Pathogenesis Of Diabetic Foot Ulcers Research Articles

Neutrophil Migration is a Crucial Factor in Wound Healing and the Pathogenesis of Diabetic Foot Ulcers: Insights into Pharmacological Interventions.

Diabetic foot ulcers (DFUs) pose a significant clinical challenge, characterized by impaired wound healing, chronic inflammation, and increased risk of infection. Neutrophils, as critical components of the innate immune response, play a pivotal role in the initial stages of wound healing, particularly during the inflammatory phase. This review explores the intricate relationship between neutrophil migration, inflammation, and the pathogenesis of DFU and drugs that can impact neutrophil production and migration. Neutrophils contribute to infection control through phagocytosis and release pro-inflammatory cytokines and reactive oxygen species, which, when dysregulated, can impede the wound healing process. Furthermore, the chronic hyperglycemic state characteristic of diabetes mellitus has been implicated in impairing neutrophil functions, including chemotaxis and oxidative burst. This compromised neutrophil response prolongs the inflammatory phase and disrupts the delicate balance required for efficient wound healing. Neutrophil extracellular traps (NETs), a unique form of neutrophil defence, have also been implicated in DFU pathogenesis, potentially exacerbating inflammation and tissue damage. Understanding the intricate interplay between neutrophil migration, dysregulated inflammatory responses, and hyperglycemia-driven impairments is essential for developing targeted therapeutic strategies for DFUs. This review sheds light on the critical role of neutrophils in DFU pathogenesis, and innovative and advanced treatment strategies for DFU, highlighting the potential for novel interventions to restore the balance between pro-inflammatory and wound healing processes, ultimately improving clinical outcomes for individuals with DFU.

SFRP2 modulates functional phenotype transition and energy metabolism of macrophages during diabetic wound healing.

Diabetic foot ulcer (DFU) is a serious complication of diabetes mellitus, which causes great health damage and economic burden to patients. The pathogenesis of DFU is not fully understood. We screened wound healing-related genes using bioinformatics analysis, and full-thickness skin injury mice model and cellular assays were used to explore the role of target genes in diabetic wound healing. SFRP2 was identified as a wound healing-related gene, and the expression of SFRP2 is associated with immune cell infiltration in DFU. In vivo study showed that suppression of SFRP2 delayed the wound healing process of diabetic mice, impeded angiogenesis and matrix remodeling, but did not affect wound healing process of control mice. In addition, suppression of SFRP2 increased macrophage infiltration and impeded the transition of macrophages functional phenotypes during diabetic wound healing, and affected the transcriptome signatures-related to inflammatory response and energy metabolism at the early stage of wound healing. Extracellular flux analysis (EFA) showed that suppression of SFRP2 decreased mitochondrial energy metabolism and increased glycolysis in injury-related macrophages, but impeded both glycolysis and mitochondrial energy metabolism in inflammatory macrophages. In addition, suppression of SFRP2 inhibited wnt signaling-related genes in macrophages. Treatment of AAV-SFRP2 augmented wound healing in diabetic mice and demonstrated the therapeutic potential of SFRP2. In conclusions, SFRP2 may function as a wound healing-related gene in DFU by modulating functional phenotype transition of macrophages and the balance between mitochondrial energy metabolism and glycolysis.

Pterostilbene Reverses Epigenetic Silencing of Nrf2 and Enhances Antioxidant Response in Endothelial Cells in Hyperglycemic Microenvironment.

