RESUMEN
OBJECTIVE: The aim of this study was to investigate whether ASA VI controls osteoarthritis (OA) by regulating mitochondrial function. METHODS: Primary chondrocytes were isolated and cultured from rat knee joints. The chondrocytes were treated with ASA VI and interleukin-1ß (IL-1ß) to simulate the inflammatory environment of OA. Cell viability, apoptosis, inflammatory cytokine levels, and extracellular matrix (ECM) component levels were assessed. Mitochondrial function, including ATP levels, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and mitochondrial DNA content, was evaluated. The expression of Sirtuin 3 (Sirt3), a key regulator of mitochondrial homeostasis, was examined. Additionally, a rat OA model was established by destabilizing the medial meniscus, and the effects of ASA VI on cartilage degeneration were assessed. RESULTS: ASA VI treatment improved cell viability, reduced apoptosis, and decreased IL-6 and TNF-α levels in IL-1ß-induced chondrocytes. ASA VI also upregulated Collagen II and Aggrecan expression, while downregulating ADAMTS5 and MMP-13 expression. Furthermore, ASA VI mitigated IL-1ß-induced mitochondrial dysfunction by increasing ATP levels, restoring mitochondrial membrane potential, reducing ROS production, and preserving mitochondrial DNA content. These effects were accompanied by the activation of Sirt3. In the rat OA model, ASA VI treatment increased Sirt3 expression and alleviated cartilage degeneration. CONCLUSION: ASA VI exerts chondroprotective and anti-inflammatory effects on IL-1ß-induced chondrocytes by improving mitochondrial function through Sirt3 activation. ASA VI also attenuates cartilage degeneration in a rat OA model. These findings suggest that ASA VI may be a potential therapeutic agent for the treatment of osteoarthritis by targeting mitochondrial dysfunction.
RESUMEN
The polar oceans play a vital role in regulating atmospheric CO2 concentrations (pCO2) during the Pleistocene glacial cycles. However, despite being the largest modern reservoir of respired carbon, the impact of the subarctic Pacific remains poorly understood due to limited records. Here, we present high-resolution, 230Th-normalized export productivity records from the subarctic northwestern Pacific covering the last five glacial cycles. Our records display pronounced, glacial-interglacial cyclicity superimposed with precessional-driven variability, with warm interglacial climate and high boreal summer insolation providing favorable conditions to sustain upwelling of nutrient-rich subsurface waters and hence increased export productivity. Our transient model simulations consistently show that ice sheets and to a lesser degree, precession are the main drivers that control the strength and latitudinal position of the westerlies. Enhanced upwelling of nutrient/carbon-rich water caused by the intensification and poleward migration of the northern westerlies during warmer climate intervals would have led to the release of previously sequestered CO2 from the subarctic Pacific to the atmosphere. Our results also highlight the significant role of the subarctic Pacific in modulating pCO2 changes during the Pleistocene climate cycles, especially on precession timescale ( ~ 20 kyr).
RESUMEN
The present study aimed to observe the content difference of macrophage migration inhibitory factor [MIF; novoprotein recombinant human MIF (n6his) (ch33)], TGFß1 and MMP13 in patients with and without ligamentum flavum (LF) hypertrophy and investigate the roles of MIF in LF hypertrophy. The concentration of MIF, TGFß1 and MMP13 in LF were detected by ELISA in a lumbar spinal stenosis (LSS) group and a lumbar disc herniation (LDH) group. Culture of primary LFs and identification were performed for the subsequent study. Cell treatments and cell proliferation assay by CCK8 was performed. Western blot and quantitative PCR analysis were used to detect the expression of TGFß1, MMP13, type I collagen (COL1) and type III collagen (COL3) and Src which were promoted by MIF. The concentration of MIF, TGFß1 and MMP13 were higher in the LSS group compared with the LDH group. Culture of primary LFs and identification were performed. Significant difference in LFs proliferation occurred with treatment by MIF at a concentration of 40 nM for 48 h (P<0.05). The gene and protein expression of TGFß1, MMP13, COL1, COL3 and Src were promoted by MIF (P<0.05). Proliferation of LFs was induced by MIF and MIFinduced proliferation of LFs was inhibited by PP1 (a Src inhibitor). MIF may promote the proliferation of LFs through the Src kinase signaling pathway and can promote extracellular matrix changes by its proinflammatory effect. MIF and its mediated inflammatory reaction are driving factors of LF hypertrophy.