OBJECTIVE: To screen out the key metabolites related to diabetic foot (DF) by integrating genome-wide association studies (GWAS) and metabolome genome-wide association studies (mGWAS). METHODS: The literature databases such as PubMed and China national knowledge infrastructure(CNKI), as well as genomics databases such as PAN UKBB, FinnGen, and IEU Open GWAS were systematically retrieved from database estobilishment to November 2024 on DF-related single nucleotide polymorphisms and genome-wide association studies. DF-single nucleotide polymorphism-metabolite network was constructed by mGWAS package and mGWAS-Explorer platform. The causal relationship between key factors was evaluated by two-sample Mendelian randomization. The genetic correlation between DF and 575 metabolites (source:IEU Open GWAS) was evaluated by linkage disequilibrium score regression. In vitro experiments were conducted to induce injury of human umbilical vein endothelial cells with 30 mM glucose and intervene with 20 μM γ-tocopherol. Changes in cell migration, scratch healing and tube formation function were detected. RESULTS: Twenty-senen literatures on single nucleotide polymorphism literatures and 3 studies on GWAS were included. Genetic analysis results showed DF-related single nucleotide polymorphisms were enriched in vascular endothelial dysfunction-related pathways (such as fluid shear stress and atherosclerosis). The results of metabolic network analysis screened out 19 associated metabolites, among which 12 such as γ -tocopherol and pyruvate had significant genetic correlations with DF. Mendelian randomization suggested matrix metalloproteinase-9(MMP-9) might be a potential driver of DF (β=0.658, P=0.063 8), and the occurrence of DF could reduce the level of high-density lipoprotein (β=-0.002, P=0.015 2). The results of in vitro experiments confirmed that γ -tocopherol could improve endothelial dysfunction induced by high glucose, specifically manifested as an increase in the number of cell migrations, improvement in the scratch healing rate, and recovery of tubule formation ability (P<0.05). CONCLUSION DF has a genetic basis centered on vascular endothelial dysfunction, and its occurrence can lead to further metabolic disorders. The key single nucleotide polymorphism loci integrated provided molecular markers for the risk stratification of foot ulcers in diabetic patients. In addition, γ -tocopherol has demonstrated clinical application potential as a therapeutic drug for DF by significantly improving the function of vascular endothelial cells in a high-glucose environment.
Humans ; Diabetic Foot/drug therapy* ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Genomics ; Metabolomics ; Metabolome

OBJECTIVE: To explore clinical efficacy of vancomycin-loaded antibiotic bone cement combined with induced membrane grafting for the treatment of diabetic foot ulcers(DFU). METHODS: Totally 68 DFU patients treated with bone cement combined with induced membrane grafting from November 2019 to November 2021 were retrospectively analyzed, including 37 males and 31 females, aged from 51 to 79 years old with an average of (63.63±7.85) years old;47 patients on the right side and 21 patients on the left side;28 patients with grade 2, 31 patients with were grade 3, and 9 patients with grade 4 according to Wagner's grades;the diameter of the wound ranged from 20.40 to 96.99 mm with an average of (59.67±23.26) mm. The time of wound healing, the number of operations, the survival of postoperative skin grafting, the number of postoperative recurrence and the rate of amputation were observed. RESULTS: All 68 patients were followed up for 12 to 18 months with an average of (15.06±2.12) months. The wound healing time ranged from 42 to 65 d with an average of (51.50±7.24) d, the numbers of operation ranged from 2 to 3 with an average of (2.25±0.44) times. All skin grafts were survived well after operation, without recurrence and amputation cases. CONCLUSION Vancomycin-containing antibiotic bone cement combined with induced membrane grafting is effective in treating DFU, and the operation is simple and reliable.
Humans ; Male ; Female ; Middle Aged ; Vancomycin/therapeutic use* ; Bone Cements/therapeutic use* ; Aged ; Diabetic Foot/therapy* ; Skin Transplantation ; Anti-Bacterial Agents/therapeutic use* ; Retrospective Studies ; Wound Healing/drug effects*

