Increase of PCSK9 expression in diabetes promotes VEGFR2 ubiquitination to inhibit endothelial function and skin wound healing.

Diabetic foot ulcers (DFUs) are a serious vascular disease. Currently, no effective methods are available for treating DFUs. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid levels to promote atherosclerosis. However, the role of PCSK9 in DFUs remains unclear. In this study, we found that the expression of PCSK9 in endothelial cells (ECs) increased significantly under high glucose (HG) stimulation and in diabetic plasma and vessels. Specifically, PCSK9 promotes the E3 ubiquitin-protein ligase NEDD4 binding to vascular endothelial growth factor receptor 2 (VEGFR2), which led to the ubiquitination of VEGFR2, resulting in its degradation and downregulation in ECs. Furthermore, PCSK9 suppresses the expression and activation of AKT, endothelial nitric oxide synthase (eNOS), and ERK1/2, leading to decreased nitric oxide (NO) production and increased superoxide anion (O2._) generation, which impairs vascular endothelial function and angiogenesis. Importantly, using evolocumab to limit the increase in PCSK9 expression blocked the HG-induced inhibition of NO production and the increase in O2._ production, as well as inhibited the phosphorylation and expression of AKT, eNOS, and ERK1/2. Moreover, evolocumab improved vascular endothelial function and angiogenesis, and promoted wound healing in diabetes. Our findings suggest that targeting PCSK9 is a novel therapeutic approach for treating DFUs.

Global trends in publications regarding macrophages-related diabetic foot ulcers in the last two decades.

BACKGROUND: Diabetic foot ulcers (DFUs) are one of the most severe and popular complications of diabetes. The persistent non-healing of DFUs is the leading cause of ampu-tation, which causes significant mental and financial stress to patients and their families. Macrophages are critical cells in wound healing and perform essential roles in all phases of wound healing. However, no studies have been carried out to systematically illustrate this area from a scientometric point of view. Although there have been some bibliometric studies on diabetes, reports focusing on the investigation of macrophages in DFUs are lacking. AIM: To perform a bibliometric analysis to systematically assess the current state of research on macrophage-related DFUs. METHODS: The publications of macrophage-related DFUs from January 1, 2004, to December 31, 2023, were retrieved from the Web of Science Core Collection on January 9, 2024. Four different analytical tools: VOSviewer (v1.6.19), CiteSpace (v6.2.R4), HistCite (v12.03.07), and Excel 2021 were used for the scientometric research. RESULTS: A total of 330 articles on macrophage-related DFUs were retrieved. The most published countries, institutions, journals, and authors in this field were China, Shanghai Jiao Tong University of China, Wound Repair and Regeneration, and Aristidis Veves. Through the analysis of keyword co-occurrence networks, historical direct citation networks, thematic maps, and trend topics maps, we synthesized the prevailing research hotspots and emerging trends in this field. CONCLUSION: Our bibliometric analysis provides a comprehensive overview of macrophage-related DFUs research and insights into promising upcoming research.

Two-Step Conservative Surgery for Complicated Forms of Diabetes-Related Foot Osteomyelitis.

Diabetes-related foot osteomyelitis (DFO) is a common yet complex condition, often complicated by concurrent soft tissue infections (STIs). This study evaluates the efficacy of a two-step conservative surgical approach, hypothesizing that it offers comparable outcomes to a one-step procedure. Conducted on a cohort of 93 patients with DFO, the study categorized cases into two types: OM1 (osteomyelitis without STI) and OM2 (osteomyelitis with STI). OM2 was further subdivided into OM2a (early diagnosis) and OM2b (late diagnosis), with OM2 patients undergoing initial soft tissue debridement followed by elective bone surgery. The results indicated no significant differences in infection recurrence or amputation rates between the two surgical approaches, with recurrence observed in 20.7% of cases and amputations in 10.8%. The two-step procedure was associated with higher inflammatory responses and greater need for antibiotics and hospital admissions. However, these factors did not translate into increased recurrence or amputation compared to the one-step procedure. The study supports the two-step approach as a safe and effective method for managing complicated DFO cases, providing a viable alternative to immediate amputation or single-stage surgery. Despite some limitations, including regional specificity and potential underdiagnosis in late-diagnosed cases, the findings offer valuable insights for clinical management and suggest further research to refine treatment protocols. The study's strengths include confirmed histopathological diagnoses and consistent follow-up, reinforcing the validity of the two-step surgical approach for complex DFO treatment.

