Introduction Sjögren's syndrome creates a lymphoma-prone inflammatory niche and confers one of the highest autoimmune risks of B-cell non-Hodgkin lymphoma. Yet the genetic and cellular mechanisms that remodel this pre-neoplastic niche into a tumor-supportive immune microenvironment remain unclear. We integrated human genetics, single-cell transcriptomics and functional cell biology to identify an actionable mediator of this transition. Methods We combined bidirectional Mendelian randomization, directionality filtering, MHC-exclusion sensitivity analyses (chromosome 6: 25–35 Mb), colocalization and summary-based HLA fine-mapping. Single-cell RNA sequencing of salivary gland and splenic marginal-zone lymphoma was used to localize genetic risk, reconstruct cross-disease B-cell states and infer intercellular signaling. Mechanistic dependence was tested in IFN-γ-stimulated Raji B-lymphoma cells, and clinical relevance was evaluated in a public chronic lymphocytic leukemia cohort. Results Genetic liability to Sjögren's syndrome increased marginal-zone/MALT, diffuse large B-cell and overall non-Hodgkin lymphoma risk, and effects collapsed after MHC exclusion and resolved to the class II 8.1 ancestral haplotype. Single-cell analysis localized risk to salivary B cells and revealed disease-associated remodeling toward a lymphoid, MIF-rich, CD74-receiving microenvironment, with plasma cells as the largest MIF source. HLA-class-II/CD74 programs increased along the Sjögren-to-lymphoma B-cell trajectory. In Raji cells, MIF activated AKT/NF-κB/BCL-xL signaling and viability. ISO-1 or CD74 knockdown suppressed the pathway and increased cleaved PARP, whereas AKT activation partially rescued signaling and viability. Higher CD74 expression marked adverse outcome in an external B-cell malignancy cohort. Conclusion Convergent genetic, single-cell and perturbation evidence positions CD74 as a candidate organizer of a lymphoma-supportive immune microenvironment linking inherited MHC class II risk to B-cell survival. The MIF–CD74 axis provides a translational tumor-microenvironment target that requires tissue-level and prospective validation.
Psoriasis is a systemic autoimmune dermatosis characterized by cutaneous microbiome dysbiosis and inflammatory cell infiltration. Current pharmacological interventions are often limited by inadequate skin penetration, systemic toxicity, low bioavailability, and the potential disruption of the skin's native microbial ecosystem. In this study, we found that two live bacterial species, Propionibacterium acnes (PA) and Lactobacillus rhamnosus (LR), when encapsulated in hydrogels, exhibit significant therapeutic efficacy against psoriasis. Upon topical application, the hydrogel acts as an effective delivery vehicle, prolonging bacterial survival and enhancing colonization. These live bacteria help restore microbial homeostasis by competitively excluding pathogenic species. Moreover, both the bacteria and their metabolites modulate local immune responses, mitigating excessive immune activation and thereby achieving superior therapeutic outcomes in psoriasis management. This work suggests a promising avenue for the clinical application of live bacteria in the treatment of psoriasis. V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
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.
