Advanced glycation end products regulate macrophage apoptosis and influence the healing of diabetic foot wound through miR-361-3p/CSF1R and PI3K/AKT pathway
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SUBMITTER: Jin Y
PROVIDER: S-EPMC10835292 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundDiabetic chronic foot ulcers pose a significant therapeutic challenge around the world, resulting in adverse effects and complications in patients. D-mannose is enriched in cirtus peel and exerts beneficial effects among various diseases, especially against inflammation-related disorders.MethodsHere, we examined the potential effect of D-mannose during wound healing process in streptozotocin (STZ)-induced diabetes mice in vivo and by culturing keratinocytes under high glucose condition in vitro. The skin lesion healing was recorded in photos and evaluated by histochemical staining. What's more, the advanced glycation end products (AGEs) concentration in blood and mice skin was quantified. Apoptotic cells were assessed by flow cytometry and Western blotting. Inflammatory cytokines and cellular differential gene expression levels were measured by real-time PCR. The expression of the AMPK/Nrf2/HO-1 signaling-related molecules was determined by Western blotting.ResultsWe first found that topical supplementation of D-mannose remarkably improved skin wound healing in diabetes mice. Furthermore, both in vivo and in vitro experiments demonstrated that D-mannose reduced the AGEs generation. Mechanistically, D-mannose inhibited AGEs, then upregulated AMPK/Nrf2/HO-1 signaling in the context of high glucose to maintain keratinocyte normal functions, which positively influenced macrophage and fibroblast to accelerate diabetic wound healing. Noteworthily, these protective effects of D-mannose were abolished by the pretreatment with inhibitors of AGEs or AMPK.ConclusionAs far as we know, this is the first study exploring the protective role of D-mannose on diabetic wound healing via topical supplementation. We find that D-mannose protects keratinocytes from high glucose stimulation via inhibition of AGEs formation as well as orchestrates inflammatory microenvironment in diabetic wounded skin, suggesting its supplementation as a potential therapy to promote refractory wound healing in diabetic patients.
| S-EPMC11748336 | biostudies-literature
Project description:Purpose:We used a human corneal epithelial cell (HCE) line to determine the involvement of the advanced glycation end products (AGEs) / receptor for AGEs (RAGE) couple in corneal epithelium wound healing. Methods:After wounding, HCE cells were exposed to two major RAGE ligands (HMGB1 and AGEs), and wound healing was evaluated using the in vitro scratch assay. Following wound healing, the HCE cells were used to study the influence of the RAGE ligands on HCE proliferation, invasion, and migration. Activation of the nuclear factor (NF)-κB signaling pathway by the AGEs/RAGE couple was tested using a luciferase reporter assay. Functional transcriptional regulation by this pathway was confirmed by quantification of expression of the connexin 43 target gene. For each experiment, specific RAGE involvement was confirmed by small interfering RNA treatments. Results:AGEs treatment at a dose of 100 µg/mL significantly improved the wound healing process in a RAGE-dependent manner by promoting cell migration, whereas HMGB1 had no effect. No significant influence of the AGEs/RAGE couple was observed on cell proliferation and invasion. However, this treatment induced an early activation of the NF-κB pathway and positively regulated the expression of the target gene, connexin 43, at both the mRNA and protein levels. Conclusions:Our results demonstrate that the RAGE pathway is activated by AGEs treatment and is involved in the promotion of corneal epithelial wound healing. This positive action is observed only during the early stages of wound healing, as illustrated by the quick activation of the NF-κB pathway and induction of connexin 43 expression.
| S-EPMC7401750 | biostudies-literature
Project description:Diabetic keratopathy (DK) is an important diabetic complication at the ocular surface. Chronic low-grade inflammation mediated by the NLRP3 inflammasome promotes pathogenesis of diabetes and its complications. However, the effect of the NLRP3 inflammasome on DK pathogenesis remains elusive. Wild-type (WT) and Nlrp3 knockout (KO) C57 mice were used to establish a type I diabetes model by intraperitoneal injection of streptozotocin. The effect of the NLRP3 inflammasome on diabetic corneal wound healing and never regeneration was examined by a corneal epithelial abrasion model. Western blot, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA) and pharmacological treatment were performed to investigate the regulatory mechanism of advanced glycation end products (AGEs) on NLRP3 inflammasome activation and corneal wound healing in vivo. The cultured mouse corneal epithelial cells (TKE2) were used to evaluate the effect and mechanism of AGEs on NLRP3 inflammasome activation in vitro. We revealed that NLRP3 inflammasome-mediated inflammation and pyroptosis contributed to DK pathogenesis. Under physiological conditions, the NLRP3 inflammasome was required for corneal wound healing and nerve regeneration. However, under a diabetic scenario, sustained activation of the NLRP3 inflammasome resulted in postponed corneal wound healing and impaired nerve regeneration. Mechanistically, the accumulated AGEs promoted hyperactivation of the NLRP3 inflammasome through ROS production. Moreover, genetically and pharmacologically blocking the AGEs/ROS/NLRP3 inflammasome axis significantly expedited diabetic corneal epithelial wound closure and nerve regeneration. Our results revealed that AGEs-induced hyperactivation of the NLRP3 inflammasome resulted in delayed diabetic corneal wound healing and impaired nerve regeneration, which further highlighted the NLRP3 inflammasome as a promising target for DK treatment.
