epidermal-growth-factor and Diabetes-Mellitus

Topics: Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Randomized Controlled Trials as Topic; Wound Healing

To evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) in treating diabetic foot ulcers (DFUs), we conducted both database searches (PubMed, MEDLINE, EMBASE, CENTRAL, and Web of Science) and reference searches for randomised controlled trials from the inception of databases to 30 January 2020. Two reviewers independently scrutinised the trials, extracted data, and assessed the quality of trials. The primary outcome was the proportion of complete healing. The secondary outcomes were mean time to complete healing and adverse events. A subgroup analysis was performed by different administration routes. Statistical analyses were performed in RevMan 5.3. The time to complete healing Kaplan-Meier curves was pooled in the R software. Of the 156 citations, 9 trials (720 participants) met eligibility criteria and were included. The rhEGF achieved a higher complete healing rate than placebo (OR: 2.79, [95% CI: 1.99, 3.99]). The rhEGF also significantly shorten complete healing time (MD: -14.10 days, [95% CI: -18.03, -10.16]). Subgroup analysis showed that topical application was superior to intralesional injection, but that may be because of different ulcer severity they included. No significant difference was shown in adverse events. Results were coherent with sensitivity analyses. Therefore, rhEGF is an effective and safe treatment for DFUs.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Injections, Intralesional; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome; Wound Healing

Two major initiatives are under way to correct the beta-cell deficit of diabetes: one would generate beta-cells ex vivo that are suitable for transplantation, and the second would stimulate regeneration of beta-cells in the pancreas. Studies of ex vivo expansion suggest that beta-cells have a potential for dedifferentiation, expansion, and redifferentiation. Work with mouse and human embryonic stem (ES) cells has not yet produced cells with the phenotype of true beta-cells, but there has been recent progress in directing ES cells to endoderm. Putative islet stem/progenitor cells have been identified in mouse pancreas, and formation of new beta-cells from duct, acinar and liver cells is an active area of investigation. Peptides, including glucagon-like peptide-1/exendin-4 and the combination of epidermal growth factor and gastrin, can stimulate regeneration of beta-cells in vivo. Recent progress in the search for new sources of beta-cells has opened promising new opportunities and spawned clinical trials.

Topics: Cell Differentiation; Diabetes Mellitus; Embryo, Mammalian; Embryo, Nonmammalian; Epidermal Growth Factor; Exenatide; Gastrins; Glucagon; Glucagon-Like Peptide 1; Islets of Langerhans; Pancreas; Peptide Fragments; Peptides; Protein Precursors; Regeneration; Stem Cells; Venoms

To determine differences in inflammatory markers expressed in diabetic macular edema (DME) patients with and without obstructive sleep apnea (OSA).. This was a prospective, cross-sectional study. Patients with treatment naive DME were enrolled in the study. They were stratified into 2 groups based on Apnea Hypopnea Index (AHI) from overnight polysomnography: OSA + (AHI ≥ 15) and OSA - (AHI<15). Multiplex immunoassay was performed for aqueous and serum cytokines including VEGF, placental growth factor (PGF), ICAM, IL2, IL3, IL6, IL8, IL10, IL17, vascular cell adhesion molecule-1 (VCAM1), monocyte attractant protein-1 (MCP1), epidermal growth factor (EGF) and platelet derived growth factor (PDGF). Statistical significance was defined as p < 0.004 using Bonferroni correction.. 32 DME positive patients were enrolled in the study; of which 17 patients were OSA + and 15 OSA-. The OSA + cohort had significantly higher levels of serum EGF (p = 0.003), and trended towards higher levels of most serum cytokines including ICAM and IL6. OSA- cohort had significantly higher levels of aqueous IL17 compared to the OSA + cohort (2.97 ± 1.7 vs. 1.4 ± 0.46 pg/mL, p = 0.004). There were no significant differences in other aqueous cytokines.. OSA + group trended towards higher levels of most serum inflammatory markers, suggesting a greater pro-inflammatory state. However, they did not have significantly greater level of aqueous cytokines.

Topics: Biomarkers; Cross-Sectional Studies; Cytokines; Diabetes Mellitus; Diabetic Retinopathy; Epidermal Growth Factor; Female; Humans; Inflammation Mediators; Interleukin-6; Macular Edema; Placenta Growth Factor; Prospective Studies; Sleep Apnea, Obstructive

Advanced modalities are used for wounds where conventional treatment is insufficient in diabetic foot patients. In this study, we investigated the effects of using Epidermal growth factor (EGF) and NPWTmodalities alone or in combination on the frequency and level of amputation. In the retrospective study, which included 286 patients in total, 76 patients were referred with the decision of amputation or amputation was planned during hospitalization. After the treatments, amputation and distalization of amputation were found 73.3% and 33.3% in the conventional treatment patients. While 86.4% amp and 18.2% amp distalization were found in negative pressure wound therapy (NPWT) only patients, this rate was 52.4% and 90.5% in EGF + NPWT patients, 50% and 83.3% in EGF only patients. While amp and distalization rates were found to be significantly better in those receiving only EGF or EGF + NPWT (

Topics: Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Negative-Pressure Wound Therapy; Retrospective Studies; Wound Healing

