The objective of this study was to enhance the membrane permeability and anticancer effectiveness of (20S)-protopanaxadiol (PPD) by introducing triphenylphosphonium into the OH group at the C-3 site. This study shows that the anti-proliferation activity of CTPPPPD, with an IC50 value of 1.65 ± 0.10 μmol/L, was 33-times better than that of PPD (with an IC50 value of 54.56 ± 4.56 μmol/L) and superior to that of cisplatin (with an IC50 value of 1.82 ± 0.25 μmol/L) against A549 cells. Biological examinations suggested that CTPPPPD treatment reduced the growth rate of A549 cells, increased the permeability of cell membranes, and changed the structure of chromosomal DNA in a concentration-dependent manner. Annexin V/PI assay and flow cytometry were employed to detect the effect of CTPPPPD on the apoptosis of A549 cells. The results showed that CTPPPPD could induce the apoptosis of A549 cells, and the apoptosis rate of A549 cells treated with 0, 1.0, 2.0, and 4.0 μM of CTPPPPD for 24 h was 0%, 4.9%, 12.7%, and 31.0%, respectively. The integration of transcriptomics and metabolomics provided a systematic and detailed perspective on the induced antitumor mechanisms. A combined analysis of DEGs and DAMs suggested that they were primarily involved in the central carbon metabolism pathway in cancer, as well as the metabolism of aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate. Central carbon metabolism in cancer-related genes, i.e., SLC16A3, FGFR3, LDHA, PGAM1, and SLC2A1, significantly reduced after treatment with CTPPPPD. In particular, the dominant mechanism responsible for total antitumor activity may be attributed to perturbations in the PI3K-AKT, MAPK, and P53 pathways. The findings derived from transcriptomics and metabolomics were empirically confirmed through q-PCR and molecular docking. Further analyses revealed that CTPPPPD could be a promising lead for the development of protopanaxadiol for non-small-cell lung cancer (NSCLC) drugs.

Chronic stress induces behavioral abnormalities through coordinated neuroendocrine, inflammatory, oxidative, metabolic, and gut microbial disturbances. Plant-derived volatile fractions may modulate stress-related neurobehavioral responses, yet their antioxidant and anti-inflammatory effects and associated neurobiological mechanisms remain insufficiently characterized. In this study, Ginkgo biloba leaf essential oil (GbO) was extracted from air-dried leaves by hydrodistillation, chemically characterized by GC–MS, and evaluated in a chronic unpredictable mild stress (CUMS) mouse model using behavioral, biochemical, molecular, hippocampal metabolomic, and gut microbiota analyses. HS-SPME–GC–MS tentatively identified 70 volatile constituents detected in at least two independent extraction batches, including 65 constituents consistently detected. In CUMS mice, inhaled GbO, particularly at the higher exposure level, attenuated depression- and anxiety-like behavioral abnormalities without altering general locomotor activity. GbO reduced serum corticosterone and peripheral and hippocampal pro-inflammatory cytokines, alleviated hippocampal oxidative imbalance, and decreased Iba-1 and GFAP signals. These changes were accompanied by reduced NF-κB activation, enhanced Nrf2/HO-1-related antioxidant signaling, and improved BDNF/TrkB/CREB-related neurotrophic signaling and PSD95-associated synaptic integrity. Hippocampal metabolomics further showed partial correction of stress-associated disturbances in neurotransmitter, lipid, inflammatory, and energy/redox metabolism, while 16S rRNA sequencing revealed partial restoration of gut microbial diversity and community structure. Collectively, these findings indicate that inhaled GbO exerts antioxidant and anti-inflammatory effects in CUMS mice in association with coordinated neuroimmune, neurotrophic, metabolic, and gut microbial remodeling.

Leaf development underpins physiological performance and secondary metabolite accumulation, yet its influence on phyllosphere fungal communities in perennial medicinal plants such as ginseng (Panax ginseng C.A. Meyer) remains poorly understood. Understanding how developmental stage affects leaf chemistry and microbial assembly is important for linking plant metabolism with aboveground microbial ecology. We analyzed ginseng leaves across four developmental stages (S1-S4) using physiological measurements, ginsenoside profiling, untargeted metabolomics, ITS amplicon sequencing, fungal association networks, and metabolite-fungus correlations. Leaf physiological traits and ginsenoside content peaked at stage S2, representing a developmental optimum. Metabolomics revealed early enrichment of sugar phosphates, nucleotide metabolites, and membrane lipids, followed by late accumulation of raffinose-family oligosaccharides, phenylpropanoids, flavonoids, oxylipin-related lipids, and brassinosteroid-linked metabolites. Fungal richness and evenness increased from S1 to S4, with communities shifting from Ascomycota-dominated at early stages to Basidiomycota-enriched on senescing leaves. Fungal association networks showed stage-related increases in network size and changes in topological organization. Integrative analyses indicated that stage-specific metabolic changes were closely associated with fungal community succession, with amino acid, carbohydrate, lipid, flavonoid, and terpenoid pathways potentially linked to stage-specific fungal association patterns. Ginseng leaf development was accompanied by coordinated physiological and metabolic reprogramming that was associated with shifts in phyllosphere fungal composition and inferred association networks. These findings highlight leaf developmental stage as an important context for aboveground microbial dynamics and provide a framework for linking plant metabolism with microbial ecology in perennial crops, while emphasizing that causal relationships between specific metabolites and fungal taxa require further experimental validation.