👤 Arian Saffari

Symptomatic neuromas result from disorganized nerve growth at the site of amputation, causing pain that affects recovery and quality of life. In patients with diabetes mellitus (DM), nerve regeneration is impaired, compounded by comorbidities such as obesity, hypertension, and hyperlipidemia. Surgical approaches including targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) have shown promise for managing symptomatic neuroma, but their effectiveness in diabetic patients is uncertain due to unique challenges in nerve regeneration. This narrative review explores the protective effects of DM on symptomatic neuroma formation and to evaluate the implications for surgical intervention. A systematic search of PubMed was conducted, and relevant studies discussing symptomatic neuroma formation in amputees were included. Symptomatic neuromas were reported in 9.5-50% of amputees involving 9.5% of upper extremity, and 3.8% of lower extremity amputees. Younger age and proximal amputations were identified as significant risk factors. While it is suggested that Interleukin (IL)-10 and brain-derived neurotropic factor (BDNF) levels are involved in protecting against symptomatic neuroma formation, IL-1β and IL-6 promote neuroma formation. Although evidence is mixed, some evidence suggests that DM and diabetic peripheral neuropathy decrease symptomatic neuroma formation by impairing axonal regeneration, altering the extracellular matrix and modulating inflammatory responses. Although surgical approaches such as TMR and RPNI have shown potential in reducing neuroma-related pain, further studies are needed to ensure that this benefit extends to diabetic patients whose disease puts them at increased risk of postoperative complications. Additional studies are required to confirm these findings and optimize surgical strategies for high-risk patient populations. Show less

Redox active ultrafine particles (UFP, d < 0.2 μm) promote vascular oxidative stress and atherosclerosis. Notch signaling is intimately involved in vascular homeostasis, in which forkhead box O1 (FOXO1) acts as a co-activator of the Notch activation complex. We elucidated the importance of FOXO1/Notch transcriptional activation complex to restore vascular regeneration after UFP exposure. In a zebrafish model of tail injury and repair, transgenic Tg(fli1:GFP) embryos developed vascular regeneration at 3 days post amputation (dpa), whereas UFP exposure impaired regeneration (p < 0.05, n = 20 for control, n = 28 for UFP). UFP dose dependently reduced Notch reporter activity and Notch signaling-related genes (Dll4, JAG1, JAG2, Notch1b, Hey2, Hes1; p < 0.05, n = 3). In the transgenic Tg(tp1:GFP; flk1:mCherry) embryos, UFP attenuated endothelial Notch activity at the amputation site (p < 0.05 vs. wild type [WT], n = 20). A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) inhibitor or dominant negative (DN)-Notch1b messenger RNA (mRNA) disrupted the vascular network, whereas notch intracellular cytoplasmic domain (NICD) mRNA restored the vascular network (p < 0.05 vs. WT, n = 20). UFP reduced FOXO1 expression, but not Master-mind like 1 (MAML1) or NICD (p < 0.05, n = 3). Immunoprecipitation and immunofluorescence demonstrated that UFP attenuated FOXO1-mediated NICD pull-down and FOXO1/NICD co-localization, respectively (p < 0.05, n = 3). Although FOXO1 morpholino oligonucleotides (MOs) attenuated Notch activity, FOXO1 mRNA reversed UFP-mediated reduction in Notch activity to restore vascular regeneration and blood flow (p < 0.05 vs. WT, n = 5). Innovation and Conclusion: Our findings indicate the importance of the FOXO1/Notch activation complex to restore vascular regeneration after exposure to the redox active UFP. Antioxid. Redox Signal. 28, 1209-1223. Show less