Avoiding the loss of functional beta cell mass is critical for preventing or treating diabetes. Currently, the molecular mechanisms underlying beta cell death are partially understood, and there is a need to identify new targets for developing novel therapeutics to treat diabetes. Previously, our group established that Mig6, an inhibitor of EGF signaling, mediates beta cell death under diabetogenic conditions. The objective here was to clarify the mechanisms linking diabetogenic stimuli to beta cell death by investigating Mig6-interacting proteins. Using co-immunoprecipitation and mass spectrometry, we evaluated the binding partners of Mig6 under both normal glucose (NG) and glucolipotoxic (GLT) conditions in beta cells. We identified that Mig6 interacted dynamically with NumbL, whereas Mig6 associated with NumbL under NG, and this interaction was disrupted under GLT conditions. Further, we demonstrated that the siRNA-mediated suppression of NumbL expression in beta cells prevented apoptosis under GLT conditions by blocking the activation of NF-κB signaling. Using co-immunoprecipitation experiments, we observed that NumbL's interactions with TRAF6, a key component of NFκB signaling, were increased under GLT conditions. The interactions among Mig6, NumbL, and TRAF6 were dynamic and context-dependent. We proposed a model wherein these interactions activated pro-apoptotic NF-κB signaling while blocking pro-survival EGF signaling under diabetogenic conditions, leading to beta cell apoptosis. These findings indicated that NumbL should be further investigated as a candidate anti-diabetic therapeutic target.

Topics: Adaptor Proteins, Signal Transducing; Apoptosis; Diabetes Mellitus; Epidermal Growth Factor; Humans; Insulin-Secreting Cells; Intracellular Signaling Peptides and Proteins; NF-kappa B; TNF Receptor-Associated Factor 6

The aim of this study is to analyze the application effect of traditional Chinese medicine (TCM) comprehensive nursing in diabetic foot patients.. 230 patients with diabetic foot admitted to Third people's Hospital of Haikou from January 2019 to April 2022 were classified as two groups, which consisted of a control group (n = 95) and an experimental group (n = 135). The control group took routine nursing intervention, while the experimental group took TCM comprehensive nursing intervention. The effect of intervention was compared by inflammatory factors (B-FGF, EGF, VEGF, and PDGF), wound area, self-rated anxiety scale (SAS), and self-rated depression scale (SDS).. After nursing, the levels of B-FGF, EGF, VEGF, and PDGF were higher in the experimental group (all p < 0.05). The total effective rate of diabetic foot recovery in the experimental group was 94.87% (74/78), higher than 87.67% (64/73) in the control group (p = 0.026). After nursing, the scores of SAS and SDS in the experimental group were lower than those in the control group (all p < 0.05).. The application of TCM comprehensive nursing in diabetic foot patients can greatly change the levels of B-FGF, EGF, VEGF, and PDGF in wound tissue, promote the healing of ulcer surface, improve patients' anxiety and depression, and enhance the quality of life of patients.

Topics: Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Medicine, Chinese Traditional; Quality of Life; Vascular Endothelial Growth Factor A

Diabetic foot ulcers (DFUs) cause high morbidity and mortality despite best treatment. Thus, new products are urgently needed to treat DFUs. Intralesional epidermal growth factor (EGF) (Heberprot-p) is considered to be an adjuvant therapy to standard of care (SOC) in DFUs. In the present study, the effect of Heberprot-p treatment on wound healing is compared to standard treatment.. The data of patients with DFUs were retrospectively analysed. The patients who had had DFUs of at least four weeks' duration and who had been treated in the wound clinic between January 2014 and 2017 were included in the study. The patients were divided into study and control groups. The study group consisted of patients in whom intralesional recombinant human EGF, Heberprot-p 75μg, was applied; the control group consisted of the remaining patients in whom EGF was not applied. The efficacy of Heberprot-p treatment in Wagner 2 and 3 DFUs were retrospectively investigated.. The study group (n=29 patients) who received Heberprot-p treatment was found to have shorter treatment times and higher rates of wound healing than the control group (n=22 patients). Although the amputation rate in the study group was less than the control group, the difference was not statistically significant.. Heberprot-p therapy is a promising treatment in DFUs, which can be routinely used as an adjunct to standard care.

Topics: Amputation, Surgical; Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Retrospective Studies; Treatment Outcome; Wound Healing

Chronic nonhealing diabetic wounds are a serious complication of diabetes, with a high morbidity rate that can cause disability or death. The long period of inflammation and dysfunctional angiogenesis are the main reasons for wound-healing difficulty in diabetes. In this study, a multifunctional double-layer microneedle (DMN) is constructed to control infection and promote angiogenesis, meeting the multiple demands of the healing process of a diabetic wound. The double-layer microneedle is consisted in a hyaluronic acid substrate and a mixture of carboxymethyl chitosan and gelatin as the tip. The antibacterial drug tetracycline hydrochloride (TH) is loaded into the substrate of the microneedle to achieve rapid sterilization and promote resistance to external bacterial infections. The microneedle tip loaded with recombinant human epidermal growth factor (rh-EGF) is inserted into the skin, in response to gelatinase produced by resident microbe and disassociate to achieve the enzymatic response release. The double-layer drug-loaded microneedles (DMN@TH/rh-EGF) have antibacterial and antioxidant effects, and promote cell migration and angiogenesis in vitro. In an in vivo diabetic wound model, using rats, the DMN@TH/rh-EGF patch is able to inhibit inflammation, promote angiogenesis, collagen deposition, and tissue regeneration during the wound healing process, promoting its healing.