| S-EPMC8741862 | biostudies-literature
Project description:Chronic and non-healing skin wounds are some of the most significant complications in patients with advanced diabetes. A contributing mechanism to this pathology is the non-enzymatic glycation of proteins due to hyperglycemia, leading to the formation of advanced glycation end products (AGEs). AGEs bind to the receptor for AGEs (RAGE), which triggers pro-inflammatory signals that may inhibit the proliferative phase of wound healing. Soluble forms of RAGE (sRAGE) may be used as a competitive inhibitor of AGE-mediated signaling; however, sRAGE is short-lived in the highly proteolytic wound environment. We developed a recombinant fusion protein containing the binding domain of RAGE (vRAGE) linked to elastin-like polypeptides (ELPs) that self-assembles into coacervates at around 30-31 °C. The coacervate size was concentration and temperature-dependent, ranging between 500 and 1600 nm. vRAGE-ELP reversed several AGE-mediated changes in cultured human umbilical vein endothelial cells, including a decrease in viable cell number, an increase in levels of reactive oxygen species (ROS), and an increased expression of the pro-inflammatory marker, intercellular adhesion molecule-1 (ICAM-1). vRAGE-ELP was stable in elastase in vitro for 7 days. When used in a single topical application on full-thickness excisional skin wounds in diabetic mice, wound closure was accelerated, with 90% and 100% wound closure on post-wounding days 28 and 35, respectively, compared to 62% and 85% on the same days in animals treated with vehicle control, consisting of ELP alone. This coacervate system topically delivering a competitive inhibitor of AGEs has potential for the treatment of diabetic wounds.
| S-EPMC10927318 | biostudies-literature
Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. Recently, disorders of metabolism are thought to be the center of many diseases such as OPLL. Advanced glycation end product (AGE) are accumulated in many extracellular matrixes such as ligament fibers, and it can functions as cellular signal through its receptor (RAGE), contributing to various events such as atherosclerosis or oxidative stress. However, its role in OPLL formation is not yet known. Therefore, we performed high-through-put RNA sequencing on primary posterior longitudinal ligament cells treated with different doses of AGEs (1µM, 5µM and negative control), with or without BMP2 (1µM).
2016-02-16 | GSE65952 | GEO
Project description:This study was aimed to correlate the pre- and 6-month postpercutaneous coronary intervention (PCI) serum concentrations of advanced glycation end products (AGE), soluble receptors for advanced glycation end products (sRAGE), AGE/sRAGE ratio, and serum malondialdehyde (MDA) levels with in-stent restenosis (ISR) among patients receiving either a drug-eluting stent (DES) or a bare-metal stent (BMS).In-stent restenosis remains as an adverse outcome following PCI. Sixty consecutive nondiabetic, Caucasian male patients, diagnosed with a non-ST-elevation myocardial infarction who received either a DES or BMS via PCI, were enrolled. Baseline levels of serum AGE, sRAGE, AGE/sRAGE ratios, MDA, and angiographic parameters were determined at stenting and at 6 months. Patients with and without ISR at 6 months were compared on both baseline and 6-month biomarker levels and within stent types.The pre-PCI serum AGE levels and AGE/sRAGE ratios were higher in ISR patients compared with non-ISR patients, while the pre-PCI and post-PCI serum sRAGE levels were lower in ISR patients compared with non-ISR patients. The pre and post-PCI levels of MDA were also higher in ISR patients. Comparing stent types, relative levels of MDA between those with and without ISR at the respective time points were similar, although changes between time points appeared type specific.Post-PCI ISR correlates with low serum values of sRAGE and high serum values of AGE, MDA, and AGE/sRAGE ratio which are present at stenting. The associations of baseline AGE, sRAGE, AGE/sRAGE, and MDA levels with ISR appear consistent between stent types.
