Promotion of angiogenesis is crucial for bone tissue repair, and the poor activity of angiogenic cells and growth factors is the main problem in angiogenesis. New proangiogenic nanomaterials are urgently needed to be a promising strategy for this issue. Nb promotes bone formation and fracture healing, possibly by increasing vascular endothelial growth factor (VEGF) production. Nanoniobium particles (nNb) may promote angiogenesis. However, the effect of nNb on angiogenesis is unclear, limiting its application. This study confirmed that nNb significantly promoted angiogenesis. nNb increased and Ras-related C3 botulinum toxin substrate (Rac) family small guanosine triphosphatase (GTPase) 1 (Rac1) expression, inducing F-actin aggregation at the front edge of cells and the formation of pseudopodia to mediate cell migration, further promoting angiogenesis. We discovered that cyclin-dependent kinase-like 5 (CDKL5) is a new signaling molecule that activates Rac1. V-ets erythroblastosis virus E26 oncogene homolog (ETS) domain-containing protein (ELK1), regulating CDKL5 and Rac1, plays an upstream regulatory role. When ELK1 was inhibited, CDKL5 and Rac1 levels were decreased. ELK1, CDKL5 or Rac1 are effective regulatory targets of angiogenesis. Inhibiting expression of ELK1, CDKL5 or Rac1 decreased angiogenesis. Thus, nNb has good angiogenic effects. The ELK1-CDKL5-Rac1 signaling pathway regulates the migration of endothelial cells to promote angiogenesis. nNb can be used in bone tissue engineering as a new nanomaterial, and it will promote the development of a new strategy for tissue engineering. Graphical abstract
Urate transporter 1 (URAT1, encoded by SLC22A12 ) is a key mediator of renal urate reabsorption and an important pharmacological target for urate-related disorders. Sodium butyrate (BuNa), a gut microbiota derived short-chain fatty acid, has been implicated in host metabolic regulation, but its role in renal urate transport remains unclear. Here, using molecular docking, cellular thermal shift assays, immunoprecipitation-mass spectrometry and multi-omics analyses, we identified free fatty acid receptor 2 (FFAR2) as a direct target of BuNa in renal proximal tubular HK2 cells . BuNa binding upregulated FFAR2 and promoted URAT1 expression and urate uptake via an FFAR2-dependent pathway. Mechanistically, BuNa/FFAR2 signaling acts via GNAQ to activate PLCβ, generating diacylglycerol and engaging a PKC-dependent p38 MAPK/ELK1 cascade that upregulates arrestin beta 2 (ARRB2). ARRB2 directly binds to IκB, preventing its phosphorylation-dependent degradation, thereby stabilizing IκB and inhibiting NF-κB nuclear translocation. Within the SLC22A12 promoter, NF-κB (RELA/p50) and hepatocyte nuclear factor 1 beta (HNF1β) compete for overlapping binding sites. By blocking NF-κB nuclear entry, BuNa relieves this competition, permitting HNF1β-driven SLC22A12 transcription. Thus, BuNa enhances URAT1-mediated urate reabsorption in HK2 cells via an FFAR2/GNAQ/p38 MAPK/ELK1/ARRB2 axis that stabilizes IκB, suppresses NF-κB, and relieves the competitive binding between NF-κB and HNF1β on the SLC22A12 promoter. These findings establish a previously unrecognized gut microbiota–kidney axis linking microbial BuNa to renal urate homeostasis through a novel transcriptional regulatory circuit.
危险品化学品经营许可证（带存储）