Topics: Animals; Anti-Bacterial Agents; Diabetes Mellitus; Epidermal Growth Factor; Humans; Inflammation; Rats; Wound Healing

The current study aims to understand the mechanisms behind regulated cell death (RCD) in diabetic nephropathy and identify related biomarkers through bioinformatics and experimental validation. Datasets of bulk and single-cell RNA sequencing were obtained from public databases and analyzed using gene set variation analysis (GSVA) with gene sets related to RCD, including autophagy, necroptosis, pyroptosis, apoptosis, and ferroptosis. RCD-related gene biomarkers were identified using weighted gene correlation network analysis (WGCNA). The results were verified through experiments with an independent cohort and

Topics: Adaptor Proteins, Signal Transducing; Biomarkers; Diabetes Mellitus; Diabetic Nephropathies; Epidermal Growth Factor; Humans; Membrane Proteins; Necroptosis; Regulated Cell Death

Diabetic nephropathy (DN) is a prevalent and debilitating disease that represents the leading cause of chronic kidney disease which imposes public health challenges Tongmai Jiangtang capsule (TMJT) is commonly used for the treatment of DN, albeit its underlying mechanisms of action are still elusive.. This study retrieved databases to identify the components and collect the targets of TMJT and DN. Target networks were constructed to screen the core components and targets. Samples from the GEO database were utilized to perform analyses of targets and immune cells and obtain significantly differentially expressed core genes (SDECGs). We also selected a machine learning model to screen the feature genes and construct a nomogram. Furthermore, molecular docking, another GEO dataset, and Mendelian randomization (MR) were utilized for preliminary validation. We subsequently clustered the samples based on SDECG expression and consensus clustering and performed analyses between the clusters. Finally, we scored the SDECG score and analyzed the differences between clusters.. This study identified 13 SDECGs between DN and normal groups which positively regulated immune cells. We also identified five feature genes (. TMJT may alleviate DN via core components (e.g. Denudatin B, hancinol, hirudinoidine A) targeting SDECGs (e.g. SRC, EGF, GAPDH), with the involvement of feature genes and modulation of immune and inflammation-related pathways. These findings have potential implications for clinical practice and future investigations.

Topics: Cluster Analysis; Databases, Factual; Diabetes Mellitus; Diabetic Nephropathies; Epidermal Growth Factor; Humans; Molecular Docking Simulation

To determine the role of the intralesional recombinant epidermal growth factor (rEGF) in the healing and prevention of extremity amputation in advanced diabetic foot ulcer patients.. Observational study.. Department of Cardiovascular Surgery, Duzce State Hospital, Duzce, Turkey, between November 2018 and September 2019.. A total of 58 patients with diabetic foot ulcers that were treated at the study place were enrolled. The lesions were graded with Wagner Classification System. EGF (75 microg of Heberprot-P) vials were stored at +4°C and cold-chain requirements were followed. EGF 5 mL was dissolved with 0.09% saline solution; and 0.5-1 ml of the solution was injected into the tissues and edge of the lesions regularly. The data was evaluated at the end of two years of the treatment period. The primary objective was wound healing, formation of granulation tissue; and the secondary objective was the prevention of lower extremity amputation.. Diabetic foot ulcers wound healing was achieved in 93.1% (n=54) of patients with the formation of granulation tissue. The complete recovery was observed in 94.1% (n=32) of the patients who had Grade III and IV lesions. Lower extremity amputation was performed in two (3.4%) subjects. The lesions of two patients required flap surgery. The most common adverse events were tremor and syncope.. Recombinant epidermal growth factor is highly effective for the treatment of diabetic foot ulcers and prevention of extremity amputation. Intralesional rEGf provides efficient and safe wound healing/closure in patients with diabetic foot ulcers. Key Words: Amputation, Epidermal growth factor, Diabetic foot, Wound healing.

Topics: Amputation, Surgical; Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Turkey; Wound Healing

Kidney biopsies of patients with diabetic nephropathy (DN) and normal kidney function may exhibit interstitial fibrosis (IF) without reduction of glomerular filtration rate (GFR) because of hyperfiltration. The aim of our study was to analyse the performance of a set of biomarkers of tubular injury to estimate the extent of IF in patients with DN and normal kidney function.. This cross-sectional study included 118 adults with DN diagnosed by kidney biopsy and GFR ≥90 mL/min/1.73 m2 and a control group of healthy subjects. We measured the urinary excretion of monocyte chemoattractant protein-1 (MCP-1) neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), β2-microglobulin and dickkopf-3 protein (DKK-3) at the time of kidney biopsy. GFR was measured by chromium-51 labeled ethylenediamine tetraacetic acid (Cr-EDTA) (measured GFR). IF was quantified using a quantitative morphometric procedure. Predictive multivariate models were developed to estimate the IF surface.. Patients with DN showed significantly higher levels of DKK-3, MCP-1 and L-FABP and significantly lower levels of epidermal growth factor (EGF) than healthy controls. There were no significant between-group differences in the levels of β2-microglobulin, KIM-1 or NGAL. IF was negatively associated with EGF and positively with age, proteinuria, MCP-1, DKK-3 and L-FABP, but not with β2-microglobulin, KIM-1, NGAL or GFR. The best model to predict IF surface accounted for 59% of its variability and included age, proteinuria, EGF, DKK-3 and MCP-1.. Our study provides a model to estimate the IF in DN that can be useful to assess the progression of IF in patients with normal kidney function.

