RBD) and ACE2 being a key antiviral target. Given that SARS-CoV-2 predominantly affects the respiratory system and approximately 25% of patients suffering from corona virus disease 2019 (COVID-19) with gastrointestinal symptoms, we are committed to identifying more active ingredients in QFPDD that target the respiratory and gastrointestinal tracts of COVID-19 patients. Among medicinal plants, ephedra and liquorice derived from QFPDD, along with two other Chinese herbs, Platycodon grandiflorum and Radix Rhei Et Rhizome (rhubarb), have garnered our interest. These herbs have historically been used in traditional Chinese medicine (TCM) for treating infectious diseases with respiratory and digestive symptoms. Here, we established a library containing all components of the four individual herbs gathered from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and performed structure-based virtual screening to identify potential ACE2/S-RBD inhibitors. Subsequently, we selected 10 ingredients from the top 30 candidates and evaluated their activities using a pseudovirus neutralization assay. Delphinidin and deapio platycodin D (DPD) showed significant antiviral potential with half-maximal inhibitory concentration (IC₅₀) values of 45.35 μM and 1.38 μM, respectively. Furthermore, delphinidin also inhibited the 3-chymotrypsin-like protease (3CL^pro), indicating its dual-viral target inhibitory potential. Notably, DPD effectively suppressed HCoV-229E replication in BEL-7402 cells. This study not only provides a strategy for rapid identifying antiviral agents from TCM in anticipation of future pandemics but also offers theoretical and experimental evidence to support for the clinical use of QFPDD.

Two concise and efficient synthetic routes were developed for the synthesis of three 1,7-diarylheptanoids (1–3) containing a 1,4-pentadiene unit, which were originally isolated from Ottelia acuminata var. acuminata. The first approach focused on the construction of linear diarylheptanoids 1 and 3 featuring a (1E,4E)-pentadiene moiety, via a Suzuki coupling reaction. The second strategy enabled the synthesis of sixteen-membered macrocyclic ether 2 with a (1Z,4E)-pentadiene unit. The challenging macrocyclization was successfully accomplished through an Ullmann coupling. Notably, the formation of the Z-olefin within the macrocyclic framework was promoted by the inherent ring strain of diarylether-type heptane system, which preferentially stabilizes this particular configuration.

Propolis, consisting of plant-derived materials, wax, and bee secretions, is abundant in bioactive constituents like flavonoids, phenolic compounds, and terpenes, which enhance its various biological functions. These encompass antioxidant, anti-inflammatory, antibacterial, anticancer, antidiabetic, and immunomodulatory properties. Propolis has demonstrated effectiveness in the prevention and treatment of multiple illnesses, including cardiovascular disease, atherosclerosis, infections, diabetes, wound healing, and burns. Its extensive health benefits endorse its application in medications, nutritional supplements, and cosmetics, where it is acknowledged as a safe and efficacious natural product. Propolis, whether utilized in its raw state, as extracts, or in conjunction with other products, exhibits considerable promise in alternative medicine and nutritional health. Propolis extracts are crucial to examine as a key component in health and wellness, offering prospective applications in disease prevention and therapeutic support Further research is necessary to clarify its molecular mechanisms, examine potential allergic reactions, and determine ideal dosages for various ages. This article provides a comprehensive comparative examination of various propolis types, emphasizing their distinct phytochemical contents and varying biological effects concurrently. It integrates results from both in vitro and in vivo investigations, enhancing the comprehension of health applications and mechanisms of action, grounded comparisons in pertinent prior studies.