The epigenetic regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal redox transcription factor, plays a crucial role in maintaining cellular homeostasis. Recent research has underscored the significance of epigenetic modifications of Nrf2 in the pathogenesis of diabetic foot ulcers (DFUs). This study investigates the epigenetic reversal of Nrf2 by pterostilbene (PTS) in human endothelial cells in a hyperglycemic microenvironment (HGM). The activation potential of PTS on Nrf2 was evaluated through ARE-Luciferase reporter assays and nuclear translocation studies. Following 72 h of exposure to an HGM, mRNA expression and protein levels of Nrf2 and its downstream targets NAD(P)H quinone oxidoreductase 1 (NQO1), heme-oxygenase 1(HO-1), superoxide dismutase (SOD), and catalase (CAT) exhibited a decrease, which was mitigated in PTS-pretreated endothelial cells. Epigenetic markers, including histone deacetylases (HDACs class I-IV) and DNA methyltransferases (DNMTs 1/3A and 3B), were found to be downregulated under diabetic conditions. Specifically, Nrf2-associated HDACs, including HDAC1, HDAC2, HDAC3, and HDAC4, were upregulated in HGM-induced endothelial cells. This upregulation was reversed in PTS-pretreated cells, except for HDAC2, which exhibited elevated expression in endothelial cells treated with PTS in a hyperglycemic microenvironment. Additionally, PTS was observed to reverse the activity of the methyltransferase enzyme DNMT. Furthermore, CpG islands in the Nrf2 promoter were hypermethylated in cells exposed to an HGM, a phenomenon potentially counteracted by PTS pretreatment, as shown by methyl-sensitive restriction enzyme PCR (MSRE-qPCR) analysis. Collectively, our findings highlight the ability of PTS to epigenetically regulate Nrf2 expression under hyperglycemic conditions, suggesting its therapeutic potential in managing diabetic complications.

Diabetic Foot Ulcers: A Review of Debridement Techniques.

Diabetic foot ulcers (DFUs) are a prevalent complication of diabetes mellitus (DM) and lead to significant morbidity and mortality. Patients with DM have a lifetime risk of DFUs as high as 34%. The pathogenesis of DFUs is multifactorial, and the most common underlying causes are poor glycemic control, peripheral neuropathy, peripheral vascular disease, foot deformity, and poor foot care. Diabetic lower-extremity complications are also a significant burden in terms of healthcare costs. In the United States alone, the direct cost of diabetic foot care has been estimated to be $8,659 per patient, with total annual medical costs for managing diabetic foot disease ranging from $9 to $13 billion. Given the risk of amputation and poor wound healing, the fast, accurate diagnosis and treatment of DFUs are critical. Measures to prevent DFUs include glycemic control and annual foot inspections. For patients with DFUs, off-loading and local wound care are critical for wound healing. Debridement is the standard of care for DFU wounds, and several techniques exist. In this review, we discuss the current practices of diabetic wound care, different methods of debridement and their practical use in DFUs, and novel debridement approaches with the potential for improving wound-healing outcomes.

Diagnosis and treatment of diabetic foot ulcer complicated with lower extremity vasculopathy: Consensus recommendation from the Chinese Medical Association (CMA), Chinese Medical Doctor Association (CMDA).

Diabetic foot ulcer complicated with lower extremity vasculopathy is highly prevalent, slow healing and have a poor prognosis. The final progression leads to amputation, or may even be life-threatening, seriously affecting patients' quality of life. The treatment of lower extremity vasculopathy is the focus of clinical practice and is vital to improving the healing process of diabetic foot ulcers. Recently, a number of clinical trials on diabetic foot ulcers with lower extremity vasculopathy have been reported. A joint group of Chinese Medical Association (CMA) and Chinese Medical Doctor Association (CMDA) expert representatives reviewed and reached a consensus on the guidelines for the clinical diagnosis and treatment of this kind of disease. These guidelines are based on evidence from the literature and cover the pathogenesis of diabetic foot ulcers complicated with lower extremity vasculopathy and the application of new treatment approaches. These guidelines have been put forward to guide practitioners on the best approaches for screening, diagnosing and treating diabetic foot ulcers with lower extremity vasculopathy, with the aim of providing optimal, evidence-based management for medical personnel working with diabetic foot wound repair and treatment.

Integrated genetic analysis of diabetic complications: Bioinformatics insights into foot ulcers, neuropathy and peripheral artery disease.

