Stem Cell Research & Therapy•2025•DOI: 10.1186/s13287-025-04613-x
Background Osteoarthritis (OA) is a joint disorder that severely affects patients’ mobility, overall health, and ability to perform daily activities. Despite advancements in therapeutic strategies, stem cell-based therapies for OA still face challenges, particularly in enhancing the antioxidative capacity of stem cells to improve therapeutic outcomes. Therefore, this study aimed to explore the potential of β-sitosterol in this context. Methods This study evaluated the protective effects of β-sitosterol on bone marrow-derived mesenchymal stem cells (BMSCs) and chondrocytes under oxidative stress conditions and assessed its potential in promoting cartilage repair in a rabbit OA model. Cell viability, gene expression, oxidative stress markers, and mitochondrial function were examined. In vivo therapeutic effects were evaluated through histological and immunohistochemical analyses. Results The results revealed that β-sitosterol significantly enhanced BMSC viability, upregulated the expression of Col2a1 and aggrecan, while inhibiting MMP13 expression. Furthermore, β-sitosterol effectively alleviated oxidative stress and preserved mitochondrial function in BMSCs. Notably, BMSCs pretreated with β-Sitosterol exhibited a higher potential for facilitating cartilage regeneration in the OA model, as evidence by histopathological analysis. Conclusions These findings suggest that β-sitosterol possesses significant antioxidative and chondroprotective properties, which enhance the therapeutic efficacy of BMSCs in addressing OA-related cartilage damage.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025092
Accumulating evidence suggests that NLRP3-mediated alveolar macrophage (AM) pyroptosis and subsequent high mobility group box protein 1 (HMGB1) secretion play significant roles in the pathogenesis of acute respiratory distress syndrome (ARDS). Nrf2 has been shown to be individually involved in regulating pyroptosis. In this study, we investigate the ability of CDDO-imidazolide, a potent Nrf2 activator, to regulate AM pyroptosis and HMGB1 secretion in sepsis-associated ARDS, along with its underlying mechanism. The in vitro alveolar macrophage (AM) pyroptosis model, established by stimulating J774A.1 cells with LPS and ATP, was treated with CDDO-imidazolide or utilized Nrf2-knockout cells. The mice are intraperitoneally administered with CDDO-imidazolide before the in vivo sepsis-associated ARDS model is constructed via caecal ligation perforation and the Nrf2 inhibitor, ML385. In vitro studies reveal that the use of 3-MA to prohibit PINK1/Parkin-dependent mitophagy aggravates NLRP3-mediated pyroptosis and HMGB1 release in J774A.1 cells via LPS and ATP exposure. CDDO-imidazolide also significantly prevents NLRP3-mediated pyroptosis and HMGB1 release to increase PINK1/Parkin-dependent mitophagy, but these effects are not detected in Nrf2-knockout macrophages. Most importantly, CDDO-imidazolide significantly alleviates NLRP3 inflammasome protein expression in the lung tissues of septic mice and HMGB1 protein levels in the serum and bronchoalveolar lavage fluid (BALF), which can be reversed by ML385. Taken together, our results demonstrate that CDDO-imidazolide prominently protects the lungs by promoting Nrf2 activation and enhancing PINK1/Parkin mitophagy to inhibit AM pyroptosis and HMGB1 release. These findings provide novel insights for therapeutic strategies for sepsis-associated ARDS.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024171
Ozone (O3), a prevalent atmospheric pollutant, can induce lung injury. However, the molecular mechanisms of O3-induced acute lung inflammatory injury remain unclear. In this study, we investigate the abnormal changes in and molecular mechanism of mitochondrial homeostasis in alveolar macrophages (AMs) in O3-induced acute lung inflammatory injury mice. Mitochondria and mitochondrial reactive oxygen species (mtROS) are labeled with Mito-Tracker® Deep Red and MitoSOX Red, respectively. Mitochondrial DNA (mtDNA) in AMs from the bronchoalveolar lavage fluid (BALF) is detected via real-time PCR, and the expressions of mitochondrial fusion/fission-related and biogenesis-related proteins in AMs are determined via immunofluorescence staining. Our data show that in O3-induced acute lung inflammatory injury mice, the number of AMs and the protein expression of the NLRP3 inflammasome complex in the lung tissue are increased. In AMs from O3-exposed mice, the number of mitochondria, mtROS, and fission-related protein DRP1 are increased, but the levels of Na+-K+-ATPase, fusion-related protein OPA1, biogenesis-related protein NRF1 and mtDNA are significantly decreased. Compared with that in O3-exposed WT mice, lung inflammation is attenuated, especially the indicators of mitochondrial homeostatic imbalance in AMs, which are alleviated in NLRP3‒/‒ and Caspase-1‒/‒ mice after O3 exposure. These findings indicate that the NLRP3 inflammasome-mediated imbalance in mitochondrial homeostasis in AMs contributes to O3-induced acute lung inflammatory injury. This study may provide a new target for the prevention of lung inflammation induced by O3.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025092
Sepsis-associated acute respiratory distress syndrome (ARDS) is driven by alveolar macrophage (AM) pyroptosis and high mobility group box 1 (HMGB1) release, yet therapeutic options remain limited. This study evaluates CDDO-imidazolide (CDDO-Im), a potent Nrf2 activator, in modulating AM pyroptosis and HMGB1 secretion. In vitro, J774A.1 macrophages stimulated with LPS and ATP exhibited NLRP3-mediated pyroptosis and HMGB1 release, which was aggravated by 3-MA inhibition of PINK1/Parkin-dependent mitophagy. CDDO-Im significantly attenuated pyroptosis and HMGB1 release while enhancing PINK1/Parkin mitophagy; these effects were abolished in Nrf2-knockout macrophages. In vivo, caecal ligation perforation (CLP) induced septic ARDS in mice. Intraperitoneal CDDO-Im reduced NLRP3 inflammasome protein expression in lung tissues and HMGB1 levels in serum and bronchoalveolar lavage fluid (BALF). Co-administration of the Nrf2 inhibitor ML385 reversed these protective effects. The data demonstrate that CDDO-Im activates Nrf2, which promotes PINK1/Parkin-mediated mitophagy, thereby suppressing AM pyroptosis and HMGB1 release. This mechanism alleviates sepsis-induced ARDS, offering a potential therapeutic strategy. The study was supported by the National Natural Science Foundation of China (81900081, 82170089), and the authors declare no conflicts of interest.