Topics: Adult; Biomarkers; Chemokine CCL2; Cross-Sectional Studies; Diabetes Mellitus; Diabetic Nephropathies; Edetic Acid; Epidermal Growth Factor; Fatty Acid-Binding Proteins; Fibrosis; Glomerular Filtration Rate; Humans; Kidney; Lipocalin-2; Proteinuria

Topics: Albuminuria; Angiopoietin-1; Angiopoietin-2; Animals; Diabetes Mellitus; Diabetic Nephropathies; Epidermal Growth Factor; Mice; Mice, Obese; Protein-Tyrosine Kinases

Topics: Animals; Chitosan; Collagen; Dextrans; Diabetes Mellitus; Epidermal Growth Factor; Fibroblasts; Hydrogels; Mice; Wound Healing

To investigate the effect of transverse tibial bone transport on the treatment of Wagner Stage 4 diabetic foot.. From January 2017 to October 2019, a total of 19 patients with Wagner Stage 4 diabetic foot ulcers were recruited. All patients were treated with transverse tibial bone transport. A detailed follow-up was carried out at 1 week, 1 month, 3 months, 6 months, and 1 year after surgery. The wound healing rate and the limb salvage rate at 1 year after the surgery were evaluated. Preoperative and 3-month postoperative digital subtraction angiography (DSA) were obtained. The level of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) before surgery and on 1st, 4th, 11th, 18th, 28. The wound healing rate and the limb salvage rate were both 94.74% in the patients at 1 year after the surgery. DSA showed the thickening of the calf and foot arteries, clear visualization, and a rich vascular network. The levels of VEGF, bFGF, and PDGF on the 11th, 18th, 28. Transverse tibial bone transport can improve the blood circulation of the affected limbs, promote the healing of diabetic foot wounds, and reduce the amputation rate of the affected limbs. Transverse tibial bone transport can promote the healing of Wagner Stage 4 diabetic foot.

Topics: Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Fibroblast Growth Factor 2; Humans; Osteogenesis, Distraction; Platelet-Derived Growth Factor; Treatment Outcome; Vascular Endothelial Growth Factor A

Diabetic foot ulcer (DFU) is a serious health problem. Major amputation increases the risk of mortality in patients with DFU; therefore, treatment methods other than major amputation come to the fore for these patients. Graft applications create an appropriate environment for the reproduction of epithelial cells. Similarly, epidermal growth factor (EGF) also stimulates epithelization and increases epidermis formation. In this study, we aimed to compare patients with DFU treated with EGF and those treated with a split-thickness skin graft.. Patients who were treated for DFU in the general surgery clinic were included in the study. The patients were evaluated retrospectively according to their demographic characteristics, wound characteristics, duration of treatment, and treatment modalities.. There were 26 patients in the EGF group and 21 patients in the graft group. The mean duration of treatment was 7 weeks (4-8 weeks) in the EGF group and 5.3 weeks (4-8 weeks) in the graft group (P < .05). In the EGF group, wound healing could not be achieved in one patient during the study period. In the graft group, no recovery was achieved in three patients (14.2%) in the donor site. Graft loss was detected in four patients (19%), and partial graft loss was observed in three patients (14.2%). The DFU of these patients were on the soles (85.7%). These patients have multiple comorbidities.. EGF application may be preferred to avoid graft complications in the graft area and the donor site, especially in elderly patients with multiple comorbidities and wounds on the soles.

Topics: Aged; Amputation, Surgical; Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Retrospective Studies; Skin Transplantation

This study's objective is to analyze the effect of epidermal growth factor (EGF) nanoparticles on the healing of diabetic skin wounds and also, simultaneously, to investigate the mechanism of EGF nanoparticles to promote healing. In this manuscript, EGF nanoparticles were prepared, and also the drug loading rate of EGF nanoparticles was measured. In the meantime, a diabetic skin wound model was prepared with the use of rats. Then, the rats were split into four groups: EGF nanogroup, EGF group, empty particle group, and control group. Additionally, the results indicate that this study was successful in preparing EGF nanoparticles with a stable performance, and the drug was released for 24 hours. The wound healing in the EGF nanoparticle group was quicker than that in the EGF group. Furthermore, the area of EGF receptor-positive cells in the wound surface of the EGF nanogroup was higher than that of the EGF group, with the results demonstrating that EGF nanoparticles upregulated the expression of EGF receptors in wound surface cells, promoted wound surface healing, and had better efficacy than EGF.

Topics: Animals; Diabetes Mellitus; Epidermal Growth Factor; Nanoparticles; Rats; Regeneration; Skin; Ulcer; Wound Healing

In this work, poly(ethylene glycol)-b-poly[3-acrylamidophenylboronic acid-co-styrene] (PEG-b-P(PBA-co-St) has been firstly synthesized for loading of insulin to form insulin-loaded micelles. Insulin-loaded micelles (ILM) and epidermal growth factor (EGF) are further embedded into the composite hydrogels that can be rapidly gelled by mixing of oxidized hyaluronic acid (OHA) and succinyl chitosan (SCS). Then, the morphology, rheology, degradation, swelling and cytotoxicity properties of the as-prepared composite hydrogels are further investigated to evaluate their physical properties and biocompatibility of as the wound dressing. The as-prepared composite hydrogels show the excellent cell compatibility and low toxicity. To evaluate the wound healing ability of as-prepared composite hydrogels, the tests of wound healing in vivo are conducted on streptozotocin-induced rat models. And the as-prepared composite hydrogels with ILM and EGF show an excellent wound healing performance for promotion of fibroblast proliferation and tissue internal structure integrity, as well as the deposition of collagen and myofibrils. These results suggest that the as-prepared composite hydrogels with loading of ILM and EGF could be a promising candidate for wound healing applications.

