Foot ulcers are one of the most common and severe complication of diabetes mellitus with significant resultant morbidity and mortality. Multiple factors impair wound healing include skin injury, diabetic neuropathy, ischemia, infection, inadequate glycemic control, poor nutritional status, and severe morbidity. It is currently believed that oxidative stress plays a vital role in diabetic wound healing. An imbalance of free radicals and antioxidants in the body results in overproduction of reactive oxygen species which lead to cell, tissue damage, and delayed wound healing. Therefore, decreasing ROS levels through antioxidative systems may reduce oxidative stress‐induced damage to improve healing. In this context, we provide an update on the role of oxidative stress and antioxidants in diabetic wound healing through following four perspectives. We then discuss several therapeutic strategies especially dietary bioactive compounds by targeting oxidative stress to improve wounds healing.

Small interfering RNA (siRNA) is a potential method of gene silencing to target specific genes. Although the U.S. Food and Drug Administration (FDA) has approved multiple siRNA-based therapeutics, many biological barriers limit their use for treating diseases. Such limitations include challenges concerning systemic or local administration, short half-life, rapid clearance rates, nonspecific binding, cell membrane penetration inability, ineffective endosomal escape, pH sensitivity, endonuclease degradation, immunological responses, and intracellular trafficking. To overcome these barriers, various strategies have been developed to stabilize siRNA, ensuring their delivery to the target site. Chemical modifications implemented with nucleotides or the phosphate backbone can reduce off-target binding and immune stimulation. Encapsulation or formulation can protect siRNA from endonuclease degradation and enhance cellular uptake while promoting endosomal escape. Additionally, various techniques such as viral vectors, aptamers, cell-penetrating peptides, liposomes, and polymers have been developed for delivering siRNA, greatly improving their bioavailability and therapeutic potential.

Sphingosine-1-phosphate (S1P), a key regulator of vascular homeostasis and angiogenesis, is enriched in exosomes derived from platelet-rich plasma (PRP-Exos). However, the potential role of PRP-Exos-S1P in diabetic wound healing remains unclear. In this study, we investigated the underlying mechanism of PRP-Exos-S1P in diabetic angiogenesis and wound repair. Exosomes were isolated from PRP by ultracentrifugation and analysed by transmission electron microscopy, nanoparticle tracking analysis and western blotting. The concentration of S1P derived from PRP-Exos was measured by enzyme-linked immunosorbent assay. The expression level of S1P receptor1–3 (S1PR1–3) in diabetic skin was analysed by Q-PCR. Bioinformatics analysis and proteomic sequencing were conducted to explore the possible signalling pathway mediated by PRP-Exos-S1P. A diabetic mouse model was used to evaluate the effect of PRP-Exos on wound healing. Immunofluorescence for cluster of differentiation 31 (CD31) was used to assess angiogenesis in a diabetic wound model. In vitro, PRP-Exos significantly promoted cell proliferation, migration and tube formation. Furthermore, PRP-Exos accelerated the process of diabetic angiogenesis and wound closure in vivo. S1P derived from PRP-Exos was present at a high level, and S1PR1 expression was significantly elevated compared with S1PR2 and S1PR3 in the skin of diabetic patients and animals. However, cell migration and tube formation were not promoted by PRP-Exos-S1P in human umbilical vein endothelial cells treated with shS1PR1. In the diabetic mouse model, inhibition of S1PR1 expression at wounding sites decreased the formation of new blood vessels and delayed the process of wound closure. Bioinformatics analysis and proteomics indicated that fibronectin 1 (FN1) was closely related to S1PR1 due to its colocalization in the endothelial cells of human skin. Further study supported that FN1 plays an important role in the PRP-Exos-S1P-mediated S1PR1/protein kinase B signalling pathway. PRP-Exos-S1P promotes angiogenesis in diabetic wound healing via the S1PR1/protein kinase B/FN1 signalling pathway. Our findings provide a preliminary theoretical foundation for the treatment of diabetic foot ulcers using PRP-Exos in the future.

Diabetic foot ulcer (DFU) is one of the most serious and alarming diabetic complications, which often leads to high amputation rates in diabetic patients. Machine learning is a part of the field of artificial intelligence, which can automatically learn models from data and better inform clinical decision‐making. We aimed to develop an accurate and explainable prediction model to estimate the risk of in‐hospital amputation in patients with DFU. A total of 618 hospitalised patients with DFU were included in this study. The patients were divided into non‐amputation, minor amputation or major amputation group. Light Gradient Boosting Machine (LightGBM) and 5‐fold cross‐validation tools were used to construct a multi‐class classification model to predict the three outcomes of interest. In addition, we used the SHapley Additive exPlanations (SHAP) algorithm to interpret the predictions of the model. Our area under the receiver‐operating‐characteristic curve (AUC) demonstrated a 0.90, 0.85 and 0.86 predictive ability for non‐amputation, minor amputation and major amputation outcomes, respectively. Taken together, our data demonstrated that the developed explainable machine learning model provided accurate estimates of the amputation rate in patients with DFU during hospitalisation. Besides, the model could inform individualised analyses of the patients' risk factors.

Insulin resistance (IR) correlates closely with cardiovascular disease. C1q/TNF-related protein-3 (CTRP3) is a novel adipokine that modulates insulin activity in various diseases. This study investigated the relationship between CTRP3 and IR as well as systemic inflammation in newly diagnosed obese and hypertensive patients (NCT02226471). Serum CTRP3 levels, anthropometric, inflammatory and metabolic parameters were measured in 180 obesity and essential hypertensive patients and in 66 normal weight, normotensive subjects. The serum CTRP3 levels in the obesity group were lower than those in the NW group; these levels were also lower in hypertensive subjects than in normotensive subjects. After adjusting for gender, systolic blood pressure (SBP) and diastolic blood pressure (DBP), a modestly linear relationship was observed between CTRP3 and waist circumference (WC) (r = -0.168, p = 0.009), waist-to-hip ratio (WHR) (r = -0.183, p = 0.004), homeostasis model assessment of IR (HOMA-IR) (r = -0.264, p = 0.000), triglycerides (TG) (r = -0.136, p = 0.034), fasting blood glucose (FBG) (r = -0.155, p = 0.016), fasting insulin (FINS) (r = -0.248, p = 0.000) and homeostasis model assessment of β-cell insulin secretion (HOMA-β) (r = -0.128, p = 0.047). Multiple stepwise regression analysis revealed that gender, DBP and HOMA-IR were independently associated with serum CTRP3 levels. CTRP3 was an independent factor affecting blood pressure and IR, and may play an important role in the pathogenesis of obesity and hypertension.