Tuberculosis (TB) is a leading infectious disease killer and one of the major causes of deaths worldwide. Although TB is a curable and preventable disease, in 2023, approximately 10.8 million people fell ill with TB and there were an estimated 1.25 million of deaths worldwide. Despite some research progress for new drug candidates, drug repurposing, and new regimens, there is still an urgent need for the new medicins to treat TB, especially due to the growing cases of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug resistance is a challenging obstacle to TB care and prevention globally, making TB harder and longer to treat, often with poorer outcomes for patients. The Actinomycetota encompass Gram-positive bacteria that produce a milieu of bioactive metabolites, including antibiotics, antiproliferative drugs, immunosuppressive agents, and other important medical molecules. Actinomycetota have a special place in the therapeutic arsenal to fight TB, as rifamycins, aminoglycosides, and cycloserine are derived from Streptomyces species, one of the most important genera in this phylum. Furthermore, hundreds of antimycobacterial metabolites have been isolated from Actinomycetota and can serve as effective drugs or useful agents for the discovery of new lead compounds to combat TB. The present review covers more than 171 isolated substances as potential antimycobacterial agents discovered between the years 1972 to 2024. Among the most potent compounds, with MIC in the submicromolar range, steffimycins, ilamycins/rufomycins, nosiheptide, actinomycins, lassomycin and boromycin are the most promising compounds. These compounds represent highly promising candidates for development of new antitubercular drugs. Additionally, some of these substances also demonstrated activity against resistant Mycobacterium tuberculosis (Mtb) strains, which is particularly relevant given the difficulty of treating MDR and XDR strains. Thus, actinobacteria have played and continue to play an important role in fight TB, remaining a promising source of antibiotic metabolites. Their unique metabolic diversity enables the production of metabolites with innovative mechanisms of action, making them a strategic reservoir for discovering therapies against untreatable forms of the disease.

The resurgence of interest in traditional herbal remedies stems from an increasing appreciation for their complex phytochemical profiles and potential for synergistic therapeutic effects. However, the therapeutic potential of plant extracts is often limited by poor absorption and potential toxicity related to conventional delivery methods. This review explores the application of nanocarrier-mediated delivery systems, such as nanoparticles (NPs), liposomes, and nanoemulsions, to address these challenges. These biocompatible carriers offer enhanced stability and targeted delivery of herbal compounds, improving their efficacy and reducing unwanted side effects. By enabling precise distribution, nanotechnology optimizes the potency of herbal medicine across diverse applications, including regenerative medicine, wound healing, anticancer, and infection treatment. This review provides a systematic description of successful applications of nano-delivery technologies, nanoparticles, liposomes, nanoemulsions, and hybrid carriers, for the targeted delivery of some well-characterized herbal bioactives (curcumin, allicin, berberine, resveratrol etc.) and the enhanced therapeutic performance of herbal bioactives across a variety of preclinical models.

Strophioglandins A-C (1-3), three highly rearranged norditerpenoids featuring an unusual tricyclo[6.4.1.0^4,13]tridecane core, were isolated from Strophioblachia glandulosa var. cordifolia. Integrated spectroscopic analyses, X-ray crystallography, and ECD calculations synergistically determined their molecular architectures. Remarkably, all compounds manifested potent anti-inflammatory effects in LPS-activated RAW264.7 cells with IC₅₀ values ranging from 7.83 ± 1.11 to 15.09 ± 1.21 μM. Mechanism study revealed that strophioglandin A (1), the most potent compound, could suppress the expression of multiple inflammatory factors by inhibiting the P38 and Erk1/2 MAPK signaling pathways.

Polysaccharides are the primary active constituents of Polygonatum kingianum Coll. et Hemsl. However, the comprehensive characterization of P. kingianum polysaccharides (PKP) remains scarce, impeding investigations into the structure-activity relationship. In this study, a novel polysaccharide, PKP1, was purified using Cellulose DE-52 and Sephadex G-50 column chromatography, and its complete structure was elucidated through monosaccharide composition analysis, methylation analysis, as well as 1D and 2D NMR analysis. The results revealed that PKP1 primarily comprised Fru and Glc, exhibiting a molecular weight of 5.3 × 10³ Da and a polymer dispersity index of 1.20. The completed structure of PKP1 consisted of β-D-Fruf-(2 → , → 1,2)-β-D-Fruf-(6 → , → 1)-β-D-Fruf-(2 → and → 1)-α-D-Glcp-(6 → as the main chain sugar residues, with β-D-Fruf-(2 → and → 2)-β-D-Fruf-(6 → serving as the side chains sugar residues. The detailed structure of PKP1 suggested it is a novel Fru-dominated neutral polysaccharide. Biological assays indicated that PKP1 significantly reduced the levels of NO, IL-6, and TNF-α in RAW264.7 macrophages, while also exerting regulatory effects on the gut microbiota structure and its metabolites in vitro. Our findings enriched the understanding of the structural characteristics of P. kingianum polysaccharides and laid a solid foundation for considering P. kingianum as a potential functional food supplement.

