RESUMEN
Synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare and refractory autoinflammatory disease, and there is no consensus on its treatment. Stellate ganglion block (SGB) blocks sympathetic nerves, ameliorates immune dysfunction, and alleviates stress response, which has been used to treat various chronic pain syndromes, arrhythmias, and post-traumatic stress disorder (PTSD). Also, the SGB has been reported to be successfully used to treat certain skin diseases, autoinflammatory diseases, and menopausal symptoms. In this study, over 3 years of follow-up, we found that SGB successfully intervened the symptoms of SAPHO syndrome, including sternoclavicular joint arthritis and palmoplantar pustulosis.
Asunto(s)
Síndrome de Hiperostosis Adquirido , Bloqueo Nervioso Autónomo , Ganglio Estrellado , Humanos , Síndrome de Hiperostosis Adquirido/diagnóstico , Síndrome de Hiperostosis Adquirido/terapia , Bloqueo Nervioso Autónomo/métodos , Femenino , Resultado del Tratamiento , Persona de Mediana Edad , AdultoRESUMEN
Older livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation. The potential mechanism remains unclear. Here, we demonstrate older livers exhibit increased ferroptosis during HIRI. Inhibiting ferroptosis significantly attenuates older HIRI phenotypes. Mass spectrometry reveals that fat mass and obesity-associated gene (FTO) expression is downregulated in older livers, especially during HIRI. Overexpressing FTO improves older HIRI phenotypes by inhibiting ferroptosis. Mechanistically, acyl-CoA synthetase long chain family 4 (ACSL4) and transferrin receptor protein 1 (TFRC), two key positive contributors to ferroptosis, are FTO targets. For ameliorative effect, FTO requires the inhibition of Acsl4 and Tfrc mRNA stability in a m6A-dependent manner. Furthermore, we demonstrate nicotinamide mononucleotide can upregulate FTO demethylase activity, suppressing ferroptosis and decreasing older HIRI. Collectively, these findings reveal an FTO-ACSL4/TFRC regulatory pathway that contributes to the pathogenesis of older HIRI, providing insight into the clinical translation of strategies related to the demethylase activity of FTO to improve graft function after older donor liver transplantation.
Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Coenzima A Ligasas , Ferroptosis , Hígado , Receptores de Transferrina , Daño por Reperfusión , Regulación hacia Arriba , Daño por Reperfusión/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Animales , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Ferroptosis/genética , Hígado/metabolismo , Hígado/patología , Ratones , Receptores de Transferrina/metabolismo , Receptores de Transferrina/genética , Masculino , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Ratones Endogámicos C57BL , Humanos , Trasplante de Hígado , Estabilidad del ARN/genética , Antígenos CDRESUMEN
Hepatic ischemia-reperfusion injury (HIRI) is a prevalent issue during liver resection and transplantation, with currently no cure or FDA-approved therapy. A promising drug, Cyclosporin A (CsA), ameliorates HIRI by maintaining mitochondrial homeostasis but has systemic side effects due to its low bioavailability and high dosage requirements. This study introduces a biomimetic CsA delivery system that directly targets hepatic lesions using mesenchymal stem cell (MSC) membrane-camouflaged liposomes. These hybrid nanovesicles (NVs), leveraging MSC-derived proteins, demonstrate efficient inflammatory chemotaxis, transendothelial migration, and drug-loading capacity. In a HIRI mouse model, the biomimetic NVs accumulated at liver injury sites entered hepatocytes, and significantly reduced liver damage and restore function using only one-tenth of the CsA dose typically required. Proteomic analysis verifies the protection mechanism, which includes reactive oxygen species inhibition, preservation of mitochondrial integrity, and reduced cellular apoptosis, suggesting potential for this biomimetic strategy in HIRI intervention.