Atherosclerosis (AS) is associated with a high incidence of cardiovascular events, yet the mechanisms underlying this association remain unclear. Our previous study found that Atherosclerotic endothelial injury is closely associated with ferroptosis in ApoE^-/- mice. Ferroptosis is a novel mode of cell death induced by decreased antioxidant capacity of the organism and accumulation of reactive oxygen species. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy is an important regulator of sudden ferroptosis in cells. However, the role of NCOA4 in AS and the exact mechanism by which it regulates the ferritinophagy response remain unclear. Herein, we report that NCOA4 expression is elevated in ApoE^-/- mice and endothelial cells and is significantly correlated with AS. NCOA4 expression promoted ferroptosis, and was positively correlated with ferritinophagy response. Mechanistically, our findings indicate that LOX-1 is a key upstream target that influences the function of NCOA4. The specific pathway is related to the activation of cGAS-STING signaling to upregulate NCOA4 expression. Moreover, our findings demonstrate the "Gualou-Xiebai" herb pair can regulate LOX-1 to inhibit ferroptosis. Collectively, our results provide evidence of a connection between NCOA4-mediated promotion of AS and suggest that targeting upstream molecules regulating NCOA4 could be a potential therapy for AS.

Aim: The aim of this work was to optimize a nanoemulsion formulation and explain its absorption mechanism in improving the oral bioavailability of paeonol. Method: The bioavailability of paeonol was compared between paeonol nanoemulsion group and paeonol suspension group. The in situ single-pass intestine perfusion method, in vitro everted gut sacs method, Western blot analysis and Caco-2 cell transport studies were used to investigate the absorption mechanism of nanoemulsion. Results: Nanoemulsion was proved to enhance the bioavailability of paeonol. P-glycoprotein (P-gp) mediated efflux might be the main reason affecting the oral absorption of paeonol. The prepared nanoemulsion prevented the P-gp-mediated efflux and enhanced the bioavailability of paeonol. Conclusion: The overall results revealed that nanoemulsion was an effective vehicle to improve the oral bioavailability of paeonol which resulted from the prevention of P-gp efflux probably.

Objective: The aim of this study was to optimize baicalin nanoemulsion, clarify the absorption mechanisms of nanoemulsion improving the exposure of baicalin, and assess the potential of employing nanoemulsion as nanosystem for insoluble drugs. Significance: A novel nanoemulsion formulation was successfully prepared to enhance oral exposure of baicalin. Methods: Pseudo-ternary phase diagrams were utilized to evaluate nanoemulsion area. Physicochemical properties of optimal nanoemulsion formulation were investigated. The exposure of baicalin from the nanoemulsion was compared with baicalin suspension. The in situ single-pass intestine perfusion (SPIP) method and chylomicron-blocked rat model were used to study the absorption mechanisms of nanoemulsion. Results: Baicalin nanoemulsion was nearly spherical in shape with the average droplet size of 58.43 nm, and the zeta potential was –8.18 ± 1.2 mV. The stability test showed that baicalin nanoemulsion was very stable. Pharmacokinetic study indicated that baicalin nanoemulsion showed 14.56-fold improvement in exposure in comparison to baicalin suspension. The results of SPIP and chylomicron flow blocking study showed that intestinal absorption and lymphatic transport process contributed to its systemic exposure. Conclusions: Based on the results, optimal nanoemulsion might be promising nanosystems for oral delivery of baicalin to satisfy clinical requirements.

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder characterized by memory loss, language impairment, personality changes and intellectual decline. Taking into account the key pathological features of AD, such as low levels of acetylcholine, beta-amyloid (Aβ) aggregation, oxidative stress and dyshomeostasis of biometals, a new series of paeonol derivatives 5a–5d merging three different functions, i.e., antioxidant, anti-acetylcholinesterase (AChE) activity, metal chelating agents for AD treatment have been synthesized and characterized. Biological assays revealed that compared with paeonol (309.7 μM), 5a–5d had a lower DPPH IC₅₀ value (142.8–191.6 μM). 5a–5d could significantly inhibit hydrogen peroxide-induced neuronal PC12 cell death assessed by MTT assay in the concentration range of 5–40 μM. AChE activity was effectively inhibited by 5a–5d, with IC₅₀ values in the range of 0.61–7.04 μM. 5a–5d also exhibited good metal-chelating ability. All the above results suggested that paeonol derivatives may be promising multifunctional agents for AD treatment.