Autologous Platelet-Rich Gel Accelerates Diabetic Wound Healing Through Inhibition of Ferritinophagy.

Aims: The objective was to examine the efficacy of autologous platelet-rich gel (APG) in treating diabetic wound and investigate the association between APG and ferritinophagy. Methods: A total of 32 patients with diabetic foot (DF) and Wagner grade 1 to 2 were included. Within the APG group, individuals with DF received weekly APG treatment. In the non-APG group, DF patients received daily dressing changes. Flow cytometry quantified the proportion of endothelial progenitor cells (EPCs) in peripheral blood on days 0 and 10. The diabetic rat model was induced using Streptozotocin. Two circular skin wounds were created on the backs of rats. The normal glucose group received daily dressing changes on the wound. In the diabetic group, the left wound underwent daily dressing changes, whereas the right wound was treated with APG once a week. CD34 levels were tested 7 days after the skin damage. The levels of glutathione peroxidase 4 (GPX4), Nuclear Receptor Coactivator 4 (NCOA4), Light chain 3 (LC3), and Masson staining were quantified on 14 days. The wound area and wound healing rate were separately measured at 0 and 14 days after the injury, regardless of DF patients or diabetic rats. Results: The wound healing rate was higher in the APG group than in the non-APG group, regardless of DF patients or diabetic rats. The APG group had a greater ΔEPCs% in DF patients than the non-APG group. Regarding rat experiment, the APG group exhibited lower levels of NCOA4, and LC3 expressions and a shorter wound healing time. However, the APG group showed higher levels of CD34 expression, GPX4 protein, and collagen fibers than the non-APG group. Conclusions: Autologous platelet-rich gel accelerated the wound healing rate in diabetic populations and rats. Autologous platelet-rich gel promoted EPCs counts, collagen fiber volume, and vessel numbers. Autologous platelet-rich gel decreased LC3 and NCOA4 expression, but increased GPX4 protein expression. The possible mechanism was the inhibition of ferritinophagy.

Sex differences in symptom network structure of depression, anxiety, and self-efficacy among people with diabetes: a network analysis.

Aims: The present study aims to explore the relations between symptoms of depression and anxiety and self-efficacy among people with diabetes. At the same time, we also examined the sex difference between network structures. Methods: This study recruited 413 participants with diabetes, and they completed Generalized Anxiety Disorder Scale (GAD-7), Patient Health Questionnaire (PHQ-9), and the Self-efficacy for Diabetes (SED). Symptom network analysis and network comparison test were used to construct and compare the depression-anxiety symptom network models of the female and male groups. Finally, we conducted flow diagrams to explore the symptoms directly or indirectly related to self-efficacy. Results: The strongest edges in the depression-anxiety symptom networks are the edge between "GAD3" (Excessive worry) and "GAD4" (Trouble relaxing) and the edge between "PHQ1" (Anhedonia) and "PHQ4" (Energy) in the female and male groups, respectively. Most of the symptoms with the highest EI and bridge EI are related to worry and nervousness. Additionally, in the flow diagram of the female group, "PHQ6" (Guilt) has a high negative association with self-efficacy. Conclusion: Females with diabetes are more vulnerable to depression and anxiety. Interventions targeting key symptoms in the network may be helpful in relieving the psychological problems among people with diabetes.

Platelet-rich plasma promotes diabetic ulcer repair through inhibition of ferroptosis.

Background: Ferroptosis, a newly discovered form of cell death, can accumulation activates lipid peroxidation and excessive oxidative stress in a high glucose environment. These phenomena suggest there may be ferroptosis pathways in the pathological processes associated with diabetic ulcer (DU). Platelet-rich plasma (PRP) promotes the healing of DU wounds, which may be achieved by the regulation of ferroptosis pathways. Hence, the present study aimed to investigate this association and uncover the potential underlying mechanisms. Methods: Cell injury models induced by high glucose were constructed using EA.HY926 (vascular endothelial cells), HSF (fibroblasts), and rat DU models. The MDA, total ROS, total SOD content, the gene and protein expression of GPX4, SLC7A11, and ACSL4, and the expression levels of inflammatory cytokines IL-1ß, IL-10, and NLRP3 was subsequently used to evaluate the important role of ferroptosis in the pathological process of DU, and elucidating the molecular mechanism of PRP in ulcer repair. Results: The results show that compared with the DU control group, the healing rate of the dorsal ulcer wound in the PRP intervention group was accelerated, and the expression levels of inflammatory cytokines IL-1ß, IL-10, and NLRP3 in the granulation tissue of ulcer wounds was lower. Further, the expression levels of CD31 and VEGF were higher, the gene and protein expression levels of GPX4 and SLC7A11 were increased, the expression levels of ACSL4 were less, the SOD content was higher, and the MDA content was lower. Conclusions: In this study, ferroptosis was preliminarily verified in DUs at the cellular and animal levels, while PRP could inhibit ferroptosis and significantly improve the migration and regeneration ability of fibroblasts and vascular endothelial cells induced by high glucose.

AGEs-induced MMP-9 activation mediated by Notch1 signaling is involved in impaired wound healing in diabetic rats.

AIMS: To elucidate the relationship between advanced glycation end products (AGEs), Notch1 signaling, nuclear factor-kappa B (NF-κB), and matrix metalloproteinase-9 (MMP-9) in diabetic wound healing in vitro and in vivo. METHODS: We incubated primary keratinocytes with AGEs alone or AGEs along with γ-secretase inhibitor DAPT, and established diabetic rat wound model by intraperitoneal streptozotocin treatment. The Notch1 signaling components and MMP-9 expression were detected by qPCR, western blotting and gelatin zymography. RESULTS: The exposure of primary keratinocytes to AGEs led to a significant increase in Notch intracellular domain (NICD), Delta-like 4 (Dll4), and Hes1; however, Notch1 expression was inhibited by the RAGE siRNA. Furthermore, MMP-9 activation was up-regulated, secondary to AGEs treatment. In contrast, increased MMP-9 expression by AGEs-stimulation was eliminated after treatment with DAPT. NF-κB activation participated in the Notch1-modulated MMP-9 expression. Notably, in the diabetic animal model, inhibition of the Notch signaling pathway with DAPT attenuated NICD and MMP-9 overexpression, improved collagen accumulation, and ultimately accelerated diabetic wound healing. CONCLUSIONS: These findings identified that activation of the Notch1/NF-κB/MMP-9 pathway, in part, mediates the repressive effects of AGEs on diabetic wound healing and that targeting this pathway may be a potential strategy to improve impaired diabetic wound healing.