Osteoarthritis (OA) is the most common arthritis that is characterized by the progressive synovial inflammation and loss of articular cartilage. Although GYY4137 is a novel and slow-releasing hydrogen sulfide (H₂S) donor with potent anti-inflammatory properties that may modulate the progression of OA, its underlying mechanism remains unclear. In this study, we validated the protective role of GYY4137 against OA pathological courses and elucidated its underlying regulatory mechanisms. Cell transfection, immunofluorescence staining, EdU assay, transmission electron microscopy, mitochondrial membrane potential measurement, electrophoretic mobility shift assay, sulfhydration assay, qPCR and western blot assays were performed in the primary mouse chondrocytes or the mouse macrophage cell line raw 264.7 for in vitro study. DMM-induced OA mice model and Macrophage-specific p65 knockout (p65^f/f LysM-CreER^T2) mice on the C57BL/6 background were used for in vivo study. We found that GYY4137 can alleviate OA progress by suppressing synovium pyroptosis in vivo. Moreover, our in vitro data revealed that GYY4137 attenuates inflammation-induced NLRP3 and caspase-1 activation and results in a decrease of IL-1β production in macrophages. Mechanistically, GYY4137 increased persulfidation of NF-kB p65 in response to inflammatory stimuli that results in a decrease of cellular reactive oxygen species (ROS) accumulation and ameliorates mitochondrial dysfunctions. Using site-directed mutagenesis, we showed that H₂S persulfidates cysteine38 in p65 protein and hampers p65 transcriptional activity, and p65 mutant impaired macrophage responses to GYY4137. These findings suggest a mechanism by which GYY4137 through redox modification of p65 participates in inhibiting NLRP3 activation by OA to regulate inflammatory responses. Thus, we propose that GYY4137 represents a promising novel therapeutic strategy for the treatment of OA.

Spinal multiple myeloma (MM) and metastases are two common cancer types with similar imaging characteristics, for which differential diagnosis is needed to ensure precision therapy. The aim of this study is to establish radiomics models for effective differentiation between them. Enrolled in this study were 263 patients from two medical institutions, including 127 with spinal MM and 136 with spinal metastases. Of them, 210 patients from institution I were used as the internal training cohort and 53 patients from Institution II were used as the external validation cohort. Contrast-enhanced T1-weighted imaging (CET1) and T2-weighted imaging (T2WI) sequences were collected and reviewed. Based on the 1037 radiomics features extracted from both CET1 and T2WI images, Logistic Regression (LR), AdaBoost (AB), Support Vector Machines (SVM), Random Forest (RF), and multiple kernel learning based SVM (MKL-SVM) were constructed. Hyper-parameters were tuned by five-fold cross-validation. The diagnostic efficiency among different radiomics models was compared by accuracy (ACC), sensitivity (SEN), specificity (SPE), area under the ROC curve (AUC), YI, positive predictive value (PPV), negative predictive value (NPY), and F1-score. Based on single-sequence, the RF model outperformed all other models. All models based on T2WI images performed better than those based on CET1. The efficiency of all models was boosted by incorporating CET1 and T2WI sequences, and the MKL-SVM model achieved the best performance with ACC, AUC, and F1-score of 0.862, 0.870, and 0.874, respectively. The radiomics models constructed based on MRI achieved satisfactory diagnostic performance for differentiation of spinal MM and metastases, demonstrating broad application prospects for individualized diagnosis and treatment.