Diabetic foot ulcer (DFU) is one of the common chronic complications in diabetic patients. Its course is complex and the therapeutic effect is limited, which seriously affects the quality of life of patients. In recent years, significant progress has been made in the research on the mechanism of DFU wound repair. Studies have found that dysregulation of the inflammatory microenvironment, vascular dysfunction, obstruction of re-epithelialization, insufficient collagen deposition, and formation of wound biofilms are the core factors affecting healing. Intervention strategies targeting these mechanisms have become research hotspots. For instance, hydrogel scaffolds could provide an appropriate healing microenvironment, immune regulation strategies could promote inflammation resolution and tissue remodeling, and stem cell exosomes and growth factors have shown good potential in cell migration, angiogenesis, and matrix remodeling. Various natural compounds, such as components from Chinese herbal medicines, are also applied in diabetic foot ulcers. And it demonstrates excellent anti-inflammatory and restorative capabilities. However, existing research still faces obstacles in clinical translation, such as the immaturity of individualized treatment strategies and the difficulty of animal models in simulating complex clinical situations. By systematically summarizing the latest research progress on the repair mechanism of DFU, it is expected to provide theoretical support for precise treatment.
Humans ; Diabetic Foot/drug therapy* ; Wound Healing ; Animals

Diabetic ulcer(DU) is a chronic and refractory ulcer which often occurs in the foot or lower limbs. It is a diabetic complication with high morbidity and mortality. The pathogenesis of DU is complex, and the therapies(such as debridement, flap transplantation, and application of antibiotics) are also complex and have long cycles. DU patients suffer from great economic and psychological pressure while enduring pain. Therefore, it is particularly important to promote rapid wound healing, reduce disability and mortality, protect limb function, and improve the quality of life of DU patients. By reviewing the relevant literatures, we have found that autophagy can remove DU wound pathogens, reduce wound inflammation, and accelerate ulcer wound healing and tissue repair. The main autophagy-related factors microtubule-binding light chain protein 3(LC3), autophagy-specific gene Beclin-1, and ubiquitin-binding protein p62 mediate autophagy. The traditional Chinese medicine(TCM) treatment of DU mitigates clinical symptoms, accelerates ulcer wound healing, reduces ulcer recurrence, and delays further deterioration of DU. Furthermore, under the guidance of syndrome differentiation and treatment and the overall concept, TCM treatment harmonizes yin and yang, ameliorates TCM syndrome, and treats underlying diseases, thereby curing DU from the root. Therefore, this article reviews the role of autophagy and major related factors LC3, Beclin-1, and p62 in the healing of DU wounds and the intervention of TCM, aiming to provide reference for the clinical treatment of DU wounds and subsequent in-depth studies.
Humans ; Ulcer/therapy* ; Medicine, Chinese Traditional ; Beclin-1 ; Quality of Life ; Wound Healing ; Diabetes Complications ; Autophagy ; Diabetic Foot/drug therapy* ; Diabetes Mellitus/genetics*

Chronic wounds such as diabetic foot ulcers are epidemic, which bring huge burdens to both the patients and the society. However, with current treatment methods, diabetic foot ulcers often heal poorly and recur frequently, so it is urgent and important to find new and advanced therapies. Stem cell therapy has been proved by a large number of pre-clinical and clinical studies as a potential treatment for chronic wounds. However, the acquisition of stem cells often depends on invasive techniques, and immunogenicity and limited cell survival in vivo also limit the large-scale application and promotion of stem cell therapy. In the recent years, with the development and advance of induced pluripotent stem cell (iPSC) technology, it has shown a strong translational potential in the treatment of chronic wounds such as diabetic foot ulcers. This article reviews the applications and prospect of iPSCs in animal wound healing models including diabetic ulcers and limb ischemia, the limitations of their clinical application, and the methods to improve their safety.
Animals ; Diabetes Mellitus ; Diabetic Foot/drug therapy* ; Induced Pluripotent Stem Cells ; Wound Healing

