Effective application of an innovative acemannan-enriched glycolipid sphere dressing in diabetic foot ulcer wound healing: A case report and review of literature

Background Diabetic foot ulcers (DFUs) are a common and serious complication of diabetes, often leading to amputation and decreased quality of life. Current treatment methods have limited success rates, highlighting the need for new approaches. This study investigates the potential of tibial transverse transport (TTT) to promote wound healing in DFUs. Methods To test this hypothesis, the study used New Zealand White rabbits to establish a diabetic model and simulate foot ulcers, followed by the treatment of unilateral TTT or bilateral TTT. The study employed histological analysis, flow cytometry, ELISA, and qPCR to assess the impact of TTT on tissue repair and endothelial progenitor cell (EPC) mobilization and homing, aiming to understand the underlying biological processes in wound healing. Results TTT significantly enhanced wound healing in diabetic rabbit foot ulcers. Specifically, bilateral TTT led to complete wound healing by day 19, faster than the unilateral TTT group, which healed by day 26, and the sham operation group, which nearly healed by day 37. Histological analysis showed improved tissue architecture, collagen deposition, and neovascularization in TTT-treated groups. Furthermore, TTT treatment resulted in a significant increase in VEGFR2 expression and VEGFR2/Tie-2 positive cells, particularly in the bilateral group. These findings were corroborated by qPCR results, which showed increased expression of VEGFA and CXCL12 by TTT. Conclusions: TTT may be a promising treatment for DFUs, significantly enhancing wound healing by stimulating EPC mobilization and homing mediated angiogenesis. This novel approach could substantially improve treatment outcomes for diabetic patients with chronic foot ulcers.

Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that can result in severe consequences. The cost of treating DFUs is high, and there is a lack of new therapies available in developing countries. This has created a demand for complementary and alternative treatments. The objective of this study was to assess the impact of aloe vera gel on the healing process of diabetic foot ulcers. The study was a double-blind, randomized, controlled clinical trial. The study samples were 66 patients with diabetic foot ulcers who were randomly assigned to two groups (intervention and control). All ulcers in both groups were washed with normal saline and dressed in sterile gauze. The ulcers in the intervention group were covered with a thin layer of Aloe Vera gel before the dressing. The Bates-Jensen Wound Assessment Tool (BWAT) was used on three occasions, including before the intervention period and at the end of each week. Data were analyzed using SPSS 16. After three weeks, there was a notable contrast in the recovery pattern of the two groups. The patients who had aloe vera gel added to their dressing showed a more substantial decrease in the mean scores of their BWAT. These findings are promising and suggest that Aloe vera may be a safe and effective adjunctive treatment for diabetic foot ulcers. However, further research is needed to confirm these results and to investigate the underlying mechanisms of aloe vera's therapeutic effect on diabetic foot ulcers.

The non-healing of diabetic foot ulcers (DFU) is a major cause of high disability, morbidity, and mortality. Thus, new therapeutic targets and methods to help healing in patients with DFUs are major research hotspots. This study examined the molecular differences between healing and non-healing DFUs to identify genes associated with DFU healing. Differentially expressed genes (DEGs) were identified by bioinformatics. Samples were collected from patients with healing (n=10) and non-healing (n=10) DFUs from September 2021 to September 2022. Interleukin (IL)-34 expression was measured by ELISA and qRT-PCT. The fibroblasts from healing and non-healing DFU were divided according to their gene signatures and subdivided based on their gene expression profile differences. A comparison of fibroblast subpopulation characteristics revealed that the proportion of subpopulation 4 was significantly higher in non-healing DFUs than in healing DFUs. Subpopulation 4 had 254 upregulated genes and 2402 downregulated genes in the non-healing compared with the healing DFUs. The DEGs were involved in several biological functions, including cytokine activity, receptor-ligand activity, signaling receptor activator activity, and receptor regulator activity. IL-34 was downregulated in non-healing compared with healing DFUs, suggesting a possible role of IL-34 in DFU healing. In the clinical specimens, IL-34 was significantly downregulated in non-healing DFUs, consistent with the bioinformatics results. IL-34 expression is downregulated in non-healing DFU. IL-34 appears to be involved in DFU healing, but the exact causal relationship remains to be explored.

