JOURNAL/nrgr/04.03/01300535-202408000-00034/figure1/v/2026-05-08T111955Z/r/image-tiff Spinal cord injury-induced motor dysfunction is associated with neuroinflammation. Studies have shown that the triterpenoid lupenone, a natural product found in various plants, has a remarkable anti-inflammatory effect in the context of chronic inflammation. However, the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown. In this study, we established an impact-induced mouse model of spinal cord injury, and then treated the injured mice with lupenone (8 mg/kg, twice a day) by intraperitoneal injection. We also treated BV2 cells with lipopolysaccharide and adenosine 5′-triphosphate to simulate the inflammatory response after spinal cord injury. Our results showed that lupenone reduced IκBα activation and p65 nuclear translocation, inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B, and enhanced the conversion of proinflammatory M1 microglial cells into anti-inflammatory M2 microglial cells. Furthermore, lupenone decreased NLRP3 inflammasome activation, NLRP3-induced microglial cell polarization, and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway. These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes.

Intervertebral disc degeneration (IDD) has been generally accepted as the major cause of low back pain (LBP), which imposes massive clinical and socioeconomic burdens. Previous studies have demonstrated that oxidative stress and inflammation-induced senescence and apoptosis of nucleus pulposus cells (NPCs) are the main cellular processes that cause IDD. Arginase II (ARG2), an enzyme involved in a variety of pathological processes, including cellular senescence, apoptosis, oxidative stress, and inflammation, has been shown to promote degeneration in several degenerative diseases, including osteoarticular diseases. Based on previous studies, we hypothesized that ARG2 deficiency might be conducive to the treatment of IDD by inhibiting the dyshomeostasis of the extracellular matrix (ECM), and the oxidative stress and inflammatory response-induced senescence and apoptosis via NF-κB. In this study, we found that ARG2 deficiency inhibited senescence and apoptosis of NPCs, and degeneration of the ECM induced by oxidative stress and the inflammatory response. Similar results were found with the selective NF-κB pathway inhibitor JSH-23. In contrast, overexpression of ARG2 had the opposite effect. Taken together, our results suggest that ARG2 deficiency prevents IDD via NF-κB, and may therefore, be a potential therapeutic strategy for IDD.

Bone homeostasis has been a dynamic equilibrium between osteoclasts (OCs) and osteoblasts (OBs). However, excessive activation of OCs could disturb the bone homeostasis. As a result, effective medical interventions for patients are greatly demanding. NO/guanylate cyclase (GC)/cGMP signaling cascade has been previously reported to regulate bone metabolism, and GC plays a significantly critical role. Vericiguat, as a novel oral soluble guanylate cyclase (sGC) stimulator, has been firstly reported in 2020 to treat patients with heart failure. Nevertheless, the biological effects of Vericiguat on the function of OCs have not yet been explored. In this present study, we found that Vericiguat with the concentration between 0 and 8μM was noncytotoxic to bone marrow-derived monocyte-macrophage lineage (BMMs). Vericiguat could enhance the differentiation of OCs at concentration of 500nM, whereas it inhibited OC differentiation at 8μM. In addition, Vericiguat also showed dual effects on OC fusion and bone resorption in a dose-dependent manner. Furthermore, a molecular assay suggested that the dual regulatory effects of Vericiguat on OCs were mediated by the bidirectional activation of the IκB-α/NF-κB signaling pathway. Taken together, our present study demonstrated the dual effects of Vericiguat on the formation of functional OCs. The regulatory effects of Vericiguat on OCs were achieved by the bidirectional modulation of the IκB-α/NF-κB signaling pathway, and a potential balance between the IκB-α/NF-κB signaling pathway and sGC/cGMP/VASP may exist.

Intervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain. Programmed cell death, particularly necroptosis, contributes to nucleus pulposus (NP) cell loss. Mixed lineage kinase domain-like protein (MLKL) phosphorylation plays a critical role in necroptotic execution, but its upstream regulation in IVDD remains poorly defined. We analyzed human and mouse degenerative disc tissues, as well as TNF-α/Smac mimetic/Z-VAD-FMK (TSZ)-treated NP cells, to assess MLKL phosphorylation. MLKL knockdown in human NP cells and conditional knockout (CKO) in mice were performed to determine its functional role. Immunoprecipitation coupled with mass spectrometry identified potential MLKL-binding proteins. Functional assays with USP39 knockdown/overexpression, together with in vitro and in vivo IVDD models, were conducted to explore regulatory mechanisms. MLKL phosphorylation was markedly elevated in human IVDD tissues, LSI-induced mouse discs, and TSZ-stimulated NP cells. Genetic knockdown or conditional deletion of Mlkl significantly preserved extracellular matrix integrity and delayed degeneration. USP39 was identified as a novel MLKL-interacting deubiquitinase. USP39 expression was reduced in IVDD, and its overexpression inhibited MLKL ubiquitination and phosphorylation, alleviating NP cell degeneration. In vivo, AAV-mediated Usp39 delivery attenuated disc degeneration and suppressed MLKL activation. Our study reveals that MLKL phosphorylation drives necroptosis in IVDD and identifies USP39 as a critical upstream regulator that deubiquitinates MLKL. Targeting the USP39-MLKL axis provides a promising therapeutic strategy for delaying IVDD progression. This study reveals that USP39 inhibits MLKL phosphorylation through deubiquitination, thereby suppressing necroptosis of nucleus pulposus cells and alleviating IVDD. Targeting the USP39–MLKL axis provides a potential therapeutic strategy to preserve NP cell viability and slow the progression of IVDD, offering new insight for translational interventions in chronic low back pain.

Objective: This study aimed to compare bone metabolism markers between patients with hip fracture who had and did not have type 2 diabetes mellitus (T2DM). Methods: A total of 743 patients with hip fractures were enrolled in this case–control study and were further divided into T2DM and non-T2DM groups. Biochemical parameters, including fasting blood glucose, triglycerides, and total cholesterol, and bone metabolism parameters, including total serum procollagen type N-terminal propeptide and age-related type I cross-linked C-telopeptide, were collected and compared. Correlations between fasting blood glucose and triglyceride levels and bone metabolism parameters were assessed via Spearman correlation analysis. Results: The fasting blood glucose and triglyceride levels in the T2DM group were significantly higher than those in the non-T2DM group. In addition, the total serum procollagen type N-terminal propeptide and age-related type I cross-linked C-telopeptide levels in the T2DM group were significantly lower than those in the non-T2DM group. Conclusions: The fasting blood glucose levels were negatively correlated with the total serum procollagen type N-terminal propeptide and age-related type I cross-linked C-telopeptide levels. In addition, our study speculated that good glycemic control may be beneficial for bone metabolism.