Zihua Xu

Objective: This study investigates the mechanisms of ZDWX-25, a novel dual DYRK1A/GSK3β inhibitor, in alleviating tau pathology and explores its potential anti-neuroinflammatory effects. Methods: Acute tauopathy was induced by okadaic acid (OKA) and neuroinflammation by lipopolysaccharide (LPS) in mice. Cognitive function was assessed by Morris water maze and Y-maze (OKA only). Tau phosphorylation (AT8), neuronal integrity (Nissl, PSD95), microglial activation (IBA-1), and inflammatory mediators were measured. The PI3K inhibitor LY294002 was used in HT22 and BV2 cells. Results: In the OKA model, ZDWX-25 improved spatial and working memory, reduced tau hyperphosphorylation, and protected neurons. It activated PI3K/AKT; LY294002 completely blocked the GSK3β inhibitor AR-A014418, whereas both the DYRK1A inhibitor harmine and ZDWX-25 retained significant, albeit reduced, efficacy, revealing direct (PI3K/AKT-independent) GSK3β inhibition plus indirect (DYRK1A→PI3K/AKT) enhancement. ZDWX-25 also promoted microglial tau phagocytosis. In the LPS model, ZDWX-25 suppressed microglial activation and inflammatory mediators (IL-6, TNF-α, iNOS) and ameliorated cognitive deficits. Conclusion: ZDWX-25 attenuates tau pathology via dual direct/indirect mechanisms and enhances microglial clearance; it also shows preliminary anti-neuroinflammatory effects. These findings support ZDWX-25 as a multi-target candidate for Alzheimer’s disease.

Developing effective drugs for Alzheimer’s Disease (AD) is critically limited by insufficient brain exposure. To address this, structural optimization was employed to balance physicochemical properties and enhance blood-brain barrier (BBB) permeability, resulting in the development of ZJCK-6-72, a novel DYRK1A inhibitor. This study aims to comprehensively evaluate the drug-like properties and safety profile of ZJCK-6-72. Methods: A comprehensive in vitro and in vivo ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling of ZJCK-6-72 was conducted. Key assessments included pharmacokinetics, tissue distribution studies in rats, plasma protein binding assays, and metabolic stability testing. Additionally, acute toxicity was evaluated to determine the safety margin, and enzyme inhibition assays were performed to assess potential drug-drug interactions. Results: ZJCK-6-72 exhibited excellent oral bioavailability (78.03%) and extensive tissue distribution in rats. Notably, the compound demonstrated substantially enhanced brain penetration, with a brain-to-plasma ratio ranging from 1.92 to 4.63. The unbound brain-to-plasma partition coefficient (K _{p, uu} ) was determined to be 3.50, significantly exceeding unity. Metabolic studies indicated a shift towards CYP1A2 and CYP2C19 mediated pathways, with concentration-dependent inhibition observed (IC ₅₀ ≈ 1.8 μM). The acute toxicity assessment revealed an LD ₅₀ of 233.9 mg/kg bodyweight. Discussion: The high K _{p, uu} value indicates that the efficient brain entry of ZJCK-6-72 is likely driven by active uptake mechanisms rather than simple passive diffusion, confirming its ability to effectively evade efflux transporters. Although the inhibition of CYP1A2 and CYP2C19 suggests a potential for mechanism-based auto-inhibition, the acute toxicity profile demonstrates an acceptable safety margin for therapeutic development. Conclusion: ZJCK-6-72 displays an optimized pharmacokinetics profile characterized by superior unbound brain exposure. These findings support the potential of ZJCK-6-72 as a promising lead candidate for CNS-targeted AD therapy.

Acute lung injury (ALI) is a life-threatening inflammatory disorder with limited therapeutic options. This study evaluated the anti-inflammatory activity of ZLWH-38, a novel harmine derivative, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and a murine ALI model. ZLWH-38 showed low cytotoxicity and effectively inhibited the production of nitric oxide and pro-inflammatory cytokines. In macrophages, it dose-dependently reduced the expression of TNF-α, IL-6, IL-1β and iNOS, and intracellular ROS levels. Mechanistic investigations indicated that ZLWH-38 interacted with glycogen synthase kinase-3β (GSK3β) and suppressed downstream NF-κB signaling. In female C57BL/6 mice subjected to LPS-induced lung injury, prophylactic administration of ZLWH-38 markedly attenuated histopathological damage, lowered the lung wet/dry weight ratio, and decreased neutrophil infiltration and cytokine levels in bronchoalveolar lavage fluid and lung tissue. These findings suggest that ZLWH-38 ameliorates ALI by blocking GSK3β and thereby repressing downstream NF-κB signaling to curtail inflammation, offering a novel rationale and mechanistic foundation for ALI therapeutics.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and memory loss.

Background: The pathogenesis of rheumatoid arthritis (RA) is closely related to multiple disorders in the immune and metabolic systems, which indicates that a multi-target therapy strategy may have advantages over traditional single-target therapy. Huangqi Guizhi Wuwu Decoction (HGWD), as a classic traditional Chinese medicine formula that has been used to treat RA in clinic, is a potential source of multi-target natural medicine. However, its active components and mechanism of action still need further research. Methods: This study combined serum pharmacochemistry, non-targeted metabonomics, network pharmacology, and experimental verification and comprehensively analyzed the therapeutic mechanism and pharmacodynamic basis of HGWD. Results: Through HPLC-Q-TOF-MS/MS, a total of 99 chemical components were identified. Among them, 25 prototype compounds were absorbed into the systemic circulation. The study of network pharmacology indicates that these compounds are concentrated in TNF, IL-17, and MAPK signaling pathways. In collagen-induced arthritis rats, HGWD can effectively alleviate joint inflammation, inhibit the production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17), block the activation of the MAPK pathway, and restore 13 abnormal metabolic markers related to lipid and amino acid metabolism. In addition, the researchers identified and verified the combination of four active components (calycosin, paeoniflorin, 6-gingerol, and formononetin) in vitro, and its anti-inflammatory and anti-migration activities were equivalent to or stronger than those of the complete extract. Pharmacokinetic analysis also confirmed that these components were fully exposed in vivo. Conclusions: These findings reveal the mechanism of multi-component therapy of HGWD and identify the potential bioactive components, which can be used to develop multi-target therapeutic drugs for RA based on natural products.