Carnitine functions as an enhancer of NRF2 to inhibit osteoclastogenesis via regulating macrophage polarization in osteoporosis.

Osteoporosis, which manifests as reduced bone mass and deteriorated bone quality, is common in the elderly population. It is characterized by persistent elevation of macrophage-associated inflammation and active osteoclast bone resorption. Currently, the roles of intracellular metabolism in regulating these processes remain unclear. In this study, we initially performed bioinformatics analysis and observed a significant increase in the proportion of M1 macrophages in bone marrow with aging. Further metabolomics analysis demonstrated a notable reduction in the expression of carnitine metabolites in aged macrophages, while carnitine was not detected in osteoclasts. During the differentiation process, osteoclasts took up carnitine synthesized by macrophages to regulate their own activity. Mechanistically, carnitine enhanced the function of Nrf2 by inhibiting the Keap1-Nrf2 interaction, reducing the proteasome-dependent ubiquitination and degradation of Nrf2. In silico molecular ligand docking analysis of the interaction between carnitine and Keap1 showed that carnitine binds to Keap1 to stabilize Nrf2 and enhance its function. In this study, we found that the decrease in carnitine levels in aging macrophages causes overactivation of osteoclasts, ultimately leading to osteoporosis. A decrease in serum carnitine levels in patients with osteoporosis was found to have good diagnostic and predictive value. Moreover, supplementation with carnitine was shown to be effective in the treatment of osteoporosis.

The association between vitamin D and COPD risk, severity, and exacerbation: an updated systematic review and meta-analysis.

BACKGROUND: In recent years, the pleiotropic roles of vitamin D have been highlighted in various diseases. However, the association between serum vitamin D and COPD is not well studied. This updated systematic review and meta-analysis aimed to assess the relationship between vitamin D and the risk, severity, and exacerbation of COPD. METHODS: A systematic literature search was conducted in PubMed, Medline, EMBASE, Chinese National Knowledge Infrastructure, Wanfang, and Weipu databases. The pooled risk estimates were standardized mean difference (SMD) with 95% confidence interval (CI) for vitamin D levels and odds ratio (OR) with 95% CI for vitamin D deficiency. Meta-regression and subgroup analyses were performed on latitude, body mass index, and assay method. RESULTS: A total of 21 studies, including 4,818 COPD patients and 7,175 controls, were included. Meta-analysis showed that lower serum vitamin D levels were found in COPD patients than in controls (SMD: -0.69, 95% CI: -1.00, -0.38, P<0.001), especially in severe COPD (SMD: -0.87, 95% CI: -1.51, -0.22, P=0.001) and COPD exacerbation (SMD: -0.43, 95% CI: -0.70, -0.15, P=0.002). Vitamin D deficiency was associated with increased risk of COPD (OR: 1.77, 95% CI: 1.18, 2.64, P=0.006) and with COPD severity (OR: 2.83, 95% CI: 2.00, 4.00, P<0.001) but not with COPD exacerbation (OR: 1.17, 95% CI: 0.86, 1.59, P=0.326). Assay methods had significant influence on the heterogeneity of vitamin D deficiency and COPD risk. CONCLUSION: Serum vitamin D levels were inversely associated with COPD risk, severity, and exacerbation. Vitamin D deficiency is associated with increased risk of COPD and severe COPD but not with COPD exacerbation. It is worth considering assay methods in the heterogeneity sources analysis of association between vitamin D deficiency and COPD.