Wound Healing In Diabetic Mice Research Articles

Improving Cutaneous Wound Healing in Diabetic Mice Using Naturally Derived Tissue-Engineered Biological Dressings Produced under Serum-Free Conditions.

Long-term diabetes often leads to chronic wounds refractory to treatment. Cell-based therapies are actively investigated to enhance cutaneous healing. Various cell types are available to produce biological dressings, such as adipose-derived stem/stromal cells (ASCs), an attractive cell source considering their abundancy, accessibility, and therapeutic secretome. In this study, we produced human ASC-based dressings under a serum-free culture system using the self-assembly approach of tissue engineering. The dressings were applied every 4 days to full-thickness 8-mm splinted skin wounds created on the back of polygenic diabetic NONcNZO10/LtJ mice and streptozotocin-induced diabetic K14-H2B-GFP mice. Global wound closure kinetics evaluated macroscopically showed accelerated wound closure in both murine models, especially for NONcNZO10/LtJ; the treated group reaching 98.7% ± 2.3% global closure compared to 76.4% ± 11.8% for the untreated group on day 20 (p=0.0002). Histological analyses revealed that treated wounds exhibited healed skin of better quality with a well-differentiated epidermis and a more organized, homogeneous, and 1.6-fold thicker granulation tissue. Neovascularization, assessed by CD31 labeling, was 2.5-fold higher for the NONcNZO10/LtJ treated wounds. We thus describe the beneficial impact on wound healing of biologically active ASC-based dressings produced under an entirely serum-free production system facilitating clinical translation.

Facile Reactive Oxygen Species-Scavenging Supramolecular Hydrogel to Promote Diabetic Wound Healing.

Chronic wound healing impairment is a significant complication in diabetes. Hydrogels that maintain wound moisture and enable sustained drug release have become prominent for enhancing chronic wound care. Particularly, hydrogels that respond to reactive oxygen species (ROS) are sought-after for their dual capacity to mitigate ROS and facilitate controlled drug delivery at the wound site. We have strategically designed an ROS-responsive and scavenging supramolecular hydrogel composed of the simple hexapeptide Glu-Phe-Met-Phe-Met-Glu (EFM). This hydrogelator, composed solely of canonical amino acids without additional ROS-sensitive motifs, forms a hydrogel rapidly upon sonication. Interaction with ROS leads to the oxidation of Met residues to methionine sulfoxide, triggering hydrogel disassembly and consequent payload release. Cellular assays have verified their biocompatibility and efficacy in promoting cell proliferation and migration. In vivo investigations underscore the potential of this straightforward hydrogel as an ROS-scavenger and drug delivery vehicle, enhancing wound healing in diabetic mice. The simplicity and effectiveness of this hydrogel suggest its broader biomedical applications in the future.

Effect of Application of Autologous Conditioned Serum on Wound Healing in Diabetic Mice Through Inhibition of STING Pathway Activation.

Slow wound healing in diabetic patients is a common complication of diabetes. Autologous conditioned serum (ACS) therapy is an emerging and safe biological therapy, and may accelerate the wound healing in diabetes. To investigate the effect of ACS in promoting wound healing in diabetic mice and its possible mechanism. Twenty-four six-week-old male C57BL/6J mice were selected and divided into 5 groups, including control group (Ctrl), diabetic wound group (DW), ACS treatment group (DW+ACS) and STING pathway validation group (DW+ACS+DMXAA), with six mice in each group. Intervention was initiated after the back incision was performed, and wound healing was assessed on day 0, day 7, and day 14, and wound healing was assessed by hematoxylin and eosin (HE) staining of skin tissue on day 14. At the same time, the wound healing of the fibroblast markers collagen I and α-SMA was measured by immunohistochemistry and western blot. ACS treatment significantly accelerated the diabetic wound according to the wound area and HE staining results. Meanwhile, collagen I and α-SMA concentration evaluated by immunohistochemistry and western blot were remarkably elevated under the ACS interference. The STING signaling pathway was obviously activated in diabetic wound tissues. After the addition of DMXAA, an agonist of STING, the healing function of ACS was dramatically reversed. The application of ACS promotes wound healing in diabetic mice by enhancing fibroblasts. Meanwhile, the STING signaling pathway was inactivated by ACS interference. Hence, ACS can be used in the treatment of wound healing of Diabetes.

Gelatin Microspheres Based on H8-Loaded Macrophage Membrane Vesicles to Promote Wound Healing in Diabetic Mice.