Sequence analysis of microbiota in clinical human cases with diabetic foot ulcers from China.

Background: Diabetic foot ulcers (DFU) seriously threaten the health and quality of life of patients. The microbiota is the primary reason for the refractory and high recurrence of DFU. This study aimed to determine the wound microbiota at different DFU stages. Methods: Wound samples were collected from 48 patients with DFU and divided into three phases: inflammatory (I, n = 49), proliferation (P, n = 22), and remodeling (R, n = 19). The wound samples obtained at different stages were then subjected to 16S rRNA gene sequencing. The number of operational taxonomic units (OTUs) in the different groups was calculated according to the criterion of 97 % sequence similarity. The diversity of the microbiota differentially presented bacterial taxa at the phylum and genus levels, and important phyla and genera in the different groups were further explored. Results: After sequencing, 3351, 925, and 777 OTUs were observed in groups I, P, and R, respectively, and 175 OTUs overlapped. Compared with the inflammatory stage, the α-diversity of wound microbiota at proliferation and remodeling stages was significantly decreased (P < 0.05). At the phylum level, Firmicutes, Proteobacteria, Actinobacteriota, and Bacteroidota were the dominant phyla, accounting for more than 90 % of all the phyla. At the genus level, Random Forest and linear discriminant analysis effect size analyses showed that Peptoniphilus, Lactobacillus, Prevotella, Veillonella, Dialister, Streptococcus, and Ruminococcus were the signature wound microbiota for the inflammatory stage; Anaerococcus, Ralstonia, Actinomyces, and Akkermansia were important species for the proliferation stage; and the crucial genera for the remodeling stage were Enterobacter, Pseudomonas, Sondgrassella, Bifidobacterium, and Faecalibacterium. Conclusions: There were significant differences in the composition and structure of the wound microbiota in patients with DFU at different stages, which may lay a foundation for effectively promoting wound healing in DFU.

Identification of CGNL1 as a diagnostic marker in fibroblasts of diabetic foot ulcers: Insights from single cell RNA sequencing and bulk sequencing data.

OBJECTIVES: This study aimed to explore the unique transcriptional feature of fibroblasts subtypes and the role of ferroptosis in diabetic foot ulcers (DFUs). METHODS: The GEO (Gene Expression Omnibus) was searched to obtain the DFUs single-cell and transcriptional datasets. After identifying cell types by classic marker genes, the integrated single-cell dataset was used to run trajectory inference, RNA velocity, and ligand-receptor interaction analysis. Next, bulk RNA-seq datasets of DFUs were analyzed to the key ferroptosis genes. RESULTS: Here, we profile 83529 single transcriptomes from the foot samples utilizing single-cell sequencing (scRNA-seq) data of DFU from GEO database and identified 12 cell types, with fibroblasts exhibiting elevated levels of ferroptosis activity and substantial cellular heterogeneity. Our results defined six main fibroblast subsets that showed mesenchymal, secretory-reticular, secretory-papillary, pro-inflammatory, myogenesis, and healing-enriched functional annotations. Trajectory inference and cell-cell communication analysis revealed two major cell fates with subpopulations of fibroblasts and altered ligand-receptor interactions. Bulk RNA sequencing data identified CGNL1 as a distinctive diagnostic signature in fibroblasts. Notably, CGNL1 positively correlated with pro-inflammatory fibroblasts. CONCLUSIONS: Overall, our analysis delineated the heterogeneity present in cell populations of DFUs, showing distinct fibroblast subtypes characterized by their own unique transcriptional features and enrichment functions. Our study will help us better understand DFUs pathogenesis and identifies CGNL1 as a potential target for DFUs therapies.

Capturing How the Accelerometer Measured Physical Activity Profile Differs in People with Diabetic Foot Ulceration.

Diabetic Foot Ulcers (DFUs) are a major complication of diabetes, with treatment requiring offloading. This study aimed to capture how the accelerometer-assessed physical activity profile differs in those with DFUs compared to those with diabetes but without ulceration (non-DFU). Participants were requested to wear an accelerometer on their non-dominant wrist for up to 8days. Physical activity outcomes included average acceleration (volume), intensity gradient (intensity distribution), the intensity of the most active sustained (continuous) 5-120 min of activity (MXCONT), and accumulated 5-120 min of activity (MXACC). A total of 595 participants (non-DFU = 561, DFU = 34) were included in the analysis. Average acceleration was lower in DFU participants compared to non-DFU participants (21.9 mg [95%CI:21.2, 22.7] vs. 16.9 mg [15.3, 18.8], p < 0.001). DFU participants also had a lower intensity gradient, indicating proportionally less time spent in higher-intensity activities. The relative difference between DFU and non-DFU participants was greater for sustained activity (MXCONT) than for accumulated (MXACC) activity. In conclusion, physical activity, particularly the intensity of sustained activity, is lower in those with DFUs compared to non-DFUs. This highlights the need for safe, offloaded modes of activity that contribute to an active lifestyle for people with DFUs.

