Daijun Zha

JOURNAL/nrgr/04.03/01300535-202511000-00034/figure1/v/2026-04-24T022020Z/r/image-tiff Previous studies have shown that the compound ( E )-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), a pyromeconic acid derivative, possesses antioxidant and anti-inflammatory properties, inhibits amyloid-β aggregation, and alleviates scopolamine-induced cognitive impairment, similar to the phase III clinical drug resveratrol. In this study, we established a mouse model of Alzheimer’s disease via intracerebroventricular injection of fibrillar amyloid-β to investigate the effect of D30 on fibrillar amyloid-β–induced neuropathology. Our results showed that D30 alleviated fibrillar amyloid-β–induced cognitive impairment, promoted fibrillar amyloid-β clearance from the hippocampus and cortex, suppressed oxidative stress, and inhibited activation of microglia and astrocytes. D30 also reversed the fibrillar amyloid-β–induced loss of dendritic spines and synaptic protein expression. Notably, we demonstrated that exogenous fibrillar amyloid-β introduced by intracerebroventricular injection greatly increased galectin-3 expression levels in the brain, and this increase was blocked by D30. Considering the role of D30 in clearing amyloid-β, inhibiting neuroinflammation, protecting synapses, and improving cognition, this study highlights the potential of galectin-3 as a promising treatment target for patients with Alzheimer’s disease.

Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC₅₀ = 4.68 nM; huBuChE IC₅₀ = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD₅₀ > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.

Background: Amyloid β (Aβ) and neuroinflammation are recognized as crucial to the pathogenesis of Alzheimer's disease (AD). Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), a pyromeconic acid derivative, inhibits Aβ aggregation and reverses scopolamine-induced cognitive impairment. However, the in vivo therapeutic potential of D30was not known for Aβ-induced neuropathology. Thus, we investigated the effects and mechanisms of D30 in a fibril Aβ(fAβ)-induced AD mouse model. Methods: We established an AD model by intracerebroventricular injection of fAβ to determine whether D30 could alleviate fAβ-induced neuropathology. Behavior tests (Open Field, New Object Recognition, Morris Water Maze) were conducted to evaluate cognitive function. Aβ were assessed by immunohistochemistry, immunofluorescence staining, and immunoblotting of cortex and hippocampus. Glial cell morphology, neuroinflammation, and neuronal properties were assessed by immunofluorescence staining of hippocampal brain slices. Cortex and hippocampus were also subjected to ELISA and immunoblotting assays. The effects of D30 on primary microglia were measured by immunoblotting, immunofluorescence, and real-time quantitative PCR. Results: Compound D30 alleviated fAβ-induced cognitive impairment. D30 promoted the removal of injected fAβ from the hippocampus and cortex and suppressed oxidative stress and activation of microglia and astrocytes. D30 reversed the fAβ-induced loss of dendritic spines and synaptic proteins. We demonstrated for the first time that exogenous intracerebroventricular injection of fAβ greatly increased Galectin-3 (Gal-3) level in the mouse brain, and the increase in Gal-3 was blocked by D30. In addition, D30 activated the p62/Nrf2/HO-1 signaling pathway in primary microglia and promoted the disposal of Aβ and relief of fAβ-induced neuroinflammation. Thus, by its comprehensive activities in Aβ disposal, antioxidation, and anti-neuroinflammation, D30 protected synapses and cognitive function, with a strong involvement in Gal-3 regulation, thereby exhibiting novel AD therapeutic potential.

The kojic acid dimer (KAD) is a metabolite derived from developing cottonseed when contaminated with aflatoxin. The KAD has been shown to exhibit bright greenish-yellow fluorescence, but little else is known about its biological activity. In this study, using kojic acid as a raw material, we developed a four-step synthetic route that achieved the gram-scale preparation of the KAD in approximately 25% total yield. The structure of the KAD was verified by single-crystal X-ray diffraction. The KAD showed good safety in a variety of cells and had a good protective effect in SH-SY5Y cells. At concentrations lower than 50 μM, the KAD was superior to vitamin C in ABTS⁺ free radical scavenging assay; the KAD resisted the production of reactive oxygen species induced by H₂O₂ as confirmed by fluorescence microscopy observation and flow cytometry analysis. Notably, the KAD could enhance the superoxide dismutase activity, which might be the mechanism of its antioxidant activity. The KAD also moderately inhibited the deposition of amyloid-β (Aβ) and selectively chelated Cu²⁺, Zn²⁺, Fe²⁺, Fe³⁺, and Al³⁺, which are related to the progress of Alzheimer's disease. Based on its good effects in terms of oxidative stress, neuroprotection, inhibition of Aβ deposition, and metal accumulation, the KAD shows potential for the multi-target treatment of Alzheimer's disease.

We used a readily available water source, MgSO₄·2H₂O, to realize the control of the chemo-selectivity of the Ritter-type reaction efficiently.