Diabetic foot ulcers (DFU), diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) are common complications of diabetes mellitus, while diabetic peripheral neuropathy and peripheral arterial disease contribute to the pathogenesis of diabetic foot ulcers, and the pathogenic mechanisms between these three diseases still need further investigation. The keywords 'diabetic foot ulcer', 'diabetic peripheral neuropathy' and 'atherosclerosis' were used to search for related gene sets in the GEO database. Differentially expressed genes (DEGs) were screened and analysed for GO, KEGG and enrichR functional enrichment. Potential three disease biomarkers were identified by SVM-SVM-RFE and LASSO regression analysis. The results were also validated using external datasets and discriminability was measured by area under the ROC curve (AUC). Finally, biomarkers and co-upregulated genes were analysed through the GSEA and Attie Laboratories diabetes databases. A total of 11 shared genes (KRT16, CD24, SAMD9L, SRGAP2, FGL2, GPR34, DDIT4, NFE2L3, FBLN5, ANXA3 and CPA3), two biomarkers (SAMD9L and FGL2) and one co-upregulated gene (CD24) were screened. GO and KEGG pathway analysis of DEGs, enrichr enrichment analysis of shared differential genes and GSEA analysis of biomarkers showed that these significant genes were mainly focused on vasoregulatory, inflammatory-oxidative stress and immunomodulatory pathways. In this study, we used bioinformatics to investigate the intrinsic relationship and potential mechanisms of three common lower extremity complications of diabetes and identified two pivotal genes using the LASSO model and the SVM-RFE algorithm, which will further help clinicians to understand the relationship between diabetic complications, improve the diagnosis and treatment of diabetic foot problems and help doctors to identify the potential risk factors of diabetic foot.

An integrated method for IgG N-glycans enrichment and analysis: Understanding the role of IgG glycosylation in diabetic foot ulcer

Diabetic foot ulcer (DFU) is the most common and serious complication of diabetes, and its incidence, disability, and mortality rates are increasing worldwide. The pathogenesis of DFU is associated with dysregulated inflammation mediated by abnormal immunoglobulin G (IgG) glycosylation. In this study, we developed a comprehensive method for IgG N-linked glycosylation in the serum of DFU patients. Through analysis, we identified 31 IgG1 glycans, 32 IgG2 glycans, and 30 IgG4 glycans in the DFU serum. Furthermore, 13 IgG1 glycans, 12 IgG2 glycans, and 5 IgG4 glycans in the DFU groups were found to be significantly different from those of the control groups (p < 0.05). Of these, compared with the control group, one glycan was unique to DFU patients, and seven glycans were not detected in the DFU group. In terms of glycan characteristics, we observed a substantial decrease in galactosylation, sialylation and bisecting GlcNAcylation, and a significant increase in agalactosylation. Abnormal IgG N-glycosylation modifications were significantly associated with the chronic inflammation that is characteristic of DFU. Further, this is the first comprehensive analysis of subclass-specific IgG N-glycosylation in DFU patients, which not only fills the gap of DFU in terms of the pathological mechanisms related to IgG glycosylation but also may provide valuable clues for the immunotherapeutic pathway of DFU.

The role of programmed cell death in diabetic foot ulcers.

Diabetic foot ulcer, is a chronic complication afflicting individuals with diabetes, continue to increase worldwide, immensely burdening society. Programmed cell death, which includes apoptosis, autophagy, ferroptosis, necroptosis and pyroptosis, has been increasingly implicated in the pathogenesis of diabetic foot ulcer. This review is based on an exhaustive examination of the literature on 'programmed cell death' and 'diabetic foot ulcers' via PubMed. The findings revealed that natural bioactive compounds, noncoding RNAsand certain proteins play crucial roles in the healing of diabetic foot ulcers through various forms of programmed cell death, including apoptosis, autophagy, ferroptosis and pyroptosis.

Examination of Feet in People with Diabetes

Diabetic foot is a common complication of diabetes and leads to considerable morbidity and mortality. Neuropathy, deformity, infection and ischemia play a key role in the pathogenesis of diabetic foot ulcer. A multidisciplinary team approach by a nurse, physician, diabetic foot surgeon and the caregiver as well as close monitoring can prevent foot complications. Proper foot care, foot hygiene, annual foot examination and correct choice of footwear are main factors in preventing foot problems, ulceration and amputations. Physicians play a lead role in early detection and prevention of foot problems. This article will focus on how to perform foot examination in routine clinical practice.

Mapping cellular senescence networks in human diabetic foot ulcers.