From Novice to Mastery: Learning Curve and Efficacy Analysis of Short-Term Spinal Cord Stimulation for Diabetic Foot Ulcers.

BACKGROUND: To analyze the learning curve of novices in mastering short-term Spinal Cord Stimulation (st-SCS) for diabetic foot, evaluating the efficacy, safety, and difficulty of this technique. METHODS: A retrospective review of diabetic foot patients treated with st-SCS at our hospital was conducted. All procedures were performed by the same physician and patients were sequentially numbered according to the order of surgery. Learning curves were plotted using segmented linear regression and cumulative sum curves based on surgery duration. Patients were divided into two groups according to the inflection points on the learning curve: the learning group and the mastery group. Pre- and post-operative efficacy indicators were recorded and compared, along with general patient data, perioperative parameters, and incidence of complications. RESULTS: A total of 36 patients were included. Significant improvements were observed post-st-SCS in ulcer size (from 7.00 cm2 to 4.00 cm2), visual analog scale (from 7.00 to 3.00), foot temperature (from 30.06°C to 32.37°C), and pittsburgh sleep quality index (from 14.42 to 8.36) (P<0.05). The physician could proficiently perform st-SCS after 9 cases. Surgery time was significantly shorter in the mastery group (1-9 cases) compared to the learning group (10-36 cases) (28.04 vs 43.56 min, P<0.05). There were no significant differences between the two groups in baseline data, improvement in efficacy indicators, or complications (P>0.05). CONCLUSIONS: St-SCS is beneficial for wound healing, pain relief, improving peripheral circulation, and improving sleep quality. Surgeons can master this simple and safe technique in about nine cases.

[Development and Validation of a Risk Prediction Model for Prolonged Hospitalization in Patients With Diabetic Foot Ulcers]. / ç³–å°¿ç— è¶³æºƒç–¡æ‚£è€ ä½é™¢æ—¶é—´å»¶é•¿é£Žé™©é¢„æµ‹æ¨¡åž‹æž„å»ºåŠéªŒè¯.

Objective: To investigate the risk factors associated with prolonged hospitalization in patients diagnosed with diabetic foot ulcers (DFU), to develop a predictive model, and to conduct internal validation of the model. Methods: The clinical data of DFU patients admitted to West China Hospital, Sichuan University between January 2012 and December 2022 were retrospectively collected. The subjects were randomly assigned to a training cohort and a validation cohort at a ratio of 7 to 3. Hospital stays longer than 75th percentile were defined as prolonged length-of-stay. A thorough analysis of the risk factors was conducted using the training cohort, which enabled the development of an accurate risk prediction model. To ensure robustness, the model was internally validated using the validation cohort. Results: A total of 967 inpatients with DFU were included, among whom 245 patients were identified as having an extended length-of-stay. The training cohort consisted of 622 patients, while the validation cohort comprised 291 patients. Multivariate logistic regression analysis revealed that smoking history (odds ratio [OR]=1.67, 95% confidence interval [CI], 1.13 to 2.48, P=0.010), Wagner grade 3 or higher (OR=7.13, 95% CI, 3.68 to 13.83, P<0.001), midfoot ulcers (OR=1.99, 95% CI, 1.07 to 3.72, P=0.030), posterior foot ulcers (OR=3.68, 95% CI, 1.83 to 7.41, P<0.001), multisite ulcers (OR=2.91, 95% CI, 1.80 to 4.69, P<0.001), wound size≥3 cm2 (OR=2.00, 95% CI, 1.28-3.11, P=0.002), and white blood cell count (OR=1.11, 95% CI, 1.05 to 1.18, P<0.001) were associated with an increased risk of prolonged length of stay. Additionally, a nomogram was constructed based on the identified risk factors. The areas under the receiver operating characteristic (ROC) curves for both the training cohort and the validation cohort were 0.782 (95% CI, 0.745 to 0.820) and 0.756 (95% CI, 0.694 to 0.818), respectively, indicating robust predictive performance. Furthermore, the calibration plot demonstrated optimal concordance between the predicted probabilities and the observed outcomes in both the training and the validation cohorts. Conclusion: Smoking history, Wagner grade≥3, midfoot ulcers, posterior foot ulcers, multisite ulcers, ulcer area≥3 cm2, and elevated white blood cell count are identified as independent predictors of prolonged hospitalization. Therefore, it is imperative that clinicians conduct a comprehensive patient evaluation and implement appropriate diagnostic and therapeutic strategies to effectively shorten the length of stay for DFU patients.

