Purpose Abnormal glycolysis of immune cells contributed to the development of inflammatory response. Inhibition of this Warburg phenotype could be a promising strategy for preventing various inflammatory diseases. Iridin (IRD) is a natural isoflavone, and exerts anticancer, antioxidant, and anti-inflammatory effects. However, the underlying mechanism of IRD on acute inflammation remains unknown. In this study, the protective effects of IRD against lipopolysaccharide (LPS)-induced inflammation were investigated in murine macrophage RAW264.7 cells and in mice. Methods The inhibition of IRD on NO production in culture medium was detected by Griess assay while the levels of TNF-α, IL-1β, and MCP-1 were detected by ELISA assay. The effects of IRD on OCR and ECAR levels in LPS-treated macrophages were monitored by using Seahorse Analyzer. The apoptosis rate as well as the release of ROS and NO of RAW264.7 cells were analyzed by flow cytometric assay. The protective effects of IRD were investigated on LPS-induced inflammation in mice. The expressions of PKM2 and its downstream (p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2) in cells and in lung tissues were detected by Western blotting analysis. Results IRD treatment at the concentrations of 12.5–50 μM significantly inhibited the productions of TNF-α, IL-1β, MCP-1, and ROS, and suppressed the levels of glucose uptake and lactic acid in LPS-treated RAW264.7 cells. Oral administration with IRD (20–80 mg/kg) inhibited LPS-induced acute lung injury as well as inflammatory cytokine production in mice. Moreover, IRD targeted pyruvate kinase isozyme type M2 (PKM2) and suppressed its downstream p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2, which could be abolished by PKM2 agonist DASA-58 and antioxidant N-acetyl-L-cysteine, but partly be reversed by NF-κB activator CUT129 and JAK1 activator RO8191. Conclusion IRD alleviated LPS-induced inflammation through suppressing PKM2-mediated pathways, and could be a potential candidate for the prevention of inflammatory diseases.
The reduced initial stability of orthopedic implants in osteoporotic bone matrices, coupled with excessive M1 macrophage polarization at bone-implant interfaces, disrupt bone–immune homeostasis and vascularization, ultimately leading to implant loosening or failure. Inspired by the marine mussel Mytilus edulis foot protein (Mefp), a pH-responsive multifunctional bone glue (YDC-Gel-Zn) with broad-spectrum adhesion capabilities is developed for osteoporotic bone-implant integration. This pseudo-Mefp bioglue enables dual-interface adhesion via catechol-rich sequences that mediate stable metal-phenolic coordination with metallic implants and hydrogen-bonded/Michael addition-driven interactions with the bone matrix, thereby improving initial implant fixation. Under osteoporotic inflammatory microenvironments, sequential dissociation of borate ester bonds and metal‒phenolic coordination facilitates the controlled release of Zn 2 ⁺ and proangiogenic/osteogenic peptides (YDC). The released Zn 2 ⁺ remodels glutathione metabolism through glutathione S-transferase (GST)-mediated regulation of glutathione (GSH) levels, inhibits JAK1/STAT1/NLRP3 inflammasome activation, and suppresses the release of proinflammatory cytokines from senescent M1 macrophages, recalibrating the osteo-vascular-immune microenvironment. Due to its positive effects on bone regeneration and angiogenesis, the bioinspired bone bioglue demonstrated a 194% increase in fixation strength in osteoporotic rat models, achieving 93% healthy bone-implant stability. Overall, this study provides a clinically translatable strategy for stable implantation under osteoporotic conditions through synergistic mechanical adaptation, bioactivity regulation, and smart environmental responsiveness.
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