Cellular senescence, a cell fate defined by irreversible cell cycle arrest, has been observed to contribute to chronic age-related conditions including non-healing wounds, such as diabetic foot ulcers. However, the role of cellular senescence in the pathogenesis of diabetic foot ulcers remains unclear. To examine the contribution of senescent phenotypes to these chronic wounds, differential gene and network analyses were performed on publicly available bulk RNA sequencing of whole skin biopsies of wound edge diabetic foot ulcers and uninvolved diabetic foot skin. Wald tests with Benjamini-Hochberg correction were used to evaluate differential gene expression. Results showed that cellular senescence markers, CDKN1A, CXCL8, IGFBP2, IL1A, MMP10, SERPINE1, and TGFA, were upregulated, while TP53 was downregulated in diabetic foot ulcers compared to uninvolved diabetic foot skin. NetDecoder was then used to identify and compare context-specific protein-protein interaction networks using known cellular senescence markers as pathway sources. The diabetic foot ulcer protein-protein interaction network demonstrated significant perturbations with decreased inhibitory interactions and increased senescence markers compared to uninvolved diabetic foot skin. Indeed, TP53 (p53) and CDKN1A (p21) appeared to be key regulators in diabetic foot ulcer formation. These findings suggest that cellular senescence is an important mediator of diabetic foot ulcer pathogenesis.

High glucose-induced endothelial STING activation inhibits diabetic wound healing through impairment of angiogenesis

Chronic hyperglycemia-induced impairment of angiogenesis is important in diabetic foot ulcer (DFU). Additionally, the stimulator of interferon gene (STING), which is a key protein in innate immunity, mediates palmitic acid-induced lipotoxicity in metabolic diseases through oxidative stress-induced STING activation. However, the role of STING in DFU is unknown. In this study, we established a DFU mouse model with streptozotocin (STZ) injection and found that the expression of STING was significantly increased in the vascular endothelial cells of wound tissues from diabetic patients and in the STZ-induced diabetic mouse model. We further established high glucose (HG)-induced endothelial dysfunction with rat vascular endothelial cells and found that the expression of STING was also increased by high-glucose treatment. Moreover, the STING inhibitor, C176, promoted diabetic wound healing, whereas the STING activator, DMXAA, inhibited diabetic wound healing. Consistently, STING inhibition reversed the HG-induced reduction of CD31 and vascular endothelial growth factor (VEGF), inhibited apoptosis, and promoted migration of endothelial cells. Notably, DMXAA treatment alone was sufficient to induce endothelial cell dysfunction as a high-glucose treatment. Mechanistically, STING mediated HG-induced vascular endothelial cell dysfunction by activating the interferon regulatory factor 3/nuclear factor kappa B pathway. In conclusion, our study reveals an endothelial STING activation-mediated molecular mechanism in the pathogenesis of DFU and identifies STING as a novel potential therapeutic target for DFU.

Addressing the Inertia: A Holistic Approach to Diabetic Foot Evaluation.

Diabetic foot is a well-known complication with considerable morbidity and mortality related to the diabetic population. Neuropathy, deformity, infection and ischemia are important contributors to the pathogenesis of diabetic foot ulcers. A multidisciplinary team approach by physicians, nursing staff, diabetic educators and the caregiver as well as close monitoring of feet by the patient himself can prevent foot-related complications. Proper foot care, foot hygiene, annual foot examination and the correct choice of footwear are the main elements in preventing foot problems like deformity, ulceration and amputations. Physicians play a key role in the early detection and prevention of foot problems. Foot evaluation is the most neglected part of physical examination in diabetic patients. This inertia is evident in both physicians and patients. Emphasis on visual inspection and physical foot examination at every visit may address the morbidity and mortality due to diabetic neuropathy and vasculopathy. This article will highlight extensively history taking and foot examination in the diabetic foot clinic. Optimal glycemic control, simple foot care practices, knowledge and appropriate footwear use play an important role to reduce the disease burden.

Mechanisms of diabetic foot ulceration: A review.

Diabetic foot ulcers (DFUs) are associated with complex pathogenic factors and are considered a serious complication of diabetes. The potential mechanisms underlying DFUs have been increasingly investigated. Previous studies have focused on the three aspects of diabetic peripheral vascular disease, neuropathy, and wound infections. With advances in technology, researchers have been gradually conducting studies using immune cells, endothelial cells, keratinocytes, and fibroblasts, as they are involved in wound healing. It has been reported that the upregulation or downregulation of molecular signaling pathways is essential for the healing of DFUs. With a recent increase in the awareness of epigenetics, its regulatory role in wound healing has become a much sought-after trend in the treatment of DFUs. This review focuses on four aspects involved in the pathogenesis of DFUs: physiological and pathological mechanisms, cellular mechanisms, molecular signaling pathway mechanisms, and epigenetics. Given the challenge in the treatment of DFUs, we are hopeful that our review will provide new ideas for peers.