Therapeutic Effect of Stem Cells from Different Sources on Diabetic Foot Ulcers: Systematic Review and Network Meta-Analysis.

AIM: To evaluate the efficacy of stem cell therapy from different sources on the ankle-brachial index, wound closure percentage, and wound closure time in the treatment of diabetic foot ulcers (DFUs). METHODS: A literature search was conducted in PubMed, Embase, Cochrane Library's Central Register of Controlled Trials, and Web of Science, extending through June 29, 2023. Quality evaluation was done using the Cochrane's bias risk assessment tool (RoB 2.0). Employing a Bayesian approach, the statistical computations was executed with the JAGS software, leveraging the gemtc 0.8-2 and rjags 4-10 libraries, within the R environment 4.1.2. The included interventions came from peripheral blood, bone marrow, placenta, umbilical cord blood, adipose tissue, or others. RESULT: A preliminary search identified 2286 articles, of which 23 randomized controlled trials met the inclusion criteria and were ultimately included. The analysis findings indicated that mesenchymal stem cells derived from the umbilical cord (HUCMSCs) led to a notable enhanced the ankle-brachial index in patients with DFUs compared to standard treatment (MD: 0.2; 95% CI [0.01, 0.36]). HUCMSCs were found to be the optimal therapeutic approach for enhancing the ankle-brachial index (SUCRA = 82.7%). Research on the wound closure percentage revealed that compared to platelet-rich plasma (PRP), processed microvascular tissue (PMVT), peripheral blood stem cells (PBSCs), microfragmented adipose tissue (MFAT), autologous bone marrow-derived stem cell therapy (ABMSCT), adipose-derived stem cells (ASCs), and dehydrated human umbilical cord allograft (EpiCord), Huoxue Shengji Decoction (HXSJD) + ABMSCT (H_Group_hematopoietic) significantly increased the wound closure percentage in DFU patients (P < 0.05). According to the SUCRA ranking, HXSJD + ABMSCT was the best therapeutic method to increase the percentage of wound closure (SUCRA = 93.8%). CONCLUSION: This study employed a network meta-analysis method, combining direct and indirect comparisons, to analyze the latest clinical data and concluded that umbilical cord mesenchymal stem cells and the combination of HXSJD + autologous bone marrow hematopoietic stem cell treatment as adjunctive therapies for DFUs may have beneficial effects. Future research needs to focus on this.

Mechanism and application of fibrous proteins in diabetic wound healing: a literature review.

Diabetic wounds are more complex than normal chronic wounds because of factors such as hypoxia, reduced local angiogenesis, and prolonged inflammation phase. Fibrous proteins, including collagen, fibrin, laminin, fibronectin, elastin etc., possess excellent inherent properties that make them highly advantageous in the area of wound healing. Accumulating evidence suggests that they contribute to the healing process of diabetic wounds by facilitating the repair and remodel of extracellular matrix, stimulating the development of vascular and granulation tissue, and so on. However, there is currently a lack of a comprehensive review of the application of these proteins in diabetes wounds. An overview of fibrous protein characteristics and the alterations linked to diabetic wounds is given in this article's initial section. Next is a summary of the advanced applications of fibrous proteins in the last five years, including acellular dermal matrix, hydrogel, foam, scaffold, and electrospun nanofibrous membrane. These dressings have the ability to actively promote healing in addition to just covering wounds compared to traditional wound dressings like gauze or bandage. Research on fibrous proteins and their role in diabetic wound healing may result in novel therapeutic modalities that lower the incidence of diabetic wounds and thereby enhance the health of diabetic patients.

Effect of Visible and Infrared Photobiomodulation on Diabetic Foot Ulcers.