Diabetic wound healing remains a worldwide challenge for both clinicians and researchers. The high expression of matrix metalloproteinase 9 (MMP9) and a high inflammatory response are indicative of poor diabetic wound healing. H8, a curcumin analogue, is able to treat diabetes and is anti-inflammatory, and our pretest showed that it has the potential to treat diabetic wound healing. However, H8 is highly expressed in organs such as the liver and kidney, resulting in its unfocused use in diabetic wound targeting. (These data were not published, see Table S1 in the Supporting Information.) Accordingly, it is important to pursue effective carrier vehicles to facilitate the therapeutic uses of H8. The use of H8 delivered by macrophage membrane-derived nanovesicles provides a potential strategy for repairing diabetic wounds with improved drug efficacy and fast healing. In this study, we fabricated an injectable gelatin microsphere (GM) with sustained MMP9-responsive H8 macrophage membrane-derived nanovesicles (H8NVs) with a targeted release to promote angiogenesis that also reduces oxidative stress damage and inflammation, promoting diabetic wound healing. Gelatin microspheres loaded with H8NV (GMH8NV) stimulated by MMP9 can significantly facilitate the migration of NIH-3T3 cells and facilitate the development of tubular structures by HUVEC in vitro. In addition, our results demonstrated that GMH8NV stimulated by MMP9 protected cells from oxidative damage and polarized macrophages to the M2 phenotype, leading to an inflammation inhibition. By stimulating angiogenesis and collagen deposition, inhibiting inflammation, and reducing MMP9 expression, GMH8NV accelerated wound healing. This study showed that GMH8NVs were targeted to release H8NV after MMP9 stimulation, suggesting promising potential in achieving satisfactory healing in diabetic treatment.

Assessment of wound healing activity in diabetic mice treated with a novel therapeutic combination of selenium nanoparticles and platelets rich plasma

Diabetic wound healing is sluggish, often ending in amputations. This study tested a novel, two-punch therapy in mice—Selenium nanoparticles (Se NPs) and platelet-rich plasma (PRP)—to boost healing. First, a mouse model of diabetes was created. Then, Se NPs were crafted for their impressive antioxidant and antimicrobial powers. PRP, packed with growth factors, was extracted from the mice's blood. Wound healing was tracked for 28 days through photos, scoring tools, and tissue analysis. Se NPs alone spurred healing, and PRP added extra fuel. Furthermore, when used in combination with PRP, the healing process was accelerated due to the higher concentration of growth factors in PRP. Notably, the combination of Se NPs and PRP exhibited a synergistic effect, significantly enhancing wound healing in diabetic mice. These findings hold promise for the treatment of diabetic wounds and have the potential to reduce the need for lower limb amputations associated with diabetic foot ulcers. The innovative combination therapy using Se NPs and PRP shows great potential in expediting the healing process and addressing the challenges of impaired wound healing in individuals with diabetes. This exciting finding suggests this therapy could change diabetic wound management, potentially saving limbs and improving lives.

Cathelicidin LL-37 promotes wound healing in diabetic mice by regulating TFEB-dependent autophagy

Diabetic patients often experience impaired wound healing. Human cathelicidin LL-37 possesses various biological functions, such as anti-microbial, anti-inflammatory, and pro-wound healing activities. Autophagy has important effects on skin wound healing. However, little is known about whether LL-37 accelerates diabetic wound healing by regulating autophagy. In the study, we aimed to investigate the role of autophagy in LL-37-induced wound healing and uncover the underlying mechanisms involved. A full-thickness wound closure model was established in diabetic mice to evaluate the effects of LL-37 and an autophagy inhibitor (3-MA) on wound healing. The roles of LL-37 and 3-MA in regulating keratinocyte migration were assessed using transwell migration and wound healing assays. The activation of transcription factor EB (TFEB) was measured using western blotting and immunofluorescence (IF) assays of its nuclear translocation. The results showed that LL-37 treatment improved wound healing in diabetic mice, whereas these effects were reversed by 3-MA. In vitro, 3-MA decreased the effects of LL-37 on promoting HaCat keratinocyte migration in the presence of high glucose (HG). Mechanistically, LL-37 promoted TFEB activation and resulted in subsequent activation of autophagy, as evidenced by increased nuclear translocation of TFEB and increased expression of ATG5, ATG7, and beclin 1 (BECN1), whereas these changes were blocked by TFEB knockdown. As expected, TFEB knockdown damaged the effects of LL-37 on promoting keratinocyte migration. Collectively, these results suggest that LL-37 accelerates wound healing in diabetic mice by activating TFEB-dependent autophagy, providing new insights into the mechanism by which LL-37 promotes diabetic wound healing.

The Combination of Vascular Endothelial Growth Factor A (VEGF-A) and Fibroblast Growth Factor 1 (FGF1) Modified mRNA Improves Wound Healing in Diabetic Mice: An Ex Vivo and In Vivo Investigation.