LncRNA SNHG16 Knockdown Promotes Diabetic Foot Ulcer Wound Healing via Sponging MiR-31-5p.

Diabetic foot ulcers are caused by nerve abnormalities and vascular lesions in the distal lower limbs of diabetic patients. However, the causes of diabetic foot ulcers are diverse and the treatment process is complex. Therefore, understanding the pathogenesis of diabetic foot ulcers through lncRNA and formulating effective means are the key to the cure of patients. Tissues were collected from 76 diabetic foot ulcer patients and 50 non-diabetic patients undergoing traumatic amputation. Human dermal fibroblasts (HDFs) were induced by high glucose to obtain diabetic foot ulcer cell model. The lncRNA SNHG16 (SNHG16) and miR-31-5p expression in tissues and cells was detected by real-time quantitative reverse transcription PCR (RT-qPCR). Cell Counting Kit-8 (CCK-8) and Transwell assays were used to evaluate the biological behavior of the cells, and the association between SNHG16 and miR-31-5p was explored by luciferase reporting assay. SNHG16 was distinctly expressed in diabetic foot ulcer tissue samples, while miR-31-5p was decreased. In vitro cell function assays confirmed that the proliferation level was inhibited in the constructed diabetic foot ulcer cell model (HG group), as was the migration and invasion ability. After transfection with silencing SNHG16, the biological behavior of the cells was promoted. Mechanistically, SNHG16 sponge miR-31-5p regulated disease progression. Recovery experiments revealed that miR-31-5p inhibitor counteracted the effect of silencing SNHG16 on cell viability. SNHG16 knockdown may regulate the biological function of cells by targeting miR-31-5p to promote wound healing and ameliorate the condition of diabetic foot ulcer patients.

LncRNA ANRIL accelerates wound healing in diabetic foot ulcers via modulating HIF1A/VEGFA signaling through interacting with FUS.

Diabetic foot ulcer (DFU) is a frequently diagnosed complication of diabetes, and remains a heathcare burden worldwide. However, the pathogenesis of DFU is still largely unclear. The objective of this study is to delineate the function and underlying mechanism of lncRNA antisense non coding RNA in the INK4 locus (ANRIL) in endothelial progenitor cells (EPCs) and DFU mice. The DFU mouse model was established, and EPCs were subjected to high glucose (HG) treatment to mimic diabetes. qRT-PCR or western blot was employed to detected the expression of ANRIL, HIF1A, FUS and VEGFA. CCK-8 and Annexin V/PI staining were used to monitor cell proliferation and apoptosis. Wound healing, Transwell invasion and tube formation assays were conducted to assess cell migration, invasion and angiogenesis, respectively. The association between ANRIL and FUS was verified by RNA pull-down and RIP assays. Luciferase and ChIP assays were employed to investigate HIF1A-mediated transcriptional regulation of VEGFA and ANRIL. The histological alterations of DFU wound healing were observed by H&E and Masson staining. ANRIL was downregulated in peripheral blood samples of DFU patients, DFU mice and HG-treated EPCs. Mechanistically, ANRIL regulated HIFA mRNA stability via recruiting FUS. VEGFA and ANRIL were transcriptionally regulated by HIF1A. Functional experiments revealed that HG suppressed EPC proliferation, migration, invasion and tube formation, but promoted apoptosis via ANRIL/HIF1A axis. ANRIL accelerated DFU wound healing via modulating HIF1A expression in vivo. ANRIL accelerated wound healing in DFU via modulating HIF1A/VEGFA signaling in a FUS-dependent manner.

UCMSCs-derived exosomal circHIPK3 promotes ulcer wound angiogenesis of diabetes mellitus via miR-20b-5p/Nrf2/VEGFA axis.

