西南医科大学

As representatives of degenerative orthopedic diseases, intervertebral disc degenerative disease (IVDD) and osteoarthritis (OA) involve the spine and peripheral articular cartilage, respectively. Their comorbidity rate in individuals over 60 years exceeds 40

Knee osteoarthritis (KOA) is a chronic degenerative joint disease characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovial inflammation. Emerging evidence indicates that immune-inflammatory responses, particularly macrophage polarization and pyroptosis, play central roles in KOA pathogenesis. In the synovial microenvironment, macrophages exhibit functional heterogeneity beyond the classical M1/M2 paradigm, with M1-like macrophages predominating and promoting pro-inflammatory signaling through metabolic and epigenetic reprogramming. Concurrently, M2-like macrophages are reduced and functionally impaired, failing to resolve inflammation or support tissue repair. Pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasomes and Gasdermin D (GSDMD), is significantly activated in KOA synovium. M1 macrophages display heightened susceptibility to pyroptosis, releasing IL-1β, IL-18, and damage-associated molecular patterns (DAMPs), which further reinforce M1 polarization and synovial inflammation, forming a self-amplifying “inflammation–pyroptosis–re-inflammation” loop. This maladaptive feedback between macrophage polarization and pyroptosis drives chronic synovitis, cartilage matrix degradation, subchondral bone abnormalities, and persistent pain. Targeting key nodes of this network, including NLRP3, caspase-1, GSDMD, HMGB1/RAGE, and macrophage metabolic pathways, may offer novel therapeutic strategies for KOA. Understanding the interplay between macrophage heterogeneity and pyroptotic signaling provides a mechanistic framework for precision interventions aimed at restoring immune homeostasis and mitigating joint degeneration in KOA.

While impaired decision-making and reduced impulsive control have been repeatedly reported in individuals with Internet Gaming Disorder (IGD), there was accumulating evidence that controlled gaming exposure may be beneficial in certain aspects of perceptual decision-making. This study aimed to investigate perceptual decision and metacognition processing in IGD applying a post-decision wagering paradigm and drift-diffusion modeling (DDM). Results demonstrated that individuals with IGD exhibited enhanced decision accuracy and elevated drift rates during perceptual decision-making. Yet, no group differences were observed in comparison of metacognitive ability and metacognitive bias, indicating preserved metacognition in IGD. Notably, drift rates were positively correlated with anxiety and depression symptoms in the IGD group, but was negatively correlated with general self-efficacy in healthy controls (HCs), indicating compromised self-regulatory capacity and maladaptive metacognitive resource allocation patterns in IGD individuals. These findings demonstrated enhanced performance and elevated evidence accumulation efficiency during perceptual decision-making, as well as preserved metacognitive abilities in individuals with IGD, suggesting gaming may induce certain cognitive enhancement during perceptual decision-making in clinically diagnosed IGD.

Emotional disorders associated with multiple sclerosis (MS) are key drivers of disease progression. Recently, resting-state functional magnetic resonance imaging (rs-fMRI) and cerebrospinal fluid (CSF) metabolites have been found to play a crucial role in elucidating this process, but the causal relationship between them remains to be clarified. Exploring underlying mechanisms is critical for developing targeted therapies, especially combined multidimensional neuromodulation. This study employed bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between 191 rs-fMRI phenotypes and MS, while also exploring the mediating role of 338 CSF metabolites. Forward MR analysis revealed that enhanced functional connectivity in networks such as the saliency and visual networks (pheno56, pheno461, pheno624, pheno932, pheno1183) is related to an elevated risk of MS, whereas enhanced functional connectivity in the motor and attention networks (pheno2, pheno681, pheno705, pheno1322, pheno1696) is linked to a reduced risk of MS. Reverse MR analysis demonstrates that MS exhibits a positive correlation with four of these phenotypes (pheno74, pheno606, pheno767, and pheno1013), and a negative correlation with one phenotype (pheno286). Furthermore, five CSF metabolites-N-formylanthranilic acid, N6-methyllysine, succinimide, methyl glucopyranoside(alpha+beta), and hypoxanthine-were identified as key mediators in the MS process acting through resting-state brain functional networks. The study establishes causal rs-fMRI signatures affecting MS susceptibility and progression, and identifies critical CSF metabolites mediating MS effects via functional networks. These findings not only provide novel intervention targets for MS and related emotional disorders but also lay a theoretical foundation for the development of multidimensional therapeutic strategies leveraging neuromodulation techniques.

Gastric cancer (GC) is a malignant neoplasm displaying highly cancer-related mortality globally. Although our previous studies have confirmed that vitamin D possessed a direct anti-cancer effect on GC cells, the regulatory role of vitamin D on gastric tumor microenvironment (TME) remains unexplored. This study aims to expound the modulation of vitamin D on TME especially on GC-associated fibroblasts (CAFs) and to further elucidate the essential role of the CAFs-derived exosomal ingredients in tumor-stroma crosstalk. Patient-derived primary CAFs enhanced the aggressive characteristics of GC cells. When co-cultured with GC cells, CAFs pretreated with 1,25(OH)2D3 (1,25D3), the active form of vitamin D exhibited a significant inhibitory effect on cancer cell invasion and migration. Additionally, exosomes isolated from 1,25D3-pretreated CAFs were found to mediate this inhibitory effect, significantly reducing the migratory and invasive capacity of GC cells. Exosomal RNA sequencing revealed a significant upregulation of miR-378c in CAF-derived exosomes following 1,25D3 treatment. Fluorescence tracing assays confirmed that this treatment augmented the transfer of CAF-derived exosomal miRNA-378c into GC cells. Mechanistically, this elevated miR-378c directly targeted ketodihydrosphinganine reductase (KDSR) in GC cells, further leading to the attenuation of tumor growth in a 615 mice model. Immunophenotypic analysis further revealed that treatment with ago-miR-378c significantly increased intratumoral Granzyme B and CD3 levels and downregulated Foxp3 expression, indicating an activated state of antitumor immunity and a relief from immune suppression within the TME. Correspondingly, the expression of TNF-α and IL-6 was found to be up-regulated, while the immunosuppressive factor IL-10 was reduced in the ago-miR-378c group in comparison to the control group. Moreover, systemic administration of vitamin D suppressed CAF-mediated promotion of in vivo tumor growth, concomitant with elevated intratumoral miR-378c and diminished KDSR expression in a nude mice model. Taken together, our results demonstrate that vitamin D reprograms CAFs to impede GC progression and to promote an anti-tumor immune microenvironment, which might be mediated by exosomal miR-378c/KDSR axis, highlighting a potential therapeutic strategy of using vitamin D to counteract CAF-driven oncogenesis in GC.