Topics: Animals; Chitosan; Diabetes Mellitus; Epidermal Growth Factor; Hyaluronic Acid; Hydrogels; Insulin; Micelles; Rats; Wound Healing

We created and evaluated an enhanced topical delivery system featuring a combination of highly skin-permeable growth factors (GFs), quercetin (QCN), and oxygen; these synergistically accelerated re-epithelialization and granulation tissue formation of/in diabetic wounds by increasing the levels of GFs and antioxidants, and the oxygen partial pressure, at the wound site.. To enhance the therapeutic effects of exogenous administration of GFs for the treatment of diabetic wounds, we prepared highly skin-permeable GF complexes comprised of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF), genetically attached, via the N-termini, to a low-molecular-weight protamine (LMWP) to form LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and LMWP-bFGF, respectively. Furthermore, quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nanoemulsions (QCN-NE and OXY-PFOB-NE) were developed to improve the topical delivery of QCN and oxygen, respectively. After confirming the enhanced penetration of LMWP-GFs, QCN-NE, and oxygen delivered from OXY-PFOB-NE across human epidermis, we evaluated the effects of combining LMWP-GFs, QCN-NE, and OXY-PFOB-NE on proliferation of keratinocytes and fibroblasts, and the chronic wound closure rate of a diabetic mouse model.. The optimal ratios of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, LMWP-bFGF, QCN-NE, and OXY-PFOB-NE were 1, 1, 0.02, 0.02, 0.2, and 60, respectively. Moreover, a Carbopol hydrogel containing LMWP-GFs, QCN-NE, and OXY-PFOB-NE (LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL) significantly improved scratch-wound recovery of keratinocytes and fibroblasts in vitro compared to that afforded by hydrogels containing each component alone. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL significantly accelerated wound-healing in a diabetic mouse model, decreasing wound size by 54 and 35% compared to the vehicle and LMWP-GFs, respectively.. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL synergistically accelerated the healing of chronic wounds, exerting both rapid and prolonged effects.

Topics: Animals; Cell Line; Cell Proliferation; Collagen; Diabetes Mellitus; Disease Models, Animal; Emulsions; Epidermal Growth Factor; Epidermis; Fibroblast Growth Factor 2; Humans; Hydrogels; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Keratinocytes; Mice, Inbred C57BL; Molecular Weight; Nanoparticles; Octanes; Oxygen; Platelet-Derived Growth Factor; Protamines; Quercetin; Skin Absorption; Wound Healing

Diabetes mellitus is characterized by pancreatic β cell dysfunction. Previous studies have indicated that epidermal growth factor (EGF) and microRNA-124a (miR-124a) play opposite roles in insulin biosynthesis and secretion by beta cells. However, the underlying mechanisms remain poorly understood. In the present study, we demonstrated that EGF could inhibit miR-124a expression in beta cell lines through downstream signaling pathways, including mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) cascades. Further, the transcription factor ETS2, a member of the ETS (E26 transformation-specific) family, was identified to be responsible for the EGF-mediated suppression of miR-124a expression, which was dependent on ETS2 phosphorylation at threonine 72. Activation of ETS2 decreased miR-124a promoter transcriptional activity through the putative conserved binding sites AGGAANA/TN in three miR-124a promoters located in different chromosomes. Of note, ETS2 played a positive role in regulating beta cell function-related genes, including miR-124a targets, Forkhead box a2 (FOXA2) and Neurogenic differentiation 1 (NEUROD1), which may have partly been through the inhibition of miR-124 expression. Knockdown and overexpression of ETS2 led to the prevention and promotion of insulin biosynthesis respectively, while barely affecting the secretion ability. These results suggest that EGF may induce the activation of ETS2 to inhibit miR-124a expression to maintain proper beta cell functions and that ETS2, as a novel regulator of insulin production, is a potential therapeutic target for diabetes mellitus treatment.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Binding Sites; Diabetes Mellitus; Epidermal Growth Factor; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Hepatocyte Nuclear Factor 3-beta; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Inbred C57BL; MicroRNAs; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinase; Phosphorylation; Promoter Regions, Genetic; Proto-Oncogene Protein c-ets-2; Signal Transduction; Threonine

Neutrophil infiltration constitutes the first step in wound healing, although their timely clearance by macrophage engulfment, or efferocytosis, is critical for efficient tissue repair. However, the specific mechanism for neutrophil clearance in wound healing remains undefined. Here we uncover a key role for CCN1 in neutrophil efferocytosis by acting as a bridging molecule that binds phosphatidylserine, the 'eat-me' signal on apoptotic cells and integrins αvβ3/αvβ5 in macrophages to trigger efferocytosis. Both knockin mice expressing a mutant CCN1 that is unable to bind αvβ3/αvβ5 and mice with Ccn1 knockdown are defective in neutrophil efferocytosis, resulting in exuberant neutrophil accumulation and delayed healing. Treatment of wounds with CCN1 accelerates neutrophil clearance in both Ccn1 knockin mice and diabetic Lepr(db/db) mice, which suffer from neutrophil persistence and impaired healing. These findings establish CCN1 as a critical opsonin in skin injury and suggest a therapeutic potential for CCN1 in certain types of non-healing wounds.

Topics: Animals; Cell Migration Assays; Cysteine-Rich Protein 61; Cytophagocytosis; Diabetes Mellitus; Epidermal Growth Factor; Fluorescent Antibody Technique; Humans; Immunoprecipitation; Keratinocytes; Macrophages; Mice; Mice, Inbred C57BL; Neutrophils; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Receptors, Vitronectin; Reverse Transcriptase Polymerase Chain Reaction; Skin; Wound Healing

Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose responsive, and they reinstate normal glycemic control for up to 248 d. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3)-expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta-cell reprogramming through transient cytokine exposure rather than genetic modification.