Introduction: Diabetes is a highly prevalent disease worldwide. Despite routine treatments, there is no effective treatment approach for patients with diabetic foot ulcers (DFUs). A new approach to reduce complications and control DFU is low-level laser therapy (LLLT). In the present study, we evaluated the therapeutic effects of LLLT on the symptoms of DFU patients. Methods: Sixty diabetic patients with DFU were included in this randomized clinical trial and were randomly allocated into two groups of laser (n=30) and control (n=30) with signed written consent. The LLLT group underwent visible and infra-red laser therapy and conventional medical treatment, while the control group received only conventional medical treatment. The total laser irradiation sessions of the patients were 20 sessions, (three sessions a week) and each session lasted for 30 minutes over the entire surface of the wound. The power density per session for each laser was calculated to be 35.65 mW/cm2 with an energy density of 64.17 J/cm2. Results: The mean area of ulcers in the LLLT group reduced significantly (P<0.001) from 441.7±365.5 mm2 before LLLT to 163.9±213.9 mm2 from the baseline up to the last session of LLLT, indicating a 62.99% reduction in mean ulcer area. In the control group, the mean ulcer area did not change significantly. Wagner's classification of the patients in the LLLT group reduced to lower grades significantly (P<0.01), while the classification moved towards higher grades in the control group (P<0.08). Conclusion: In this study, we showed the effectiveness of LLLT in the reduction of the surface and depth of DFUs. The results documented that patients experienced significant improvements in the healing of their foot ulcers after laser therapy. It is recommended that the LLLT be considered as a non-invasive method for the treatment of DFU patients.

Molecular immunological mechanisms of impaired wound healing in diabetic foot ulcers (DFU), current therapeutic strategies and future directions.

Diabetic foot ulcer (DFU) is a foremost cause of amputation in diabetic patients. Consequences of DFU include infections, decline in limb function, hospitalization, amputation, and in severe cases, death. Immune cells including macrophages, regulatory T cells, fibroblasts and other damage repair cells work in sync for effective healing and in establishment of a healthy skin barrier post-injury. Immune dysregulation during the healing of wounds can result in wound chronicity. Hyperglycemic conditions in diabetic patients influence the pathophysiology of wounds by disrupting the immune system as well as promoting neuropathy and ischemic conditions, making them difficult to heal. Chronic wound microenvironment is characterized by increased expression of matrix metalloproteinases, reactive oxygen species as well as pro-inflammatory cytokines, resulting in persistent inflammation and delayed healing. Novel treatment modalities including growth factor therapies, nano formulations, microRNA based treatments and skin grafting approaches have significantly augmented treatment efficiency, demonstrating creditable efficacy in clinical practices. Advancements in local treatments as well as invasive methodologies, for instance formulated wound dressings, stem cell applications and immunomodulatory therapies have been successful in targeting the complex pathophysiology of chronic wounds. This review focuses on elucidating the intricacies of emerging physical and non-physical therapeutic interventions, delving into the realm of advanced wound care and comprehensively summarizing efficacy of evidence-based therapies for DFU currently available.

Evaluating the Efficacy of Topical Phenytoin in the Healing of Neuropathic Diabetic Foot Ulcers: A Comparative Study.

OBJECTIVE: This study aims to observe the outcomes of topical phenytoin treatment in healing neuropathic diabetic foot ulcers with mild infection and compare these outcomes with those obtained from conventional dressing methods. METHODS: A retrospective observational study was conducted by reviewing the medical records of patients with neuropathic diabetic foot ulcers treated at a tertiary care center from 2015 to 2020. Two groups were identified: (1) patients treated with topical phenytoin (for ulcers measuring less than 5 cm, a dosage of 100 mg was used; for ulcers measuring between 5 cm and 9 cm, a dosage of 150 mg was used; for ulcers measuring between 10 cm and 15 cm, a dosage of 200 mg was used; and for ulcers measuring greater than 15 cm, a dosage of 300 mg was used. The tablets were crushed and dispersed before administration) and (2) those were treated with conventional dressings (the conventional method includes wound wash with 0.9 normal saline and betadine solution with application of sterile gauze dressing). Data on wound healing rate, time to achieve complete healing, and recurrence rates were collected. RESULTS: The study included 120 patients, with 60 receiving topical phenytoin and 60 receiving conventional dressings. Preliminary findings indicated that the topical phenytoin group experienced a 27 (45%) reduction in ulcer size by week four, compared to a 15 (25%) reduction in the conventional group. The median time to complete healing was significantly shorter in the phenytoin group (eight weeks) compared to the conventional dressing group (12 weeks; p < 0.05). Additionally, granulation tissue appeared earlier in the phenytoin group, with an average onset of 10 days, compared to 18 days in the conventional group (p < 0.01). The incidence of ulcer recurrence was lower in the phenytoin group (6, 10%) compared to the conventional group (18, 30%; p < 0.05). CONCLUSIONS: Topical phenytoin demonstrated a promising enhancement in the healing of mildly infected neuropathic diabetic foot ulcers compared to conventional dressings. Further studies are recommended to substantiate these findings and explore the mechanisms underlying the observed benefits.