Experiments confirmed that circular RNAs contributed to the pathogenesis of diabetic foot ulcers (DFUs). CircHIPK3 was upregulated in type 2 diabetes mellitus (T2DM), but its role in DFU remained unknown. Our study aimed to investigate the regulatory functions of exosomal circHIPK3 and its potential mechanisms in DFU. Exosomal size and distribution, marker proteins, and circHIPK3 levels were evaluated by transmission electron microscope, ExoView R200, western blot, and qRT-PCR. Flow cytometry, MTT, Wound healing assays, and tube formation assays were used to assess the roles of exosomal circHIPK3 in high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs). The relationships between Nrf2/VEGFA/circHIPK3 and miR-20b-5p, and between Nrf2 and VEGFA were determined by luciferase reporter assay and RNA immunoprecipitation. We used cell and mice models to investigate the mechanisms of exosomal circHIPK3 under diabetic conditions. CircHIPK3 was significantly upregulated in exo-circHIPK3 rather than exo-vector. Exo-circHIPK3 remarkably inhibited cell apoptosis but promoted cell proliferation, migration, and tube formation in HG-treated HUVECs. Luciferase reporter and RIP assays showed that miR-20b-5p targeted and inhibited Nrf2 and VEGFA, and circHIPK3 acted as a ceRNA of miR-20b-5p to inhibit the binding to its downstream genes Nrf2 and VEGFA. Mechanistically, circHIPK3 promoted cell proliferation, migration, and angiogenesis via downregulating miR-20b-5p to upregulate Nrf2 and VEGFA. However, the overexpressed miR-20b-5p could abolish the promoting effects of circHIPK3 overexpression on cell proliferation, migration, and tube formation under HG conditions. UCMSCs-derived exosomal circHIPK3 protected HG-treated HUVECs via miR-20b-5p/Nrf2/VEGFA axis. The exosomal circHIPK3 might be a therapeutic candidate to treat DFU.

The contribution of intestinal Streptococcus to the pathogenesis of diabetic foot ulcers: An analysis based on 16S rRNA sequencing.

In this study, we intend to determine the microbial communities that are differentially expressed in diabetic foot ulcers (DFUs) from the view of species abundance difference and compositions. The EMBL-EBI database and QIIME2 platform were used to obtain and process 16S rRNA sequencing data of normal healthy and DFU samples. The LEfSe software was utilised to retrieve key intestinal bacteria differentially expressed in DFUs. Additionally, PICRUSt2, FAPROTAX and BugBase functional analyses were performed to analyse the potential microbial functions and related metabolic pathways. The correlations between intestinal microbiota and clinical indexes were evaluated using the Spearman correlation analysis. Significant differences existed in intestinal microbiota between DFU and normal healthy samples regarding species abundance difference and compositions at Kingdom, Phylum, Class, Order, Family, Genus and Species levels. Seven microbiota were demonstrated differentially expressed in DFUs that contained Bacteroidaceae, Prevotellaceae, Streptococcaceae, Lactobacillales, Bacilli, Veillonellaceae and Selenomonadales. Insulin signalling pathway may be the key pathway related to the functional significance of Streptococcus and Bacillus in the DFUs. The intestinal microbiota in DFUs exhibited susceptibility to sulphur cycling while displaying pathogenic potential. Last but not least, a close relationship between Streptococcus and the occurrence of DFUs was revealed. Taken together, this study mainly demonstrated the high abundance of Streptococcus in DFUs and its correlation with the disease occurrence.

Risk Factors Associated With Diabetic Foot Ulcers and Its Relationship With ABI and Brachial-Ankle Pulse Wave Velocity.

To evaluate the risk factors associated with diabetic foot ulcers (DFUs) and to analyze the relationship of DFUs and the value of Ankle-Brachial Index (ABI) and brachial-ankle pulse wave velocity (baPWV). In this retrospective study, the risk factors associated with DFUs were analyzed, and the value of ABI and baPWV were measured to find its relationship with DFUs. Binary logistic regression analysis indicated that neuropathy and ABI were independent risk factors for DFUs. The patients were divided into 2 groups according to the value of ABI. For patients with DFUs, the value of baPWV decreased with the decrease of ABI. In normal or high ABI group, about a quarter of patients who suffered from DFUs had a higher value of baPWV than the others without DFUs. The pathogenesis of DFUs was multifactorial. Regarding the occurrence and development of foot ulcers, the action of vascular occlusion was more important than vascular sclerosis. ABI measurements should be taken more seriously in patients with DFUs. baPWV should be taken with care in the follow-up of the patients without DFUs. However, in patients with a normal value of ABI, the degree of vascular sclerosis of patients with DFUs may be greater than those without ulceration.