Background Depression promotes breast cancer progression. Given the lack of specific targets for depression-associated breast cancer, there are currently no therapeutic drugs for this type of breast cancer.
Methods Transcriptomic analysis was conducted to identify and functionally annotate genes with differential expression in breast cancer patients exhibiting depressive symptoms. Subsequently, Mendelian randomization was employed to investigate the causal associations between these pivotal genes and breast cancer, thereby validating their potential roles as therapeutic targets. Furthermore, molecular docking techniques were utilized to screen for candidate compounds that may exert therapeutic effects on depression-associated breast cancer. The efficacy of the selected compounds was further assessed using both in vitro cellular experiments and in vivo animal models.
Results We identified IL-8 as a key gene involved in depression-mediated breast cancer progression using transcriptomics. Mendelian randomized analysis suggested that high IL-8 expression promoted breast cancer progression. Further studies demonstrated that IL-8 mediated the breast cancer-promoting effect of depression through the receptor CXCR2. Evidence from both in vitro and in vivo experiments indicates that senkyunolide H may exert its therapeutic effect by regulating CXCR2, thereby counteracting the protumor effects associated with depression in breast cancer.
Conclusion Depression activates CXCR2-mediated breast cancer cell proliferation through IL-8, and senkyunolide H regulates CXCR2 and inhibits its ability to block the cancer-promoting effects of depression, ultimately inhibiting the growth of breast cancer in the context of depression.

Modern pharmacology has found that both Realgar and Coptis chinensis can induce apoptosis in tumor cells, and traditional Chinese medicine theory suggests the possibility of combining the two, however, the specific mechanisms involved have not been elucidated. This study investigated the therapeutic mechanism of the Realgar-Coptis chinensis drug pair (RCCD) against hepatocellular carcinoma (HCC) by identifying its key active compounds and targets. Through integrated LC-MS analysis, transcriptomics, network pharmacology, and bioinformatics, we identified the mechanism of action, key bioactive compounds, and core targets. Molecular docking, molecular dynamics simulations, and microscale thermophoresis (MST) validated the binding affinity between key compounds and core targets. TIMER2.0 database was used to analyze the relationship between the core targets and HCC. H22 tumor xenograft mouse model and immunohistochemistry and pathology analyses were performed to validate the antitumor efficacy of the active compounds. RCCD has a high degree of selectivity of lipid metabolism pathway, 4-Methylumbelliferone (4-MU) was the key active compound with strong binding activity to the core target fatty acid synthase (FAS), and 4-MU down-regulated the expression of FASN in tumor tissues and induced apoptosis in HCC cells. In addition, as a hyaluronan synthase (HAS2/3) inhibitor, 4-MU interfered with the HA-dependent tumor microenvironment and fibrosis process by inhibiting HAS2/3. Thus, 4-MU may inhibit tumor progression by inhibiting FAS and HAS2/3. 4-MU extracted from RCCD exerts anti-HCC effects by modulating the activities of FAS and HAS2/3, thereby reprogramming lipid metabolism and regulating hyaluronan synthesis.

Five new heterodimers, chalasoergodimers A-E (1-5), and three known heterodimers (6-8), along with four chaetoglobosin monomers (9-12), were isolated from a marine-derived Chaetomium sp. fungus. The structures of new compounds 1-5 were elucidated by HRESIMS, NMR, chemical calculated ¹³C NMR and ECD methods. Among them, compound 1 was derived from C-2' substitution of chaetoglobosin Fex (9) with ergosta-4,6,8(14),22-tetraen-3β-ol, representing a new dimerization mode among chaetoglobosin-ergosterol derivative hybrids. Compound 2 featured substitution at NH-1' and constituted the first example of this dimeric type bearing an R-configuration at C-3''. Compounds 3-5 were formed via a Diels-Alder cycloaddition between chaetoglobosins and 14-dehydroergosterol. Furthermore, it was revealed that compound 9-12 exhibited the significant cytotoxic activity against the human non-small cell lung cancer cell (A549), with compound?12 showing the most potent effect at an IC₅₀ of 5.14 μM.