Analysis of factors influencing the recurrence of diabetic foot ulcers.

OBJECTIVE: The aim of this study is to investigate the factors influencing the recurrence of diabetic foot ulcers (DFU) and provide guidance for reducing the recurrence rate. METHODS: A total of 211 patients diagnosed with DFU who were hospitalized and discharged from the hospital from October 2015 to January 2020 were included as the study cohort. Participants were divided into two groups according to whether the foot ulcer recurred during the 2-year follow-up period: a recurrence group (n = 84) and a non-recurrence group (n = 127). The following data were collected and analyzed for the two groups of patients: general information, foot information, laboratory indicators, diabetes comorbidities, and complications. RESULTS: (1) The overall recurrence rate of diabetic foot ulcers (DFU) within 2 years was 39.8%, indicating a high recurrence rate. (2) Significant differences were observed between the two patient groups in terms of BMI, HbA1c, TBIL, CRP, financial situation, foot deformity, first ulcer on the sole of the foot, previous amputation history, Wagner grade of the first ulcer, osteomyelitis, DFU duration (>60 days), lower limb vascular reconstruction, peripheral arterial disease (PAD), and diabetic peripheral neuropathy (DPN) (t = 2.455; Z = -1.988, -3.731, -3.618; χ2 = 7.88, 5.004, 3.906, 17.178, 16.237, 5.007, 24.642, 4.782, 29.334, 10.253). No significant differences were found for the other indicators. (3) Logistic regression analysis revealed that TBIL (OR = 0.886, p = 0.036) was a protective factor against ulcer recurrence. In contrast, PAD, previous amputation history, DPN, and the first ulcer on the sole of the foot (OR = 3.987, 6.758, 4.681, 2.405; p < 0.05 or p < 0.01) were identified as risk factors for ulcer recurrence. CONCLUSION: Early screening and preventive education targeting high-risk factors such as DPN, PAD and the initial ulcer location on the sole of the foot are essential to mitigate the high long-term recurrence rate of DFU. Furthermore, the protective role of TBIL in preventing ulcer recurrence underscores the importance of monitoring bilirubin levels as part of a comprehensive management strategy for DFU patients.

Integrating bioinformatics and multiple machine learning to identify mitophagy-related targets for the diagnosis and treatment of diabetic foot ulcers: evidence from transcriptome analysis and drug docking.

Background: Diabetic foot ulcers are the most common and serious complication of diabetes mellitus, the high morbidity, mortality, and disability of which greatly diminish the quality of life of patients and impose a heavy socioeconomic burden. Thus, it is urgent to identify potential biomarkers and targeted drugs for diabetic foot ulcers. Methods: In this study, we downloaded datasets related to diabetic foot ulcers from gene expression omnibus. Dysregulation of mitophagy-related genes was identified by differential analysis and weighted gene co-expression network analysis. Multiple machine algorithms were utilized to identify hub mitophagy-related genes, and a novel artificial neural network model for assisting in the diagnosis of diabetic foot ulcers was constructed based on their transcriptome expression patterns. Finally, potential drugs that can target hub mitophagy-related genes were identified using the Enrichr platform and molecular docking methods. Results: In this study, we identified 702 differentially expressed genes related to diabetic foot ulcers, and enrichment analysis showed that these genes were associated with mitochondria and energy metabolism. Subsequently, we identified hexokinase-2, small ribosomal subunit protein us3, and l-lactate dehydrogenase A chain as hub mitophagy-related genes of diabetic foot ulcers using multiple machine learning algorithms and validated their diagnostic performance in a validation cohort independent of the present study (The areas under roc curve of hexokinase-2, small ribosomal subunit protein us3, and l-lactate dehydrogenase A chain are 0.671, 0.870, and 0.739, respectively). Next, we constructed a novel artificial neural network model for the molecular diagnosis of diabetic foot ulcers, and the diagnostic performance of the training cohort and validation cohort was good, with areas under roc curve of 0.924 and 0.840, respectively. Finally, we identified retinoic acid and estradiol as promising anti-diabetic foot ulcers by targeting hexokinase-2 (-6.6 and -7.2 kcal/mol), small ribosomal subunit protein us3 (-7.5 and -8.3 kcal/mol), and l-lactate dehydrogenase A chain (-7.6 and -8.5 kcal/mol). Conclusion: The present study identified hexokinase-2, small ribosomal subunit protein us3 and l-lactate dehydrogenase A chain, and emphasized their critical roles in the diagnosis and treatment of diabetic foot ulcers through multiple dimensions, providing promising diagnostic biomarkers and targeted drugs for diabetic foot ulcers.

