Diabetic nephropathy (DN) is a leading cause of end-stage renal disease characterized by chronic inflammation and podocyte injury. Here, we investigated the role of the SP-1/Chemerin/ChemR23 axis in DN using mouse (MPC-5) and human (PODO/TERT256) podocytes and streptozotocin-induced DN mice. High glucose upregulated SP-1, promoted its nuclear translocation and binding to the Chemerin promoter, thereby enhancing Chemerin transcription and activating the ChemR23 pathway. This signaling cascade induced NLRP3 inflammasome-associated inflammation and podocyte injury, as evidenced by decreased Nephrin and WT-1 and increased Desmin expression. These effects were mimicked by exogenous Chemerin and reversed by Chemerin silencing, ChemR23 inhibition, or SP-1 knockdown, while SP-1 overexpression exacerbated the injury. In vivo, targeting SP-1 or ChemR23 alleviated renal inflammation, improved renal function, and attenuated podocyte damage in DN mice. Collectively, our findings support SP-1-mediated activation of the Chemerin/ChemR23 axis as an important regulatory pathway contributing to NLRP3 inflammasome-associated podocyte injury in DN and suggest that this pathway warrants further investigation as a potential therapeutic target.
Background Epidemiological evidence regarding the relationship between the neutrophil‐to‐high‐density lipoprotein cholesterol ratio (NHR) and asthma‐chronic obstructive pulmonary disease overlap (ACO) remains limited. We examined the association between NHR and questionnaire‐defined ACO and evaluated the contribution of NHR within an interpretable multivariable classification framework using data from the National Health and Nutrition Examination Survey (NHANES). Methods Restricted cubic splines (RCS) and multivariable logistic regression (LR) were used to examine the association between NHR and ACO. An exploratory statistical mediation analysis evaluated whether eosinophils statistically accounted for part of the observed association. Least Absolute Shrinkage and Selection Operator (LASSO) regression and Boruta were used for feature selection, followed by comparison of five classification algorithms. The selected model was further interpreted using SHapley Additive exPlanations (SHAP). Results Higher NHR was associated with greater odds of ACO after multivariable adjustment (OR = 1.14, 95% CI: 1.06–1.24). Exploratory statistical mediation analysis suggested that eosinophils may statistically account for ~8.11% of the observed association. LASSO and Boruta identified six variables for ACO classification: glucocorticoids (GCS) use, cardiovascular disease (CVD), age, NHR, hypertension, and cancer. Among the five evaluated algorithms, LR showed the most favorable overall performance in the training dataset (ROC‐AUC = 0.869; PR‐AUC = 0.214; Brier score = 0.0176) and test dataset (ROC‐AUC = 0.847; PR‐AUC = 0.208; Brier score = 0.0183). The SHAP analysis characterized their contributions within the selected LR model. Conclusion Higher NHR was associated with greater odds of questionnaire‐defined ACO. NHR may warrant further investigation as a candidate marker of systemic inflammometabolic status within multivariable assessment frameworks. Prospective studies with standardized ACO definitions, objective spirometry, and external model validation are required before clinical application can be considered.
Background Muscle atrophy frequently accompanies osteosarcoma and is associated with unfavorable outcomes. However, the shared molecular basis underlying muscle wasting and osteosarcoma progression remains insufficiently understood. Methods Public bulk transcriptomic datasets of muscle atrophy (GSE41414) and osteosarcoma (GSE12865) were integrated to identify shared differentially expressed genes (DEGs). Candidate genes were prioritized using LASSO, SVM‐RFE, and random forest models with cross‐validation and resampling procedures. Immune infiltration analysis and single‐cell RNA sequencing (scRNA‐seq) data from osteosarcoma (GSE162454) were used to characterize the tumor microenvironment. Cell–cell communication analysis was performed to infer signaling interactions. Results Forty‐nine shared DEGs were identified, mainly enriched in extracellular matrix (ECM) organization and metabolic pathways. Integrative machine‐learning analysis prioritized PFKP and MEF2C as robust candidate regulators. Immune deconvolution revealed significant alterations in multiple immune cell subsets associated with PFKP/MEF2C expression. In the osteosarcoma single‐cell microenvironment, both genes were predominantly enriched in stromal and immune compartments. Communication modeling suggested enhanced CCL/CXCL signaling activity. Conclusions PFKP and MEF2C may represent candidate regulators linking metabolic alterations with immune remodeling in osteosarcoma‐associated muscle atrophy. These findings provide a basis for future mechanistic and translational validation.
Fracture repair is a highly coordinated regenerative process initiated within the fracture hematoma, which acts not only as a provisional clot but also as a transient immune and signaling niche. In this early microenvironment, danger sensing, coagulation, complement activation, leukocyte recruitment, stromal progenitor activation, angiogenesis, chondrogenesis, endochondral ossification, and callus remodeling are temporally linked through cytokines, chemokines, and growth factors. Short-lived increases in tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) are essential for host defense, removal of damaged tissue, and priming of osteogenic progenitors. By contrast, prolonged activation of these same mediators may impair osteoblast differentiation, promote osteoclastogenesis, compromise vascular integrity, and shift the callus toward fibrosis or nonunion. Resolution-associated signals, including IL-10, transforming growth factor-beta (TGF-β), oncostatin M, and specialized pro-resolving lipid mediators, help redirect the injured niche from inflammatory clearance toward tissue reconstruction. Chemokines such as CCL2, CXCL8, and CXCL12 regulate the recruitment and spatial positioning of monocytes, neutrophils, endothelial cells, and mesenchymal/skeletal stem and progenitor cells, whereas VEGF, BMPs, PDGF, IGF-1, and FGFs couple inflammation to vascularized cartilage-to-bone transition and matrix remodeling. In this review, we integrate recent findings from osteoimmunology, single-cell analysis, and spatial transcriptomics to propose a phase-specific framework for immunomodulation in delayed union and nonunion. We argue that fracture healing should not be approached through broad suppression of inflammation but through spatiotemporally precise immune regulation tailored to patient risk, fracture phenotype, vascular status, and mechanical stability.
Osteoarthritis (OA) is a prevalent age-related degenerative joint disease characterized by chronic inflammation and progressive extracellular matrix (ECM) degradation. Current pharmacological therapies for OA remain limited due to suboptimal efficacy and potential adverse effects. Gallic acid (GA), a naturally occurring polyphenolic compound, exhibits potent antiinflammatory and antioxidant properties in various disease models; however, its protective role in OA and the underlying mechanisms remain incompletely understood. In the present study, we investigated the chondroprotective effects of GA in interleukin (IL)-1β-stimulated primary rat chondrocytes and in a rat anterior cruciate ligament transection (ACLT) model of OA. Our results demonstrated that GA significantly suppressed the production of proinflammatory cytokines and attenuated ECM degradation in IL-1β-stimulated chondrocytes. Mechanistically, GA activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling axis, thereby inhibiting nuclear factor-kappa B (NF-κB) activation induced by IL-1β. Furthermore, GA administration effectively alleviated cartilage degeneration and slowed OA progression in ACLT rats. Collectively, these findings indicate that GA exerts protective effects against OA by suppressing chondrocyte inflammation and ECM degradation through modulation of the Nrf2/NF-κB signaling pathway. This study provides experimental evidence supporting GA as a potential therapeutic candidate for OA.