OBJECTIVE: To investigate the clinical effect of vancomycin bone cement in the treatment of diabetic foot ulcer (DFU) ruptured Wagner gradeⅡ-Ⅳ. METHODS: From March 2019 to April 2021, 32 patients with Wagner gradeⅡ-Ⅳ diabetic foot were divided into vacuum sealing drainage (VSD) group and bone cement group according to different treatment methods. There were 16 cases in VSD group, 8 males and 8 females;the age ranged from 66 to 81 (70.50±7.20) years, and the course of disease ranged from 8 to 40 (27.56±8.55) months;Wagner gradeⅡin 2 cases, grade Ⅲin 7 cases and grade Ⅳin 7 cases;debridement and VSD were used. There were 16 cases in the bone cement group, 9 males and 7 females;the age ranged from 63 to 79 (69.56±7.29) years, and the course of disease ranged from 11 to 39(22.75±11.43) months;Wagner gradeⅡ in 2 cases, grade Ⅲin 5 cases and grade Ⅳ in 9 cases;vancomycin loaded bone cement was used for treatment. The types of bacteria, negative time of bacterial culture, skin healing time, hospital stay, operation times and complications were observed and compared between two groups. RESULTS: All patients were followed up for 3 to 6 (4.00±1.07) months. The bacterial negative time, skin healing time and hospital stay in bone cement group were significantly lower than those in VSD group ( CONCLUSION Vancomycin loaded bone cement is effective in the treatment of Wagner grade Ⅱ-Ⅳ diabetic foot ulceration wounds. It can reduce the length of hospital stay, shorten the healing time of skin and kill pathogens as soon as possible. It is one of the effective methods to treat Wagner gradeⅡ-Ⅳdiabetic foot ulceration.
Bone Cements/therapeutic use* ; Child ; Child, Preschool ; Diabetes Mellitus ; Diabetic Foot/drug therapy* ; Female ; Humans ; Male ; Treatment Outcome ; Vancomycin ; Wound Healing

To analyze the outcome indicators from the randomized controlled trials(RCTs) on traditional Chinese medicine(TCM) treatment for diabetic foot, and to lay a foundation for the establishment of the core index set of the clinical trials on TCM treatment of diabetic foot. Computer retrieval of RCTs on TCM treatment of diabetic foot was performed in CNKI, Wanfang, SinoMed, PubMed, Cochrane Library, EMbase and Web of Science databases. Literature screening and data extraction were conducted independently by two researchers in strict accordance with inclusion and exclusion criteria. Any difference was resolved through discussion. A total of 72 RCTs involving 5 791 patients were included and 204 indicators were used. The number of indicators used in a single study was 2-22, with an average of 3 indicators used for each RCT. The indicators with top 16 frequency were clinical total effective rate, ankle brachial index(ABI), ulcer area, TCM syndrome integral, fibrinogen(FIB), fasting blood glucose(FBG), plasma viscosity(PV), c-reactive protein(CRP), saccharification blood of eggs(HbAlc), 2 h postprandial blood glucose(2 hPG), wound healing time, triglyce-rides(TC), TCM efficacy for syndromes, total cholesterol(TG), percutaneous oxygen partial pressure(TCPO2) and TCM symptom scores. The difference in selection of RCT indicators was large among TCM treatment methods for diabetic foot, and the combination of outcome indicators was arbitrary. The description on indexes was not standardized. Some non-laboratory examination indicators, some indicators not recommended in guidelines or not recognized in clinical practice, and some self-made indicators were not explained in detail. There was a lack of standardized evaluation criteria for indicators. The indicators had large time-point difference in measurement, and the time points were not distinguished in the measurement for diabetic foot patients with different degrees of severity. In addition, the patients with long course of treatment weren't timely measured. The characteristics of TCM or significant endpoint indicators were insufficient. It was urgent to establish the core index set of TCM in treating diabetic foot.
Blood Glucose ; Diabetes Mellitus ; Diabetic Foot/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Medicine, Chinese Traditional ; Randomized Controlled Trials as Topic ; Treatment Outcome

Chemical constituents of the Fufang Huangbai Ye( FFHB) were analyzed and identified by UPLC-ESI-LTQ-OrbitrapMS. The analysis was performed on an Waters HSS T3 reverse phase column( 2. 1 mm×100 mm,1. 8 μm). The mobile phase consisting of 0. 1% aqueous formic acid( A) and acetonitrile( B) was used with gradient elution,and the flow rate was 0. 3 mL·min~(-1).Based on the information of the accurate mass,the multistage fragment ions,the mass spectrometric data of the standard substance and the relative reference literature,the structure of the chemical constituents in FFHB were identified. Based on the identified compounds,network pharmacology study,including target prediction,functional enrichment,and molecular docking was applied to screen out the main active substances for treatment of diabetes foot and explore the potential mechanism. The results showed that a total of 138 compounds were identified,including 28 alkaloids,16 flavonoids,11 phenylethanoid glycosides,9 cycloolefins,11 cyclohexylethanol derivatives,28 phenolic acids and derivatives,3 lignans,4 terpenes,28 volatile oils and the others. Further,36 active substances for diabetes foot were screened out,and the functional enrichment showed the potential mechanism of FFHB were mainly seven functional items including inflammatory response,growth factor activity. This study combining the UPLC-LTQ-Orbitrap-MS technology and the network pharmacology provide a useful reference and basis for active compounds,quality control markers and the pharmacological mechanism of FFHB for diabetic foot treatment.
Chromatography, High Pressure Liquid ; Diabetic Foot ; drug therapy ; Drugs, Chinese Herbal ; pharmacology ; Humans ; Mass Spectrometry ; Molecular Docking Simulation ; Phytochemicals ; isolation & purification ; pharmacology

OBJECTIVETo observe the effect of Tongsaimai (TSM) tablets in treating foot trauma of diabetic foot (DF) model rats, and discuss its potential mechanism.