Adipose-derived stem cells in diabetic foot care: Bridging clinical trials and practical application.

Diabetic foot ulcers (DFUs) pose a critical medical challenge, significantly im-pairing the quality of life of patients. Adipose-derived stem cells (ADSCs) have been identified as a promising therapeutic approach for improving wound healing in DFUs. Despite extensive exploration of the mechanical aspects of ADSC therapy against DFU, its clinical applications remain elusive. In this review, we aimed to bridge this gap by evaluating the use and advancements of ADSCs in the clinical management of DFUs. The review begins with a discussion of the classification and clinical management of diabetic foot conditions. It then discusses the current landscape of clinical trials, focusing on their geographic distribution, reported efficacy, safety profiles, treatment timing, administration techniques, and dosing considerations. Finally, the review discusses the preclinical strategies to enhance ADSC efficacy. This review shows that many trials exhibit biases in study design, unclear inclusion criteria, and intervention protocols. In conclusion, this review underscores the potential of ADSCs in DFU treatment and emphasizes the critical need for further research and refinement of therapeutic approaches, with a focus on improving the quality of future clinical trials to enhance treatment outcomes and advance the field of diabetic wound care.

Dehydrated Amnion Chorion Membrane versus standard of care for diabetic foot ulcers: a randomised controlled trial.

OBJECTIVE: Diabetic foot ulcers (DFUs) continue to challenge wound care practitioners. This prospective, multicentre, randomised controlled trial (RCT) evaluated the effectiveness of a dehydrated Amnion Chorion Membrane (dACM) (Organogenesis Inc., US) versus standard of care (SoC) alone in complex DFUs in a challenging patient population. METHOD: Subjects with a DFU extending into dermis, subcutaneous tissue, tendon, capsule, bone or joint were enrolled in a 12-week trial. They were allocated equally to two treatment groups: dACM (plus SoC); or SoC alone. The primary endpoint was frequency of wound closure determined by a Cox analysis that adjusted for duration and wound area. Kaplan-Meier analysis was used to determine median time to complete wound closure (CWC). RESULTS: The cohort comprised 218 patients, and these were split equally between the two treatment groups with 109 patients in each. A Cox analysis showed that the estimated frequency of wound closure for the dACM plus SoC group was statistically superior to the SoC alone group at week 4 (12% versus 8%), week 6 (22% versus 11%), week 8 (31% versus 21%), week 10 (42% versus 27%) and week 12 (50% versus 35%), respectively (p=0.04). The computed hazard ratio (1.48 (confidence interval: 0.95, 2.29) showed a 48% greater probability of wound closure in favour of the dACM group. Median time to wound closure for dACM-treated ulcers was 84 days compared to 'not achieved' in the SoC-treated group (i.e., ≥50% of SoC-treated DFUs failed to heal by week 12; p=0.04). CONCLUSION: In an adequately powered DFU RCT, dACM increased the frequency, decreased the median time, and improved the probability of CWC when compared with SoC alone. dACM demonstrated beneficial effects in DFUs in a complex patient population. DECLARATION OF INTEREST: This study was funded by Organogenesis Inc., US. JC serves as a consultant and speaker for Organogenesis. RDD serves as a speaker for Organogenesis. OMA and MLS serve as consultants for Organogenesis. The authors have no other conflicts of interest to declare.

Effect of Using Photobiomodulation (660 Nanometers) for the Treatment of Diabetic Ulcers: Protocol for a Randomized Controlled Trial.