| S-EPMC6221796 | biostudies-literature
Project description:Aims/objectivesWound healing in people with diabetes is delayed secondary to impaired nitric oxide generation, advanced glycation end products (AGE), and poor migration of epithelial cells. We developed a novel topical esmolol hydrochloride (Galnobax) and assessed its efficacy for wound healing in streptozocin-induced diabetic hairless rat.MethodsAll experiments were performed at an animal laboratory and tertiary-care research facility. Ex vivo aldose reductase inhibition was assessed from enzymes obtained from a bacterial culture (spectrophotometer), sorbitol content in homogenized red blood cells, and AGE in glucose and bovine serum by fluorometry following the addition of esmolol in varying concentrations. A scratch assay of human fibroblasts, endothelial cells, and keratinocytes was assessed under a high-glucose environment and after esmolol by phase-contrast microscopy. The efficacy evaluation of the topical application of Galnobax (14 and 20%) or vehicle was conducted in streptozotocin-induced diabetic hairless rats, and endogenous nitrite and hydroxyproline from homogenized wound tissue were measured along with pharmacokinetic and dermal toxicity in Hanford miniature swine.ResultsEsmolol inhibited the formation of sorbitol by 59% in erythrocytes in comparison to glucose-induced sorbitol levels. AGE generation in bovine serum albumin was reduced at 1 mM esmolol concentrations (2.6 ± 1.7) compared with control (p < 0.05) and similar to that of diclofenac (2.5 ± 1.3). Esmolol at 1 and 10 µM enhanced the migration of fibroblasts, epithelial cells, and keratinocytes compared with control. The nitric oxide levels (day 7) were 44 and 112% higher with Galnobax (14%) than those of the diabetic group (p < 0.05) and the vehicle control group (p < 0.05), respectively. The days 7 and 14 hydroxyproline in the wound was higher by 22 and 44% following Galnobax (14%) compared with the diabetic and vehicle control groups. The wound area exhibited better reduction with Galnobax at 14% up to day 10 follow-up compared with the controls. The pharmacokinetic and dermal toxicity in miniature swine suggested no significant adverse event with Galnobax.ConclusionsTopical esmolol hydrochloride is a novel, safe, and effective treatment modality that acts through pleotropic mechanisms to hasten wound healing in diabetes.
| S-EPMC9446078 | biostudies-literature
Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. Recently, disorders of metabolism are thought to be the center of many diseases such as OPLL. Advanced glycation end product (AGE) are accumulated in many extracellular matrixes such as ligament fibers, and it can functions as cellular signal through its receptor (RAGE), contributing to various events such as atherosclerosis or oxidative stress. However, its role in OPLL formation is not yet known. Therefore, we performed high-through-put RNA sequencing on primary posterior longitudinal ligament cells treated with different doses of AGEs (1µM, 5µM and negative control), with or without BMP2 (1µM). mRNA profiles of Primary human posterior longitudinal ligament cells stimulated with various stimuli (Control, 1µM AGE-BSA, 5µM AGE-BSA, 1µM AGE-BSA with BMP2, 5µM AGE-BSA with BMP2) were generated by deep sequencing on Ion Proton
2016-02-16 | E-GEOD-65952 | biostudies-arrayexpress
Project description:Advanced glycation end-products (AGEs) are proteins or lipids glycated nonenzymatically by glucose, or other reducing sugars and their derivatives, such as glyceraldehyde, glycolaldehyde, methyloglyoxal and acetaldehyde. There are three different means of AGE formation: i) Maillard reactions, the polyol pathway and lipid peroxidation. AGEs participate in the pathological mechanisms underlying the development of several diseases, such as diabetes and its complications, retinopathy or neuropathy, neurological disorders (for example, Parkinson's disease and Alzheimer's disease), atherosclerosis, hypertension and several types of cancer. AGE levels are increased in patients with hyperglycaemia, and is likely the result of the high concentration of glycation substrates circulating in the blood. The present review summarises the formation and nomenclature of advanced glycation end-products, with an emphasis on the role of AGEs in the development of diabetes, neurological disorders, as well as in cancer and other pathologies. A particular focus is placed on the functions of toxic AGEs. Additionally, studies which have shown the cytotoxicity of glycated albumin and other AGEs are also discussed. Finally, the diagnostic relevance of AGEs as well as for targeting in therapeutic strategies are highlighted.
| S-EPMC7995243 | biostudies-literature
Project description:Choroidal neovascularisation (CNV) causes severe vision loss among old patients, especially those with diabetes. Previously, Cyr61 has been found to play a critical role in the pathogenesis of both AMD and diabetes. In the present study, we found that increased CNV severity together with higher expression of Cyr61 and VEGF in diabetes mice compared with control mice. Moreover, knockdown of Cyr61 decreased CNV severity. In vitro mechanism study revealed that the advanced glycation end products (AGEs) significantly increased the expression of Cyr61 in retinal pigment epithelial (RPE) cells, mimicking the effects of diabetes. In turn, the increased Cyr61 enhanced VEGF expression through FAK and PI3K/Akt pathways. Chemically blocking the above pathway significantly inhibited CNV formation, providing a new strategy for clinical prevention and treatment of CNV in related diseases.
| S-EPMC5668426 | biostudies-literature