Background: A common and complicated side effect of diabetes is diabetic foot ulcers (DFUs), which frequently lead to chronic wounds that are challenging to heal. Another technique that has gained interest is low-level laser therapy (LLLT), which speeds up the healing of diabetic foot ulcers. The purpose of this systematic review is to evaluate how well LLLT aids in the healing of diabetic foot ulcers that are chronic. Purpose: To assess the effects of low-level laser therapy on the healing of diabetic foot ulcers, particularly with regard to ulcer size reduction, pain relief, and overall wound healing. Method: A comprehensive search for English-language full-text studies published between 2015 and 2024 was conducted across a number of databases, including PubMed, ScienceDirect, and Google Scholar. Randomized controlled trials that assessed the impact of LLLT on diabetic foot ulcers are required for inclusion. Measurements of wound size, ulcer healing progress, and pain reduction were used to analyze the results. Results: The analysis includes seven studies that consistently showed benefits from using LLLT. Significant decreases in ulcer size, better tissue repair, and when comparing the treated groups to the control groups, pain relief was seen. Although different laser parameters, such as wavelengths and dosages, were reported in the research, all of them shown positive outcomes in terms of speeding up wound healing and lowering pain levels related to diabetic foot ulcers. Conclusion: Low-level laser therapy is a useful supplementary technique for promoting the healing of diabetic foot ulcers. Patients with chronic diabetic foot ulcers benefit from LLLT by experiencing less pain, faster wound healing, and an overall higher quality of life. To ascertain the optimal laser parameters and assess the long-term efficacy of LLLT in the management of diabetic wounds, more extensive research is necessary.

LncRNA GAS5 activates the HIF1A/VEGF pathway by binding to TAF15 to promote wound healing in diabetic foot ulcers

Diabetes has long been recognized as a significant global public health burden, with its complications posing serious threats to patient health and survival. Diabetic foot ulcer (DFU) is a common and severe complication of diabetes, and its prognosis is closely associated with diabetic foot infection. Diabetic foot infections (DFI) can lead to chronic, non-healing wounds and, in severe cases, may necessitate amputation. Microbial infection, the primary form of diabetic foot infections, disrupts the inflammatory and proliferative phases of DFU wound healing by forming biofilms and expressing virulence factors, ultimately contributing to the chronicity of DFU. Despite extensive research on DFU treatment, effective management remains a significant challenge due to its high susceptibility to microbial infection and frequent recurrence. This review integrates microbial infections with the physiological processes of wound healing to systematically elucidate the major pathogenic microorganisms associated with diabetic foot infections and their key pathogenic mechanisms in the healing process. In addition, we summarize current strategies for both systematic and individualized management of DFU. From etiology and pathological mechanisms to clinical treatment, this review provides new insights into the pathological mechanisms underlying chronic DFU and offers valuable guidance for clinical practice and scientific research.

