Paeonol

The tumor microenvironment (TME) plays a pivotal role in determining tumor progression and treatment response. Within the TME, redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) are critically involved in regulating intercellular and intracellular signaling. In this study, we hypothesized that conjugating an NO-releasing moiety to paeonol derivatives and introducing a chalcone structure to enhance thioredoxin reductase (TrxR) targeting would yield compounds with potent anticancer activity. Accordingly, a series of mono- and di-substituted nitrate derivatives were synthesized. The inhibitory activities of all synthesized compounds were evaluated against BGC823, HCT116, Hep G2, and MCF-7 cell lines using the CCK-8 assay. Among the paeonol chalcone derivatives, compound 11f exhibited significant antiproliferative activity across the tested cancer cell panel. It was identified as a promising candidate with potent TrxR inhibitory activity (IC₅₀ = 0.26 ± 0.17 μM in vitro; IC₅₀ = 0.33 μM in vivo). Furthermore, compound 11f induced S-phase arrest and promoted apoptosis in MCF-7 cells. These findings underscore the enhanced anticancer potential of paeonol chalcone derivatives, attributable to the synergistic effects of NO and ROS.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain, leading to a spectrum of motor and non-motor symptoms. Current pharmacological interventions for PD offer limited efficacy and are associated with significant adverse effects, thereby driving the development of novel drug delivery systems. This study aimed to enhance the therapeutic potential of paeonol by innovatively constructing paeonol-loaded liposome-exosome (Lip-Exo/Pae) hybrid nanoparticles, thereby synergistically leveraging the advantages of both liposomes and exosomes. To achieve this, we meticulously prepared paeonol-loaded liposomes using the ethanol injection method. Exosomes were successfully extracted from Salvia miltiorrhiza rhizomes via PEG co-precipitation. Subsequently, these components were integrated through freeze-thaw cycling to form the uniquely structured Lip-Exo/Pae hybrid nanoparticles. Comprehensive characterization confirmed that these hybrid nanoparticles exhibited uniform particle size and good dispersion stability, maintaining excellent colloidal stability for 28 days under refrigeration at 4 °C. In vivo fluorescence imaging demonstrated their efficient traversal of the blood-brain barrier, with targeted accumulation and sustained retention within brain tissue. In MPTP-induced PD mice, Lip-Exo/Pae significantly ameliorated behavioral deficits, including spontaneous activity, motor coordination, and balance. Furthermore, it effectively attenuated neuronal damage and iron deposition in the substantia nigra, protected dopaminergic neurons, increased the number and protein expression of tyrosine hydroxylase (TH) positive cells, and reduced oxidative stress and inflammation. The nanoparticles also exhibited favorable biocompatibility and safety profiles. This research not only provided a novel strategy for PD treatment but also overcame the limitations of single nanocarriers in drug delivery by integrating the benefits of liposomes and exosomes. Looking ahead, this study will further explore the clinical application potential of Lip-Exo/Pae hybrid nanoparticles and continuously optimize their preparation process to achieve broader applications and stronger therapeutic effects, thereby contributing to breakthroughs in the treatment of neurodegenerative diseases.