METHODMale SD rats were selected to duplicate the diabetic foot ulcer model and randomly divided into the blank control group, the model group, the metformin treatment group, and TSM 12.44, 6.22, 3.11 g x kg(-1) groups (n = 10). The healing of ulcer wounds were observed on day 1, 4, 8, 13 and 18. After 18 days, a histopathologic examination was conducted for ulcer tissues. The contents of superoxide dismutase (SOD) and malondialdehyde (MDA) were detected by hydroxylamine and TBA methods. The content of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined with the radioimmunoassay. The immunohistochemical method was used to observe the expression of vascular endothelial growth factor (VEGF) in ulcer tissues and the number of capillary vessels.

RESULTTSM could alleviate the pathological changes of diabetic foot rats, accelerate the ulcer healing on 4, 8, 13, 18 d, reduce MDA, IL-6, TNF-alpha, VEGF content in rat serum at 18 d (after the rehabilitation period), and enhance the SOD content. Specifically, the TSM 12.44 g x kg(-1) group showed significant differences compared with the model group (P < 0.05, P < 0.01). At 18 d after the treatment (the late rehabilitation period), the VEGF expression of TSM 12.44, 6.22 g x kg(-1) groups and the number of blood capillaries of the TSM 12.44 g x kg(-1) group were significantly lower than that of the model group (P < 0.05, P < 0.01).

CONCLUSIONTSM could promote the foot wound healing of DF model rats, reduce MDA, IL-6 and TNF-alpha levels in serum, increase the SOD content and decrease the VEGF expression and the number of blood capillaries in the late rehabilitation period. Its action mechanism may be related to the inhibition of oxidative stress injury and the inflammatory cell infiltration.

Animals ; Diabetic Foot ; drug therapy ; genetics ; metabolism ; physiopathology ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Interleukin-6 ; genetics ; metabolism ; Male ; Malondialdehyde ; metabolism ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; genetics ; metabolism ; Tablets ; administration & dosage ; Vascular Endothelial Growth Factor A ; genetics ; metabolism ; Wound Healing ; drug effects

OBJECTIVETo study the mechanism of treating diabetic foot by clearing heat, detoxification, activating blood, and dredging collaterals method.

METHODSSixty diabetic foot patients were randomly assigned to the treatment group and the control group, 30 cases in each group. On the basis of the same routine treatment, patients in the treatment group were treated by Qingjie Tongluo Recipe (QTR) plus external washing of Chinese herbs plus external dressing by herbs with removing necrosis and promoting granulation actions, while those in the control group were treated with routine aseptic external dressing. Three months was taken as one therapeutic course. The wound area and basic fibroblast growth factor (bFGF) were detected before and after treatment. The content of vascular endothelial growth factor (VEGF), the peripheral vascular and nerve functions were also measured. The therapeutic effects were also observed.

RESULTSAfter treatment, in the treatment group,15 patients were cured, 12 markedly effective, 2 effective, 1 ineffective, the cure rate was 50.0% and the total effective rate was 96.7%, while in the control group, 9 cases were cured, 6 markedly effective, 8 effective, 7 ineffective, the cure rate was 30.0% and the total effective rate was 76.7%. The total effective rate was better in the treatment group than in the control group (P <0. 01). The contents of bFGF and VEGF were significantly higher in the two groups after treatment (P <0.01). Besides, better results were obtained in the treatment group (P < 0.01). The blood flow speed of the dorsalis pedis artery, the inner diameter of the dorsalis pedis artery, and the common peroneal nerve conduction velocity were somewhat improved (P <0.05, P <0.01). Besides, better results were obtained in the treatment group (P <0.01).

CONCLUSIONSQTR combined external washing plus external dressing by herbs with removing necrosis and promoting granulation actions could promote the healing of diabetic foot induced ulcers, improve the vascular and nerve functions. Its efficacy was superior to that of the control group.

Aged ; Diabetic Foot ; drug therapy ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Phytotherapy