Multidrug resistance (MDR) is a major hurdle in cancer chemotherapy and makes the treatment benefits unsustainable. Combination therapy is a commonly used method for overcoming MDR. In this study we investigated the anti-MDR effect of dihydroartemisinin (DHA), a derivative of artemisinin, in combination with doxorubicin (Dox) in drug-resistant human colon tumor HCT8/ADR cells. We developed a tumor-targeting codelivery system, in which the two drugs were co-encapsulated into the mannosylated liposomes (Man-liposomes). The Man-liposomes had a mean diameter of 158.8 nm and zeta potential of −15.8 mV. In the HCT8/ADR cells that overexpress the mannose receptors, the Man-liposomes altered the intracellular distribution of Dox, resulting in a high accumulation of Dox in the nuclei and thus displaying the highest cytotoxicity (IC50=0.073 μg/mL) among all the groups. In a subcutaneous HCT8/ADR tumor xenograft model, administration of the Man-liposomes resulted in a tumor inhibition rate of 88.59%, compared to that of 47.46% or 70.54%, respectively, for the treatment with free Dox or free Dox+DHA. The mechanisms underlying the anti-MDR effect of the Man-liposomes involved preferential nuclear accumulation of the therapeutic agents, enhanced cancer cell apoptosis, downregulation of Bcl-xl, and the induction of autophagy.
Alzheimer’s disease (AD) is a prevalent neurodegenerative condition distinguished by intricate pathological mechanisms. Cinnamaldehyde, a natural active chemical sourced from the bark of Cinnamomum species, exhibits remarkable neuroprotective properties that have been validated in various neurological disorders. In this study, network pharmacology alongside zebrafish experiments was employed to investigate the molecular mechanisms and signaling pathways through which cinnamaldehyde ameliorates AD. Potential targets of cinnamaldehyde were found using the SuperPred, TargetNet, SwissTargetPrediction, and SEA databases, whilst AD-related targets were obtained from TTD, OMIM, GeneCards, and DrugBank databases. Subsequently, protein-protein interaction analysis was performed using the STRING database, followed by GO and KEGG enrichment studies via the DAVID platform. Finally, molecular docking validation was conducted using CB-Dock2. The network pharmacology results indicated that cinnamaldehyde might impact its beneficial effects on AD via regulating the toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-κB) signaling pathway. To further validate this mechanism, an AD model was established in zebrafish induced by aluminum chloride (AlCl₃). Behavioral assays demonstrated that cinnamaldehyde significantly improved AlCl₃-induced cognitive impairment. Hematoxylin-eosin and Nissl staining revealed that cinnamaldehyde attenuated neuropathological damage. Biochemical analyses indicated that cinnamaldehyde alleviated oxidative stress and restored cholinergic dysfunction. Furthermore, RT-qPCR findings indicated that cinnamaldehyde reduced inflammatory mediator expression and diminished TLR4 and NF-κB p65 mRNA levels, while western blotting confirmed reduced TLR4 and phosphorylated NF-κB p65 protein expression. In summary, cinnamaldehyde may mitigate neuroinflammation through suppressing the TLR4/NF-κB signaling pathway, thereby ameliorating AlCl₃-induced cognitive impairment, neuropathological injury, oxidative stress imbalance, and cholinergic system dysfunction in zebrafish.
Depression is a leading global health burden increasingly linked to dysregulation in glutamatergic signaling. Ionotropic glutamate receptors (iGluRs), including NMDA, AMPA, and kainate subtypes, have emerged as pivotal therapeutic targets. However, the rapid expansion of literature has led to a fragmented research landscape, creating an urgent need for a structured overview. This study aims to provide a comprehensive bibliometric analysis to map the evolution, knowledge hubs, and emerging frontiers of iGluR research in depression.We retrieved 6,843 publications (1975-2025) from Web of Science, PubMed, and Scopus, utilizing CiteSpace, VOSviewer, and Bibliometrix for visualization and trend analysis. Analysis revealed a 7.31% annual growth rate, with the United States and China leading global productivity. Research has transitioned from basic synaptic transmission mechanisms to clinical innovations, with "NMDA receptor" and "treatment-resistant depression" identified as primary hotspots. These findings provide a quantitative framework that clarifies the shift from preclinical models to rapid-acting antidepressant discovery. Here we show that bibliometric mapping provides a coherent picture of how iGluRs research in depression has evolved. The prominence of ketamine therapy highlights a successful translational trajectory. By identifying key collaborative networks and knowledge gaps, this study provides a strategic roadmap to guide future mechanistic work and the development of next-generation rapidly acting antidepressants.
Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by cognitive decline. Peripheral immune dysregulation often precedes central immune abnormalities and may therefore provide valuable clues for the early diagnosis and stratification of AD. Current research on peripheral immunity in AD remains limited. This study provides new insights into the pathogenesis and therapeutic strategies for AD. Bioinformatics and single-cell RNA sequencing were used to analyse peripheral immune-related gene expression in AD. Key genes and immune cell populations linked to AD were identified. Quercetin (Que) was selected as a potential therapeutic agent using drug prediction methods. Molecular docking, Western blotting (WB), and qRT-PCR were further performed to preliminarily assess the regulation of these hub genes by quercetin in an H2O2-induced HT22 neuronal oxidative stress model. Several immune-related genes, including ACTB, TP53, HIF1A, and BCL-2, were differentially expressed in AD. Gene function analysis revealed their involvement in processes like apoptosis and viral response. Pathway enrichment analysis highlighted the significance of the p53, apoptosis, and HIF-1 signaling pathways in AD. Single-cell sequencing identified key immune cell populations, such as CD4 + memory cells and NK cells. Drug prediction and experimental results indicated that quercetin may modulate these genes in a neuronal stress context, providing preliminary experimental support for its regulatory effects on AD-related hub genes. This study identified peripheral immune-related molecular features of AD and highlighted several hub genes that may represent shared molecular nodes linking peripheral immune alterations and central neuronal stress responses. The in vitro findings provide preliminary support for the regulatory effects of quercetin on these AD-related hub genes, although further validation in peripheral immune cell and in vivo models is still required.
Abstract Background Alzheimer’s disease (AD) is characterized by Tau aggregation, mitochondrial dysfunction, and oxidative stress, yet effective interventions targeting these pathological cascades remain limited. Therapeutic strategies that enhance autophagic and mitophagic clearance, attenuate Tau toxicity, and restore mitochondrial homeostasis are crucial for AD management. Methods This study investigated the neuroprotective effects of Pulsatilla chinensis extract (PCE) in SH-SY5Y neuronal cells and Caenorhabditis elegans (C. elegans) models of Tauopathy. Autophagic flux was evaluated by GFP-LC3 puncta formation, LC3-II conversion, and p62 degradation. Mitochondrial function was assessed through reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and ultrastructural analysis. The roles of autophagy and mitophagy were examined using 3-methyladenine (3-MA) and the Parkin inhibitor AC220. In C. elegans, locomotion, Tau aggregation, oxidative stress, and mitophagosome formation were assessed, and pink-1 knockdown was used to confirm mitophagy dependence. Results PCE significantly enhanced autophagic flux, decreased total and phosphorylated Tau (p-Tau Ser404) levels, and improved neuronal viability. It significantly reduced ROS accumulation, maintained MMP, and preserved mitochondrial morphology under both Tau overexpression and H2O2-induced oxidative stress. Inhibition of autophagy or Parkin-mediated mitophagy negated these protective effects. In C. elegans, PCE ameliorated neuromuscular dysfunction, suppressed Tau inclusions, and reduced oxidative injury, while the loss of pink-1 abolished its benefits, underscoring the critical role of mitophagy. Conclusion PCE exerts potent neuroprotective effects by promoting mitophagy, reducing Tau phosphorylation and aggregation, and restoring mitochondrial integrity. These findings reveal a novel mechanism linking mitochondrial quality control with Tau proteostasis and highlight PCE as a promising natural therapeutic candidate for AD. Graphical Abstract