Two pairs of undescribed alkaloid enantiomers, (+)-/(-)-ormohenins A (1) and B (2), were isolated from the seeds of Ormosia henryi Prain, along with four undescribed alkaloids (3, 4, 7 and 8) and seven known ones (5, 6, 9-13). Compounds 1-6 belong to the ormosanine-type alkaloids, compounds 7, 9, and 11 are of the lupinine-type, compounds 8 and 10 are classified as anagyrine-type alkaloids, 12 and 13 are cytisine-type alkaloids. The chemical structures of 1-13 were elucidated through comprehensive NMR and MS data analyses. Furthermore, the racemates (±)-1 and (±)-2 were successfully resolved into their respective optically pure enantiomers using a chiral HPLC system. The absolute configurations of compounds 1-3 were determined using single-crystal X-ray diffraction and corroborated by DFT calculations of specific rotations. The absolute configurations of 4, 7, and 8 were assigned by the experimental electronic circular dichroism (ECD) with those predicted using TDDFT calculations. Compound 12 exhibited significant acetylcholinesterase (AChE) inhibitory activity with the IC₅₀ value of 6.581 ± 1.203 μM. The neuroprotective effects of these compounds against Aβ_25-35 induced cell damage in PC12 cells were investigated, and compounds 3, 9, and 12 exhibited significant neuroprotective effects against Aβ_25-35 induced PC12 cell damage, with the EC₅₀ values of 7.99-15.49 μM, respectively.

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.

An undescribed phenylpropanoid dimer featuring a rare cyclobutane ring was isolated from the rhizomes of Kaempferia galanga L., a medicinal plant traditionally used in Southeast Asia for its anti-inflammatory and therapeutic properties. Kaemphenolide (1), along with five known constituents, was obtained by separations of methanolic extract using chromatography. The presence of a cyclobutane ring within the phenylpropanoid scaffold represents an unusual structural motif among natural products and underscores the chemical uniqueness of this molecule. To evaluate its biological relevance, 1 was tested for its ability to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The compound exhibited anti-inflammatory activity, with an IC₅₀ value of 23.1 ± 6.40 μM.

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.

Bioactive compounds from food-compatible medicinal herbs have shown promise as preventive agents against age-related neurodegenerative conditions, particularly Alzheimer's disease (AD). The present work aimed to find Lobetyolin as a new suppressor of Aβ aggregation and its interventions on abnormal metabolism in AD. Aβ-expressing Caenorhabditis elegans (strain CL4176) and wild-type worms were employed to evaluate paralysis onset, lifespan, cerebral Aβ deposition, and intracellular reactive oxygen species (ROS) after Lobetyolin administration. Untargeted ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) metabolomics coupled with RNA-seq transcriptomics was carried out to profile systemic metabolic and gene-expression changes. Differential metabolites and transcripts were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and pathway-impact analyses; hub targets were prioritized by integrating enrichment scores with in-silico docking. Lobetyolin (12.5-50 μM) markedly protected C. elegans from Aβ-driven toxicity and oxidative stress. In CL2006 worms, β-amyloid deposits fell by 54.8 ± 9.4%, while paralysis in CL4176 was delayed by 20.9 ± 4.5%. Lifespan increased by up to 18.2% in CL4176 and 25.0% in wild-type N2 worms. Concomitantly, intracellular ROS declined maximally by 28.1 ± 8.9% (N2) and 22.4 ± 3.8% (CL4176). Integrative metabolomic-transcriptomic analyses, validated by RT-qPCR, revealed selective remodeling of glutathione metabolism: gst-38 expression was suppressed, whereas gst-1 was elevated. Lobetyolin confers neuroprotective and geroprotective benefits in vivo, primarily through reprogramming glutathione-centered redox metabolism and selectively modulating glutathione-S-transferases (GST) isoforms. These findings position Lobetyolin as a promising dietary lead compound for AD prevention and healthy aging interventions.

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.

Parkinson's disease (PD), the second most common neurodegenerative disorder globally, arises from selective dopaminergic neuron degeneration. While current therapies address symptoms, disease-modifying agents remain an unmet need. Herein, we investigated Nicotiana tabacum L. (Solanaceae), a plant linked epidemiologically to reduced PD risk, as a source of multi-target neuroprotective compounds. From ultra-low nicotine (< 0.04%) tobacco leaves, we isolated 22 molecules, including a novel 21-norsesterterpenoid (Nicotiazanorpenoid A) and eight previously unreported compounds. Systematic evaluation revealed three synergistic neuroprotective mechanisms: (1) Antioxidant activity: Scopoletin (3) and isoferulic acid (6) showed significant radical scavenging capacity (ABTS assay; IC₅₀ = 27.74, and 18.13 μM, respectively); (2) Neuronal protection: cis-11,14,17-Eicosatrienoic acid methyl ester (14) enhanced survival (93.94% vs. control) in 6-OHDA-induced PC12 cells, surpassing rasagiline (88.36% at equivalent concentrations); (3) MAO-B inhibition: five compounds displayed selective inhibition, with scopoletin (3) exhibiting highest potency (K_i = 20.7 μM). Notably, plant prostaglandins (10/11) were identified as competitive MAO-B inhibitors first time through molecular docking and 100-ns MD simulations, revealing stable binding at the FAD site (ΔG = - 10.42, and- 9.75 kcal/mol, respectively).