Topics: Acinar Cells; Animals; Cell Differentiation; Cell Proliferation; Ciliary Neurotrophic Factor; Diabetes Mellitus; Epidermal Growth Factor; Hyperglycemia; Insulin-Secreting Cells; Mice; Mice, Inbred NOD; Signal Transduction

Topics: Animals; Ciliary Neurotrophic Factor; Diabetes Mellitus; Epidermal Growth Factor; Insulin-Secreting Cells

Topics: Diabetes Mellitus; Epidermal Growth Factor; Female; Humans; Infant, Newborn; Inhibitor of Apoptosis Proteins; Pregnancy; Pregnancy Complications; Survivin; Ventricular Remodeling

Multiple lines of evidence suggest that a large portion of pancreatic cancer patients suffer from either hyperglycemia or diabetes, both of which are characterized by high blood glucose level. However, the underlying biological mechanism of this phenomenon is largely unknown. In the present study, we demonstrated that the proliferative ability of two human pancreatic cancer cell lines, BxPC-3 and Panc-1, was upregulated by high glucose in a concentration-dependent manner. Furthermore, the promoting effect of high glucose levels on EGF transcription and secretion but not its receptors in these PC cell lines was detected by using an EGF-neutralizing antibody and RT-PCR. In addition, the EGFR transactivation is induced by high glucose levels in concentration- and time-dependent manners in PC cells in the presence of the EGF-neutralizing antibody. These results suggest that high glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. Our findings may provide new insight on the links between high glucose level and PC in terms of the molecular mechanism and reveal a novel therapeutic strategy for PC patients who simultaneously suffer from either diabetes or hyperglycemia.

Topics: Cell Line, Tumor; Cell Proliferation; Diabetes Mellitus; Epidermal Growth Factor; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glucose; Humans; Hyperglycemia; Pancreatic Neoplasms; Transcriptional Activation

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Gastrins; Growth Substances; Humans; Islets of Langerhans; Mice; Regeneration

Collagen is generally incapable of capturing polypeptides such as growth factors in a specific manner. In this study, we established a collagen-binding growth factor (FNCBD-EGF) consisting of epidermal growth factor (EGF) and the fibronectin collagen-binding domain. A typical yield of FNCBD-EGF was approximately 200 microg/ml culture in an Escherichia coli expression system. This fusion protein bound to gelatin and fibrillar collagen sponges, and the bound protein was not effectively eluted even with 2 M NaCl. In addition, FNCBD-EGF bound to type I, II, III, or IV collagen-coated plates, and the specificity of binding was confirmed by competitive inhibition using fibronectin. FNCBD-EGF substantially stimulated cell growth after binding to collagen-coated culture plates, whereas EGF had no effect, indicating that this fusion protein acted as a collagen-associated growth factor. In an animal model of impaired wound healing, FNCBD-EGF, but not EGF, was retained with collagen sponges at wound sites 4 d after implantation, and repair of epidermis was observed underneath the sponges. These results suggested that our fusion protein with high collagen affinity would be useful for wound healing.

Topics: Animals; Binding, Competitive; Blotting, Western; Cell Division; Cell Line; Collagen; Diabetes Mellitus; Dose-Response Relationship, Drug; Epidermal Growth Factor; Gelatin; Immunohistochemistry; Mice; Protein Binding; Rats; Recombinant Fusion Proteins; Substrate Specificity; Thermodynamics; Wounds and Injuries

Both glomerular and tubular markers have been used to follow diabetic nephropathy. However, neither albumin nor proximal tubular markers have proven useful in prepubertal diabetes. Hence we studied two markers derived from the distal tubular cells, Tamm-Horsfall protein (THP) and epidermal growth factor (EGF). The urinary excretion of THP and EGF was examined in samples obtained during the first 20 days and 1 year after diagnosis of diabetes in children aged 4-15 years. Fourteen children without and 18 with ketonuria were examined, and 17 age-matched healthy children participated as controls. The excretion rate of EGF was increased at diagnosis, while that of THP was not. After 20 days of treatment the excretion of EGF had normalized, while the excretion of THP was decreased. Similar results were obtained after 1 year. In conclusion, in spite of good metabolic control a reduced excretion of THP persisted for at least 1 year after the diagnosis of diabetes. Whether the finding of reduced excretion of THP has any biological significance awaits further study.

Topics: Adolescent; Child; Child, Preschool; Diabetes Mellitus; Epidermal Growth Factor; Female; Humans; Hypoglycemic Agents; Insulin; Ketones; Male; Mucoproteins; Reference Values; Time Factors; Uromodulin

Topics: Animals; Cell Division; Diabetes Mellitus; Diabetes Mellitus, Experimental; Epidermal Growth Factor; Heparan Sulfate Proteoglycans; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Macrophages; Muscle, Smooth, Vascular; Rats

Aldose reductase (AR), best known as the first enzyme in the polyol pathway of sugar metabolism, has been implicated in a wide variety of physiological functions and in the etiology of diabetic complications. We have determined the structures and chromosomal locations of the mouse AR gene (Aldor1) and of two genes highly homologous to Aldor1: the fibroblast growth factor regulated protein gene (Fgfrp) and the androgen regulated vas deferens protein gene (Avdp). The number of introns and their locations in the mouse Aldor1 gene are identical to those of rat and human AR genes and also to those of Fgfrp and Avdp. Mouse Aldor1 gene was found to be located near the Cald1 (Caldesmon) and Ptn (Pleiotropin) loci at the proximal end of chromosome 6. The closely related genes Fgfrp and Avdp were also mapped in this region of the chromosome, suggesting that these three genes may have arisen by a gene duplication event.