Numerous studies have confirmed that ginsenoside Rg1 can promote wound healing in diabetic foot ulcers (DFU), yet the underlying mechanisms remain unclear. This study aimed to investigate the function of miR-155 in Rg1-mediated DFU wound healing and its regulatory mechanism. A DFU mouse model was established, and wound healing was assessed using macroscopic observation and HE staining. The oxidative stress level was evaluated by ELISA and immunohistochemistry assays. In vitro, ELISA, RT-qPCR, CCK-8, transwell migration, and tube formation assays were used to evaluate oxidative stress, wound closure, and angiogenesis in high glucose (HG)-induced HUVECs, respectively. Dual luciferase-reporter assay determined the interaction between miR-155-5p and E2F2. Here, we observed that Rg1 dramatically promoted angiogenesis and alleviated oxidative stress in the DFU mouse model and HG-induced HUVECs, thus accelerating wound healing. Importantly, miR-155-5p was proved to be upregulated in DFU wound tissues and HG-induced HUVECs, and overexpression of miR-155-5p remarkably impaired angiogenesis and stimulated oxidative stress in Rg1-administrated DFU mice and HG-induced HUVECs. Moreover, E2F2, a transcriptional activator of CDCA7L, was a direct downstream target of miR-155-5p. Rescue experiments showed that the reverse roles of miR-155-5p upregulation on Rg1-mediated oxidative stress repression and angiogenesis were obviously diminished by E2F2 downregulation. Overall, our data revealed for the first time that Rg1 promoted wound healing in DFU via regulating miR-155-5p/E2F2/CDCA7L axis, which demonstrated a novel underlying mechanism of Rg1 in the treatment of DFU and provided some novel target for DFU therapy.

Diabetes mellitus can cause microvascular and macrovascular complications. Diabetic foot ulcer is the complications that often occur in DM patients, which is as much as 10%-25%. In Indonesia, the incidence of diabetic foot ulcers is 12% and DM patients can be at risk of diabetic foot ulcers as much as 55.4%. The mortality rate that occurs as a result of diabetic foot ulcers can reach around 15-30%. Patients who have diabetic foot ulcers significantly decreased vitamin D levels. This study aims to determine the effectiveness of vitamin D supplementation for wound healing in diabetic foot ulcers.

To investigate the relationship between small non-coding RNA-204-3p (miR-204-3p) and the onset and wound healing of diabetic foot ulcers (DFU) and the underlying molecular mechanism, sixty four newly diagnosed patients with T2DM without DFU (T2DM group), 82 T2DM patients with DFU (DFU group), and 60 controls with normal glucose tolerance (NC group) were included. Quantitative real-time PCR (qRT-PCR) method was used to determine miR-204-3p expression levels in peripheral blood and wound margin tissue of subjects, and to analyse the relationship between the expression of miR-204-3p and wound healing. In vitro experiments were also performed to understand the effect of miR-204-3p on high glucose induced injury of HaCaT cells (human keratinocytes). The results showed that miR-204-3p expression level of peripheral blood in the T2DM group was marked lower than that in the NC group [2.38 (1.31-5.04) vs 3.27 (1.51-6.98)] (P < .05). Similarly, the miR-204-3p expression level of peripheral blood in the DFU group was significantly lower than the T2DM group [1.15 (0.78-2.89) vs 2.38 (1.31-5.04)] (P < .01). The expression level of miR-204-3p in peripheral blood and wound margin tissues of DFU patients was positively correlated with the healing rate of foot ulcers after 8 weeks (P < .05). Multifactorial logistic regression analysis showed that decreased expression of miR-204-3p in peripheral blood was an independent risk factor for DFU (OR=2.95, P < .05). The results of in vitro experiments showed that miR-204-3p could improve the proliferation and migration of HKC cells and reduce the proportion of apoptosis of HKC cells by targeted regulation of zinc finger protein Kruppel like factor 6 (KLF6) in high glucose environment. Therefore, the decreased expression of miR-204-3p in peripheral blood and wound tissue of T2DM patients is closely related to the occurrence and poor wound healing of DFU. The down-regulated expression of miR-204-3p can reduce its ability to antagonise the functional damage of keratinocytes induced by high-glucose conditions. These results will provide potential targets for the treatment of DFU.