Syngnathoides biaculeatus, a potential functional food from marine sources, was found to enhance nonspecific immunity, but its functional ingredients have rarely been reported. Therefore, this study focused on the preparation and physicochemical properties of its water-soluble natural ingredients with their immunomodulatory activities and potential mechanisms. Firstly, we optimized the extraction method of glycoproteins from S. biaculeatus and prepared the crude glycoprotein SYB, from which the fraction glycoprotein SYB-1 was further purified. The carbohydrates of SYB-1 were 8.46% comprising mannose, glucose, and galactose, with an average molecular weight of 9.423 kDa. Amino acid analysis demonstrated that its major amino acids are glycine, glutamic acid, aspartic acid, and proline, with a total amino acid content of 88.81%. Furthermore, SYB-1 could significantly increase the cell viability of macrophages, and promote the release of NO, TNF-α, and IL-6. Metabolomics revealed that it was associated with arachidonic acid metabolism. The CYP450 enzyme family members and PTGS2 may be key targets for the regulatory role. These results suggested that the glycoprotein of S. biaculeatus may be an attractive functional food supplement from natural sources for immunocompromised populations.

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.

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.

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.

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.

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.

Nidulin is a secondary metabolite of the depsidone family produced by Aspergillus spp., and has shown promises in pharmacological applications. This study aimed to investigate the effect of nidulin on glucose metabolism in skeletal muscle, the primary site of physiological glucose disposal, and its underlying mechanisms. Using a 2-[³H]-deoxy-glucose (2-DG) uptake assay, nidulin stimulated 2-DG in L6 myotubes in a dose- and time-dependent manner. This effect of nidulin was additive to insulin and metformin, and remained effective under palmitic acid-induced insulin resistance. At the molecular level, nidulin upregulated the mRNA expression and promoted membrane translocation of glucose transporters, GLUT4 and GLUT1. Although nidulin activated AMPK and p38 signaling, pharmacological inhibition of this pathway had minimal effect on nidulin-enhanced 2-DG uptake activity. Notably, nidulin activated key insulin signaling proteins, including IRS1, AKT, and p44/42, and its effect was attenuated by an AKT inhibitor. This study further compared the upstream mechanism of nidulin with that of insulin. While nidulin did not directly activate the insulin receptor β-subunit, it modulated redox homeostasis and intracellular calcium, evidenced by increased cytosolic H₂O₂ and Ca²⁺ levels. The 2-DG uptake-enhancing effect of nidulin and its activation of AKT were suppressed by either an antioxidant or calcium chelator treatment. These findings position nidulin as a promising insulin-sensitizing agent, offering mechanistic insights and therapeutic potential for improving glucose homeostasis in type 2 diabetes.

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.

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.

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.

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.

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.

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.

Eight UbiA-type prenyltransferases were mined in Laetiporus sulphureus by bioinformatic analysis, and phylogenetic analysis showed that they have unique functions. Through heterologous expression in Aspergillus oryzae and addition of exogenous hydroquinone (HYQ, 2) substrate, it was found that LaPT3 could transfer isoprenyl groups on 2. Substrate specificity studies revealed that LaPT3 was substrate specific and could only transfer dimethylallyl diphosphate (DMAPP) using 2 as substrate to produce the product 2-(3-methylbut-2-en-1-yl) benzene-1,4-diol (1). The key active sites of LaPT3 were analyzed and two key amino acid sites near the conserved motifs were targeted for mutation, and the product yields were reduced to 60% and 29% respectively by mutating N100 to S and G208 to A. Molecular docking and site-directed mutagenesis results indicate that these two amino acid sites play a crucial role in the catalytic generation of 2 by LaPT3 to produce 1.