Topics: Aldehyde Reductase; Animals; Base Sequence; Chromosome Mapping; Chromosome Segregation; Diabetes Mellitus; Epidermal Growth Factor; Fibroblast Growth Factors; Gene Duplication; Mice; Proteins; Pseudogenes; Sequence Homology, Nucleic Acid

We have studied the influence of high glucose on basal fibroblast proliferation, growth factor induced cellular proliferation and the effects of antioxidants, protein kinase C-inhibitors and troglitazone. Fibroblast cultures were obtained from five patients undergoing mammary reduction plastic surgery. A fluorometric method was used for determining total DNA in the cell samples, DNA content being proportional to cell number. D-Glucose at 15.5 mM and above was shown to inhibit fibroblast proliferation, and the cells were resistant to growth factors such as IGF-I and EGF at this glucose concentration. H7, bisindolylmaleimide IX, troglitazone, alpha-tocopherol acetate, Q10, ascorbic acid, beta-carotene, DMTU and selenite were all found to reverse the high glucose-induced growth factor resistance observed in human fibroblasts. We believe that these findings may be of value in the understanding and future treatment of wound healing in diabetic foot ulcers.

Topics: Antioxidants; Cell Division; Cells, Cultured; Chromans; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Resistance; Enzyme Inhibitors; Epidermal Cells; Epidermal Growth Factor; Fibroblasts; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin-Like Growth Factor I; Protein Kinase C; Protein Tyrosine Phosphatases; Thiazoles; Thiazolidinediones; Troglitazone; Wound Healing

Under diabetic conditions, the Maillard reaction facilitates the production of reactive oxygen species, and the activity of antioxidant enzymes such as Cu,Zn-superoxide dismutase is decreased, resulting in a remarkable increase of oxidative stress. The oxidative stress attacks DNA, lipids, and proteins and is also thought to be involved in the pathogenesis of diabetic complications, including the progression of macroangiopathy. Proliferation of smooth muscle cells (SMCs) is known to be associated with progression of macroangiopathy and is modulated by several growth factors. At least three mitogens for SMCs, platelet-derived growth factor (PDGF), fibroblast growth factor, and heparin-binding epidermal growth factor-like growth factor (HB-EGF), are known to be produced by SMCs themselves and are considered to be the most potent growth factors in the progression of macroangiopathy as seen in diabetes. HB-EGF, but not PDGF, is regulated at the transcriptional level by 3-deoxyglucosone (3-DG), a major and highly reactive intermediate in the glycation reaction. The induction seems to be triggered by the increase of reactive oxygen species produced by 3-DG. Taken together, glycation reactions under diabetic conditions may be highly associated with the pathogenesis of diabetic macroangiography by enhancing the gene expression of HB-EGF.

Topics: Animals; Aorta; Arteriosclerosis; Deoxyglucose; Diabetes Mellitus; Diabetic Angiopathies; DNA Damage; Epidermal Growth Factor; Gene Expression; Glycation End Products, Advanced; Heparin-binding EGF-like Growth Factor; Intercellular Signaling Peptides and Proteins; Muscle, Smooth, Vascular; Oxidation-Reduction; Oxidative Stress; Platelet-Derived Growth Factor; Rats; RNA, Messenger

Recent in situ hybridization studies had demonstrated a strong increase in vascular endothelial growth factor (VEGF) mRNA expression in the hyperproliferative epithelium during wound healing. To determine potential mediators of VEGF induction during this process, we analyzed the regulation of VEGF expression in cultured human keratinocytes. We found a large induction of VEGF expression upon treatment of quiescent cells with serum, epidermal growth factor, transforming growth factor-beta 1, keratinocyte growth factor, or the proinflammatory cytokine tumor necrosis factor alpha, respectively. Since all these factors are present at the wound site during the early phase of wound healing, they might also be responsible for VEGF induction after cutaneous injury. To determine the importance of increased VEGF production for wound repair, we compared the time course of VEGF mRNA expression during wound healing of healthy control mice with the kinetics of VEGF expression during skin repair of genetically diabetic db/db mice which are characterized by impaired wound healing. In normal mice we found elevated VEGF mRNA levels during the period when granulation tissue formation occurs. In contrast, VEGF mRNA levels even declined during this period in db/db mice, suggesting that a defect in VEGF regulation might be associated with wound healing disorders.

Topics: Animals; Cells, Cultured; Diabetes Mellitus; Dose-Response Relationship, Drug; Endothelial Growth Factors; Epidermal Growth Factor; Fibroblast Growth Factor 10; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Gene Expression Regulation; Growth Substances; Interleukin-10; Keratinocytes; Lymphokines; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Wound Healing

Impaired wound healing results in significant morbidity for the surgical patient. The genetically diabetic (C57BL/KsJ-db/db) mouse is obese, hyperglycemic, insulin-resistant, and exhibits markedly impaired wound healing. Previous studies have demonstrated that the fibroblast mitogens, BB homodimer of platelet-derived growth factor (PDGF-BB) or basic fibroblast growth factor, plus insulin-like growth factor, act synergistically to enhance wound closure in the genetically diabetic mouse. The purpose of this study was to determine whether the keratinocyte mitogens, epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha), in combination with the fibroblast mitogen, PDGF-BB, would produce a similar synergistic enhancement in tissue repair. Full-thickness skin wounds created on the backs of diabetic mice received topical applications of vehicle (5% polyethylene glycol), PDGF-BB (10 micrograms), EGF (1 microgram), TGF-alpha (1 microgram), or the combination of PDGF (10 micrograms) and EGF (1 microgram) or TGF-alpha (1 microgram) for 5 consecutive days starting at wounding. Application of PDGF-BB or TGF-alpha alone to wounds in diabetic animals improved wound closure when compared to vehicle treatment. EGF did not affect healing and did not have any additive effects when combined with PDGF-BB. Significant improvements in wound closure were observed with the combination of PDGF-BB and TGF-alpha when compared to treatment with the individual growth factors. The PDGF-BB/TGF-alpha combination accelerated healing in the diabetic animals to a rate that was closer to that seen in nondiabetic mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Becaplermin; Diabetes Mellitus; Drug Synergism; Epidermal Growth Factor; Female; Mice; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Recombinant Proteins; Skin; Transforming Growth Factor alpha; Wound Healing; Wounds, Penetrating