Objective To evaluate the safety and effectiveness of application of human amniotic membrane on the treatment of diabetic foot ulcer. Methods Databases including Cochrane Central Register of Controlled Trails, PubMed, Embase, OVID, CBMDisc, CNKI, Chinese VIP Database and WANFANG Database were applied and proceedings of the American Diabetes Association were manually retrieved to select randomized controlled trials over application of human amniotic membrane on the treatment of diabetic foot ulcer published until February 2017. The bibliographies of retrieved articles were also retrieved. Two researchers selected studies according to inclusion and exclusion criteria, extracted related data, and conducted Meta-analysis by RevMan5.3 statistical software independently. Results Totally 9 studies containing 595 patients with diabetic foot ulcer were included. Meta-analysis showed: (1) Diabetic foot ulcer healing rate: Human amniotic membrane was superior to conventional treatment [71.38% (212/297) vs 28.19% (84/298) , RR=2.54, 95%CI: 2.10-3.07, P<0.001]. (2) Diabetic foot ulcer healing time: Human amniotic membrane was superior to conventional treatment (SMD=-0.97, 95%CI: -1.38--0.56, P<0.001). (3) Area reduction rate of diabetic foot ulcer: Two studies showed that human amniotic membrane might had the effect of improving the area of ulcer reduction rate (P<0.001) . (4) Complications: No patient in these trials had complications or side effect associated with human amniotic membrane. Conclusion According to the Meta-analysis of the 9 studies, human amniotic membrane dressing is effective and safe in the treatment for diabetic foot ulcer, but further studies are needed. Key words: Diabetic foot; Foot ulcer; Biological dressings; Meta-analysis

Objective: To highlight the relationship between miR-503 and wound healing of diabetic foot ulcer (DFU). Methods: Microarray analysis was used to detect the dysregulated miRNAs between the DFU tissues and normal tissues. The expression of miR-503 in tissues and serum of patients with DFU was detected by qRT-PCR technique. Then, CCK-8 assay was applied to determine the cell proliferation. TUNEL assay was used for assessing the apoptosis of cells after treatment with miR-503. Possible correlation between miR-503 and fbillin1 (FBN1) was predicted according to data accessed on RNA22 website online, and was detected for confirmation by luciferase reporter assay. Results: Microarray analysis showed that miR- 503 was significantly decreased in the DFU tissues compared with normal tissues. While marked increase in the expression of miR-503 in tissues and serum of patients with DFU was confirmed by qRT-PCR technique. Then, CCK-8 assay indicated that transfection of miR- 503 mimic obviously accelerated the cell proliferation. However, TUNEL assays suggested that miR-503 mimic inhibited the apoptosis of cells to improve the survival of fibroblasts. Besides, miR-503 AMO played a role in fibroblasts of DFU tissues exactly countering to miR-503 mimic treatment. It was predicted that MiR-503 is a complementary to the FBN1 by RNA22. Besides, SiRNA-FBN1 promoted the proliferation, but brought down the apoptosis of fibroblasts. Conclusions: MiR-503 regulates the function of fibroblasts and wound healing of patients with DFU by targeting FBN1 directly which provids a novel and critical target for diagnosis and treatment of DFU.

To investigate the relationship between small noncoding microRNA-103 (miR-103) and wound healing of diabetic foot ulcers (DFU) and the underlying molecular mechanism, forty type 2 diabetes mellitus with DFU (DFU group), and 20 patients with a chronic skin ulcer of lower limbs and normal glucose tolerance (SUC group) were included. Quantitative real-time PCR method was used to determine miR-103 expression levels in the wound margin tissue of subjects, and to analyse the relationship between the expression of miR-103 and DFU wound healing. In vitro experiments were also performed to understand the effect of miR-103 on the high glucose-induced injury of normal human dermal fibroblasts (NHDFs) cells. The results showed that the miR-103 expression level in the DFU group was significantly higher than that in the SUC group [5.81 (2.25-9.36) vs 2.08 (1.15-5.72)] (P < 0.05). The expression level of miR-103 in the wound margin tissue of DFU was negatively correlated with the healing rate of foot ulcers after four weeks (P=0.037). In vitro experiments revealed that miR-103 could inhibit the proliferation and migration of NHDF cells and promote the apoptosis of NHDF cells by targeted regulation of regulator of calcineurin 1 (RCAN1) gene expression in a high glucose environment. Down-regulation of miR-103 could alleviate high glucose-induced NHDF cell injury by promoting RCAN1 expression. Therefore, the increased expression of miR-103 is involved in the functional damage of NHDF cells induced by high-glucose conditions, which is related to poor wound healing of DFU. These research findings will provide potential targets for the diagnosis and treatment of chronic skin wounds in diabetes.

