Xin Chen

The clinical application of doxorubicin in cancer therapy is significantly limited by its severe cardiotoxicity, with complex mechanisms. No effective protective agents are currently available, creating an urgent clinical need. In this study, through structural optimization of ebselen, we developed a series of isoselenazolinones with improved water solubility and glutathione peroxidase (GPx)-like activity. The most promising acidic and basic derivatives, 7 and 12, exhibited a 7.0- and 10.4-fold increase in activity compared to the lead compound, alongside a 16- and 160-fold improvement in water solubility. Frontier molecular orbital theory calculation results showed a good correlation with the observed structure–activity relationships. Furthermore, compound 7 significantly protected cardiomyocytes from doxorubicin-induced injury, preventing 75% of the loss in cell viability at 20 μM. Preliminary mechanistic studies suggested that this protection is mediated by inhibiting oxidative stress and ferroptosis. This study provides a promising class of active compounds for the treatment of doxorubicin-induced cardiotoxicity.

Stroke poses a serious threat to human health, while there are very few drugs that can directly alleviate ischemia/reperfusion injury and improve the prognosis. Studies have shown that small-molecule activators of aldehyde dehydrogenase 2 (ALDH2) have the potential to become novel therapeutic drugs for ischemic stroke. In this study, through the systematic structural optimization of novel N-benzylaniline-based ALDH2 activators obtained from our previous virtual screening, ALDH2 activators with improved water solubility and activity were obtained. Among them, compound D10 exhibits the best activity, with a maximum activation fold reaching 114% relative to Alda-1. And the water solubility of its hydrochloride salt D27 was increased by more than 200-fold. The intravenous injection of this compound can significantly reduce the infarct area in the rat model of cerebral infarction compared with the model group. This study lays a good foundation for the future research on ALDH2 activators used in the treatment of stroke.

Anxiety disorders, as common neurological diseases in clinical practice, often coexist with depression. Epidemiological surveys indicate that approximately 85% of patients with depression exhibit significant anxiety symptoms. This comorbid state not only exacerbates clinical symptoms but also leads to treatment resistance and prolonged disease duration. This study innovatively developed a compound aromatic plant essential oil (EO) formulation with remarkable anxiolytic and antidepressant effects and systematically elucidated its mechanism of action. The study found that the essential oil formulation, administered via inhalation, could significantly improve behavioral abnormalities in animals subjected to the chronic unpredictable mild stress (CUMS) model, specifically manifesting as (1) the reversal of stress-induced weight gain retardation; (2) a significant increase in sucrose preference; (3) an increase in the total distance of spontaneous activity; and (4) the prolongation of exploration time in the open arms of the elevated plus maze. Neuropathological examinations confirmed that the formulation could effectively protect the structural integrity of hippocampal neurons and alleviate CUMS-induced neural damage. In terms of mechanism of action, the study revealed that the formulation regulates the neurotransmitter system through multiple targets: (1) the upregulation of serotonin (5-HT) and γ-aminobutyric acid (GABA) levels; (2) the downregulation of glutamate (GLU) concentration; and (3) key targets identified via network pharmacological analysis, such as ESR1, STAT3, and PPARG. These findings provide molecular-level evidence for understanding the neuromodulatory effects of aromatic essential oils. Pharmaceutical formulation studies showed that the oil-in-water (O/W) type compound essential oil microemulsion, prepared using microemulsification technology, has a uniform particle size and excellent stability, maintaining stable physicochemical properties at room temperature for an extended period, thus laying a foundation for its clinical application. This study not only validates the practical value of traditional medicine but also provides new ideas for the development of novel anxiolytic and antidepressant drugs, achieving an organic integration of traditional experience and modern technology.