Diabetic foot ulcers (DFUs) result in tissue damage or impairment of deeper structures that affect quality of life. The impacts are numerous, and even after a long treatment period, 65% of patients experience recurrence. Among the interventions used to accelerate the healing process of DFUs, photobiomodulation therapy (PBMT) is a painless, noninvasive, and low-cost treatment. To achieve effective therapeutic results optimal PBMT parameters are necessary. The positive effect of PBMT on diabetic cells may be dependent on fluence (J/cm2) and wavelength (nm). This double-blind, randomized clinical trial will be conducted at the University Clinic of Physical Therapy. One hundred patients will be randomly placed in 4 groups. A Laserpulse Ibramed (Helium-Neon, HeNe, 660 nm) with 20 W power will be used (continuous mode), with doses stipulated for each treatment group (GL1, 4 J/cm2; GL2, 8 J/cm2; GL3, 12 J/cm2) and Endophoton KLD GaAs 904 nm (ST, 10 J/cm2) for 2 nonconsecutive days per week for 10 weeks, for a total of 20 sessions. The primary outcomes will be ulcer healing rate and University of Texas classification scores. Patients' DFUs will be assessed on the 1st day, 5 weeks, and 10 weeks of treatment then 1 month after the end of treatment. This study may aid effective clinical decision-making for the management of DFUs.

Diabetic Foot Osteomyelitis in Patients with and without Peripheral Arterial Disease: Two Different Diseases?

The aim of the current study was to evaluate the outcomes of patients with diabetic foot osteomyelitis (DFO), comparing subjects with and without peripheral arterial disease (PAD). The study is a prospective study including a population of patients affected by a DFO located in the forefoot. All patients were managed by a surgical conservative approach defined by the removal of the infected bone, in association with the antibiotic therapy. Patients were divided into two groups: those with PAD (neuro-ischaemic DFO) and those without (neuropathic DFO). After 1 year of follow-up, the following outcome were evaluated and compared between groups: healing, healing time, minor amputation, major amputation, hospitalization, need for surgical re-intervention. Overall, 166 patients were included, 87(52.4%) of them had neuro-ischaemic DFO and 79 (47.6%) neuropathic DFO. Patients with neuro-ischaemic DFO in comparison to neuropathic DFO were older (72.5 ± 9 vs 64.1 ± 15.5 years, P < .0001), had longer diabetes duration (21.8 ± 5.6 vs 16.4 ± 7.6 years, P < .0001), higher rate of dialysis (13.8 vs 1.3%, P = .001) and ischaemic heart disease (79.3 vs 12.7%, P < .0001). Outcomes for neuro-ischaemic DFO and neuropathic DFO were: healing (96.5 vs 97.5%, P = .7), healing time (7.8 ± 6.2 vs 5.7 ± 3.7 weeks, P = .01), minor amputation (16.1 vs 3.8%, P = .006), major amputation (0 vs 0%, ns), hospitalization (90.8 vs 51.9%, P < .0001), surgical re-intervention (14.9 vs 8.8%, P = .004) respectively. In addition, PAD resulted in an independent predictor of minor amputation, hospitalization, and surgical re-intervention. DFO in patients with PAD was characterized by longer healing time, more cases of minor amputation, hospitalization, and surgical re-intervention. PAD independently predicted the risk of minor amputation, hospitalization, and surgical re-intervention, while it was not associated with the healing rate.

Texture differences of microchambers and macrochambers in heel pads between the elderly with and without diabetes.

OBJECTIVE: This study aims to use the texture analysis of ultrasound images to distinguish the features of microchambers (a superficial thinner layer) and macrochambers (a deep thicker layer) in heel pads between the elderly with and without diabetes, so as to preliminarily explore whether texture analysis can identify the potential injury characteristics of deep tissue under the influence of diabetes before the obvious injury signs can be detected in clinical management. METHODS: Ultrasound images were obtained from the right heel (dominant leg) of eleven elderly people with diabetes (DM group) and eleven elderly people without diabetes (Non-DM group). The TekScan system was used to measure the peak plantar pressure (PPP) of each participant. Six gray-level co-occurrence matrix (GLCM) features including contrast, correlation, dissimilarity, energy, entropy, homogeneity were used to quantify texture changes in microchambers and macrochambers of heel pads. RESULTS: Significant differences in GLCM features (correlation, energy and entropy) of macrochambers were found between the two groups, while no significant differences in all GLCM features of microchambers were found between the two groups. No significant differences in PPP and tissue thickness in the heel region were observed between the two groups. CONCLUSIONS: In the elderly with diabetes who showed no significant differences in PPP and plantar tissue thickness compared to those without diabetes, several texture features of ultrasound images were found to be significantly different. Our finding indicates that texture features (correlation, energy and entropy) of macrochambers could be used for early detection of soft tissue damage associated with diabetes.