Diabetic foot ulcer (DFU) healing is a complex and slow process that depends on several factors such as the patient's physical health. However, psychological factors such as distress, which are commonly reported by patients with DFU, may also influence DFU development and recurrence. This pilot randomised control trial (RCT) assesses the effectiveness of progressive muscle relaxation and hypnosis on DFU healing and quality of life (QoL) in distressed patients. Sixty-nine patients who received standard care treatment were randomly assigned to one of four groups: muscle relaxation (TG1), hypnosis (TG2), neutral sessions (active control: ACG), and no intervention (passive control: PCG). Primary outcomes were both DFU healing and QoL. Secondary outcomes were perceived stress, psychological morbidity, and illness (DFU) representations. Patients were assessed at baseline (T0), 2months after the baseline (T1), and 4months later (T2). Regarding primary outcomes, comparisons between groups showed significant differences only in DFU healing: TG1, TG2, and ACG reported more improvements than PCG at T1, while TG1 showed more improvements than TG2 and PCG at T2. Results for secondary outcomes revealed less threatening DFUrepresentations in TG1 compared to TG2 and ACG, and more psychological morbidity in TG2 than TG1, both at T1. Within-group analysis in primary outcomes showed DFU healing and physical QoL improvement in all groups, DFU-related QoL improvement in all groups except PCG, and an increase in mental QoL only in TG2 and ACG. Regarding secondary outcomes, results showed a decrease in DFU's representations only in TG1, and a significant decrease in stress and psychological morbidity in TG1, TG2, and ACG. Results suggest that both stress-reduction interventions should be included in the multidisciplinary treatment and rehabilitation plan for distressed patients with DFU(s).

Foot Care

Diabetic foot ulcer (DFU) is a chronic and non-healing complication of diabetes that leads to high hospital costs and, in extreme cases, to amputation. Recent studies have reported that long non-coding RNAs (lncRNAs) are linked to various diabetes-related symptoms. Thus, we aim to explore the role of lncRNA H19 in the wound healing process following DFU. Fibroblasts were isolated from the ulcer margin tissues of DFU patients, with the expression of lncRNA H19, connective tissue growth factor (CTGF) or serum response factor (SRF) altered by lentivirus infection. Next, rat models of DFU induced by high glucose and lipid diet were established, which was also infected with the corresponding lentivirus. The interaction among lncRNA H19, SRF and CTGF was determined. Afterward, cell proliferation and apoptosis, angiogenesis, ECM remodeling and wound healing in DFU tissues were evaluated to explore the effects of lncRNA H19/SRF/CTGF and MAPK signaling pathway on DFU. CTGF was poorly expressed in ulcer tissues from DFU rats and patients. CTGF overexpression was shown to activate the MAPK signaling pathway to promote cell proliferation, ECM remodeling, angiogenesis and wound healing while inhibiting cell apoptosis. lncRNA H19 was validated to elevate CTGF expression by recruiting SRF to the promoter region of CTGF, thus accelerating cell proliferation, ECM remodeling and wound healing while repressing cell apoptosis. Furthermore, MAPK signaling pathway activation is confirmed to be the underlying mechanism behind lncRNA H19/CTGF/SRF-induced results. Thus, lncRNA H19 accelerated wound healing in DFU through elevation of CTGF and activation of the MAPK signaling pathway.