Association between serum vitamin D, hs-CRP, and prooxidant-antioxidant balance with anthropometric and biochemical parameters in patients with diabetic foot ulcers

Background. Oxidative balance and inflammatory processes affect wound healing phases, and their disruption is connected with delayed wound healing. The present study aimed to assess the association between serum hs-CRP, prooxidant-antioxidant Balance (PAB), and vitamin D with anthropometric and biochemical parameters in patients with diabetic foot ulcers (DFU). Methods. Thirty-two patients with DFU were included in this study. The Spearman correlation coefficient was used to evaluate the bivariate relationship between serum hs-CRP, PAB, and vitamin D with anthropometric characteristics, glycemic status, lipid profiles, homocysteine level, liver, and kidney function tests. Results. Our data showed a significant positive association between serum hs-CRP and insulin (r = 0.417, P = 0.027), uric acid (r = 0.629, P = 0.001), creatinine (r = 0.431, P = 0.022), erythema (r = 0.36, P = 0.049), and ESR (r = 0.560, P = 0.002). Moreover, hs-CRP negatively correlated with FBS (r = –0.427, P = 0.023), total bilirubin (r = –0.639, P = 0.001), direct bilirubin (r = –0.445, P = 0.033), LDL-cholesterol (r = –0.405, P = –0.032), BMI (r = –0.398, P = 0.033) and HTN (r = –0.450, P = 0.014). Serum PAB value negatively correlated with patients age (r = –0.460, P = 0.027), and BMI (r = –0.442, P = 0.035), and positively associated with insulin level (r = 0.431, P = 0.040). A significant positive association between serum vitamin D with patient sex (r = 0.379, P = 0.047), and QUICKI (r = 0.456, P = 0.029), and negative correlation with HbA1c (r = –0.381, P = 0.045) were also determined. Conclusions. This study demonstrated that serum hs- CRP, PAB, and vitamin D are significantly associated with some anthropometric and biochemical parameters with important clinical value in patients with DFU. Low levels of vitamin D and high levels of hs-CRP and PAB may have an important role in the pathogenesis of DFU.

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers.

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein of the leucine zipper family, which mitigates inflammation and employs cytoprotective effects. Attempting to unravel the epigenetic regulation of type 2 diabetes mellitus (T2DM) and diabetic foot ulcer (DFU), we profiled the expression of eleven isoform-specific histone deacetylases (HDACs) and correlated them with NRF2 and cytokines. This study recruited a total of 60 subjects and categorized into DFU patients (n = 20), T2DM patients (n = 20), and healthy controls (n = 20). The DFU patients were subcategorized into uninfected and infected DFU (n = 10 each). We observed a progressive decline in the expression of NRF2 and its downstream targets among T2DM and DFU subjects. The inflammatory markers IL-6 and TNF-α were significantly upregulated, whereas anti-inflammatory marker IL-10 was significantly downregulated in DFU. Of note, a significant upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2,8, SIRT1, SIRT2, SIRT3, SIRT7 among DFU patients were observed. The significant positive correlation between NRF2 and SIRT1 in DFU patients suggested the vital role of NRF2/SIRT1 in redox homeostasis and angiogenesis. In contrast, the significant negative correlation between NRF2 and HDAC1, 3 and 4, implied an imbalance in NRF2-HDAC1, 3, 4 circuit. Furthermore, a significant positive correlation was observed between HDAC4 and IL-6, and the negative correlation between SIRT1 and IL-6 suggested the pro-inflammatory role of HDAC4 and the anti-inflammatory role of SIRT1 in NRF2 signaling. In conclusion, the epigenetic changes such as upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2, 8, SIRT1, SIRT2, SIRT6, SIRT7 and their association with NRF2 as well as inflammatory markers are suggestive of their roles in pathophysiology of T2DM and DFU.