We measured the amounts of epidermal growth factor receptor (EGFR) in plasma membranes from human placentas at term delivery in three groups: appropriate for gestational age (AGA), intrauterine growth-retarded (IUGR), and diabetes mellitus-complicated (DM) pregnancies. At the same time, EGFR mRNA levels were examined in three groups by dot and Northern blot analyses. Binding studies were performed using 125I-labeled human EGF as a ligand, and two classes (high and low) of binding sites were found in all specimens. Although dissociation constants (Kd) were not significantly different among three groups, the number of binding sites was significantly decreased in IUGR and DM placentas compared to that in the AGA group. Total cellular RNA was isolated from a part of the placentas used for binding studies using the guanidinium CsCl method, denatured, and dot blotted onto nitrocellulose filter. Poly(A)+ RNA was selected from the total RNA, electrophoresed in 1% agarose gel, and transferred onto nitrocellulose filters. Then, hybridization with 32P-labeled pE7 (a cDNA of EGFR), autoradiography, and densitometry were performed. The amounts of mRNA hybridized with pE7 were reduced in IUGR and DM placentas compared to that in the AGA group. The molecular sizes of EGFR mRNA were 10 and 5.6 kilobases in all three groups. These results suggest possible physiological actions of EGF on adequate feto-placental growth and development in human pregnancy.

Topics: Diabetes Mellitus; Epidermal Growth Factor; ErbB Receptors; Female; Fetal Growth Retardation; Humans; Placenta; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Reference Values; RNA, Messenger

Epidermal and platelet-derived growth factors are potent mitogens for many types of cells, including smooth muscle cells. Epidermal growth factor in blood of humans is present both in platelets (as reflected in its serum level) and in plasma, the source(s) of which remains unknown. We assayed its level in 82 diabetic patients and 53 age-matched controls. In diabetes, epidermal growth factor level was increased in serum (191 +/- 43 vs 155 +/- 64 pmol/l, p = 0.0002) and plasma (53 +/- 9 vs 38 +/- 14 pmol/l, p less than 0.0001), without any difference between the patients with and without complications. Platelet-derived growth factor level was assayed only in serum of 19 patients with uncomplicated diabetes and found elevated (222 +/- 47) as compared with 13 controls (160 +/- 26 pmol/l), (p = 0.0002). Type of diabetes, its duration, mode of therapy, control, presence of retinopathy or albuminuria (in case of epidermal growth factor), as well as C-peptide age and sex did not correlate with epidermal or platelet-derived growth factor levels. Serum but not plasma epidermal and platelet-derived growth factor were negatively correlated with serum creatinine (correspondingly, r = -0.373, p = 0.0008 and r = -0.564, p = 0.0285). It is concluded that diabetes itself and not its complications cause increased levels of epidermal growth factor in plasma and serum and of platelet-derived growth factor in serum.

Topics: Adult; Aged; C-Peptide; Diabetes Mellitus; Epidermal Growth Factor; Female; Humans; In Vitro Techniques; Male; Middle Aged; Platelet-Derived Growth Factor; Radioimmunoassay; Regression Analysis

Peritoneal effluent in CAPD patients is the result of the interaction between dialysate and patient through the peritoneal membrane. Among the factors transferred from the patient to dialysate are solutes capable of stimulating fibroblasts: Interleukin-I, Interferon-gamma, and other proteins. Insulin is a well known mitogenic coadjuvant able to act sinergistically with other mitogens in the stimulation of fibroblast proliferation under experimental conditions. Our objective has been to study the effect of insulin added to dialysate in vivo on the in vitro mitogen-induced capacity of the nocturnal peritoneal effluent in 8 diabetics. Two different samples were studied: basal and with in vivo added insulin with the patients' usual doses. A Swiss 3T3 line of mice fibroblasts was used for studies, adding 50 microliters of peritoneal effluent. To confirm in vivo potential mitogenic activity, we also added PDBu (Phorbol dibuturate), a well known mitogenic agent, to both samples. Furthermore, another growth factor, EGF (Epidermal growth factor), was also added to 5 other samples. Insulin addition to the CAPD bag transforms a non-mitogenic peritoneal effluent into a mitogenic one (mean: 4.4 times over basal). At the doses used in vivo there is no linear correlation between insulin dose and DNA synthesis (r: -0.28, NS). Both PDBu and EGF in vitro addition induced a remarkable increment in the mitogenic capacity of the peritoneal effluent. We conclude that insulin added to CAPD bags behaves as a remarkable mitogenic coadjuvant for mice fibroblasts. Consequently, its long-term and universal clinical use should be reconsidered.

Topics: Animals; Cells, Cultured; Diabetes Mellitus; Diabetic Nephropathies; Dialysis Solutions; Epidermal Growth Factor; Fibroblasts; Humans; Insulin; Mice; Mice, Inbred Strains; Mitosis; Peritoneal Dialysis, Continuous Ambulatory; Phorbol 12,13-Dibutyrate

Topics: Animals; Cell Membrane; Cells, Cultured; Diabetes Mellitus; Epidermal Growth Factor; ErbB Receptors; Hormones; Humans; Insulin Resistance; Macromolecular Substances; Mice; Microscopy, Fluorescence; Models, Biological; Receptor, Insulin; Receptors, Cell Surface