Dysregulated adipokine production is an influencing factor for the homeostatic imbalance of tendons. High levels of serum leptin may be a potential link between increasing adiposity and tendinopathy, while the detailed mechanistic explanation was not well-defined. In this study, we investigated the regulatory role of leptin in the tendon stem/progenitor cells (TSPCs) and the molecular mechanism within, and determined the effect of high levels of leptin on tendon recovery. We demonstrated that leptin reduced the viability of isolated rat TSPCs in a dose-dependent way, accompanied with increased transdifferentiation and altered gene expression of a series of extracellular matrix (ECM) enzymatic modulators. Also, we found that leptin could dose-dependently promote TSPCs senescence, while exhibiting limited effect in apoptotic or autophagic induction. Mechanistic study evidenced that leptin treatment increased the AKT/mTOR signaling activity and elevated the expression of leptin receptor (LEPR) in TSPCs, without marked change in MAPK or STAT5 activation. Further, we confirmed that rapamycin treatment, but not AKT inhibition, effectively reduced the leptin-promoted TSPCs senescence. In a rat model with Achilles wounding, exposure to leptin profoundly delayed tendon healing, which was effectively rescued with rapamycin treatment. Our results suggested that leptin could cause intrinsic cellular deficits in TSPCs and impede tendon repair through the AKT/mTOR signaling pathway. These findings evidenced for an important role of elevated leptin levels in the care of tendinopathy and tendon tears.

Differentiation of mesenchymal progenitor cells (MPCs) is critical pre-requisition for the progression of heterotopic ossification (HO). However, the facto

Intervertebral disc degeneration (IVDD), a primary cause of debilitating low back pain, is driven by a vicious cycle involving a harsh microenvironment (“soil”) and dysfunctional nucleus pulposus cells (“seeds”), which together promote pathological neurovascular ingrowth (“weeds”) and pain. A therapeutic strategy that can simultaneously “condition the soil” and “modulate the seed” is therefore paramount. Thus, we engineered a biomimetic intelligent nanoliposome (NM-LP^TK/RSV-MnCDs) for this dual purpose. The platform is camouflaged with NPC membranes for precise “seed”-homing and incorporates a reactive oxygen species (ROS)-responsive linker for on-demand drug release within the degenerative “soil.” It co-delivers carbonized Mn-containing nanodots (MnCDs) to “condition the soil” by scavenging ROS, and resveratrol (RSV) to “modulate the seed” by suppressing pro-neurovascular signaling. The nanoplatform demonstrated outstanding efficacy in vitro and in two distinct murine IVDD models. It effectively scavenged ROS, inhibited axonal and vascular growth, and preserved matrix synthesis. In vivo, it significantly attenuated disc degeneration, suppressed pathological neurovascular ingrowth, and alleviated pain-related behaviors. Mechanistically, we found this synergistic “soil-conditioning” and “seed-modulating” effect was mediated through the inactivation of the Hippo-YAP signaling pathway, which restored redox homeostasis and blocked aberrant remodeling. This study establishes a targeted, intelligent nanoplatform that synergistically alleviates IVDD and discogenic pain by restoring the disc ecosystem via Hippo pathway inhibition, presenting a precise therapeutic paradigm for degenerative disc disease and its associated neuropathic pain.

Background: Emerging evidence suggests that facet joint degeneration, disc pathology, and paraspinal muscle atrophy form a degenerative triad in young adults with lumbar disc herniation (LDH). However, the exact relationship remains unknown. This study aimed quantitatively to investigate their interrelationships through magnetic resonance imaging (MRI) morphometry. Methods: Axial T2-weighted MRI served as the assessment tool in this retrospective study enrolling 60 young patients (33 disc bulging and 27 disc herniation). Measurements obtained at the responsible segment level included: lumbar curvature (Cobb angle), Pfirrmann score, intervertebral space height, facet joint angle, mean width of the multifidus pure muscle cross-sectional area (PMCSA), and multifidus fatty infiltration grade. Parameters were statistically compared between the bulging and herniation groups. Subsequently, multivariate logistic regression assessed the correlation between LDH severity and the MRI parameters. Results: Intergroup analysis revealed statistically significant differences in age, sex distribution, treatment modality, Cobb angle, anterior/middle disc height, bilateral facet joint angles, and multifidus PMCSA ( P < 0.05). Multivariate logistic regression demonstrated that facet tropism, Pfirrmann grade, and multifidus fatty infiltration grade were independently associated with LDH severity ( P < 0.05). Conclusions: Facet tropism, intervertebral disc degeneration (quantified by Pfirrmann grade), and multifidus fatty infiltration represent established risk factors for LDH and likely contribute to its pathological cascade.