Diabetic foot ulcers (DFU) pose a significant health risk in diabetic patients, with insufficient revascularization during wound healing being the primary cause. This study aimed to assess microvessel sprouting and wound healing capabilities using vascular endothelial growth factor (VEGF-A) and a modified fibroblast growth factor (FGF1). An ex vivo aortic ring rodent model and an in vivo wound healing model in diabetic mice were employed to evaluate the microvessel sprouting and wound healing capabilities of VEGF-A and a modified FGF1 both as monotherapies and in combination. The combination of VEGF-A and FGF1 demonstrated increased vascular sprouting in the ex vivo mouse aortic ring model, and topical administration of a combination of VEGF-A and FGF1 mRNAs formulated in lipid nanoparticles (LNPs) in mouse skin wounds promoted faster wound closure and increased neovascularization seven days post-surgical wound creation. RNA-sequencing analysis of skin samples at day three post-wound creation revealed a strong transcriptional response of the wound healing process, with the combined treatment showing significant enrichment of genes linked to skin growth. f-LNPs encapsulating VEGF-A and FGF1 mRNAs present a promising approach to improving the scarring process in DFU.

Promoting the healing of diabetic wounds with an antimicrobial gel containing AgNPs with anti-infective and anti-inflammatory properties

Diabetic wounds are prone to develop chronic wounds due to bacterial infection and persistent inflammatory response. However, traditional dressings are monofunctional, lack bioactive substances, have limited bacterial inhibition as well as difficulties in adhesion and retention. These limit the therapeutic efficacy of traditional dressings on diabetic wounds. Therefore, finding and developing efficient and safe wound dressings is currently an urgent clinical need. In this study, an antimicrobial gel loaded with silver nanoparticles (AgNPs) (referred to as AgNPs@QAC-CBM) was prepared by crosslinking quaternary ammonium chitosan (QAC) with carbomer (CBM) as a gel matrix. AgNPs@QAC-CBM exhibited a reticulated structure, strong adhesion, good stability, and remarkable bactericidal properties, killing 99.9% of Escherichia coli, Staphylococcus aureus, Candida albicans, and Pseudomonas aeruginosa within 1 min. Furthermore, AgNPs@QAC-CBM improved the wound microenvironment and accelerated wound healing in diabetic mice by promoting tissue production and collagen deposition, inducing M2 macrophages, reducing pro-inflammatory factor secretion and increasing anti-inflammatory factor levels. Moreover, AgNPs@QAC-CBM was proven to be safe for use through skin irritation and cytotoxicity tests, as they did not cause any irritation or toxicity. To summarize, AgNPs@QAC-CBM showed promising potential in enhancing the diabetic wound healing process.

Improving depression-like behaviors caused by diabetes is likely to offer a new perspective for the treatment of non-healing chronic wounds.

Three phases are often involved in the intricate process of wound healing: inflammatory exudation, cell proliferation, and tissue remodeling. It is challenging for wounds to heal if conditions like ischemia, persistent pressure, infection, repetitive trauma, or systemic or localized illnesses arise during the healing process. Chronic wounds are persistent injuries that do not follow the normal healing process and fail to progress through the stages of healing within a reasonable timeframe, like diabetic ulcers, vascular ulcers, pressure sores, and infectious wounds. Various factors affect chronic wound healing. A large body of research has illuminated that psychological distress may often be related to wound healing in clinical settings. Our observations have indicated that the pace of wound healing in diabetic mice is generally slower than that of healthy mice, and mice induced by streptozotocin (STZ) and fed a high-fat diet generally exhibit depression-like behavior. Our experiment delves into whether there is an inherent correlation and provides new ideas for clinical treatment to promote wound healing. In order to explore the relationship between diabetes, depression, and wound healing, we observed wound healing through HE staining, Masson's trichrome staining, and IHC staining for CD31 and detected the depressive condition through behavioral tests. Then, RT-PCR was used to detect the mRNA expression levels of α-SMA, Col1, CD31, and VEGF in wound tissue. Finally, the related brain areas were regulated through chemical genetic methods and the process of wound healing was observed. It has been observed that the lateral habenula (LHb) areas are associated with depression-like behavior induced by diabetes. Inhibiting LHb neuronal activity mitigates these depressive symptoms and enhances wound healing. Refractory wounds can be improved by considering patients' emotional issues from a broad standpoint, which provides fresh concepts for potential clinical treatments in the future.

Polyvinyl alcohol/carboxymethyl chitosan-based hydrogels loaded with taxifolin liposomes promote diabetic wound healing by inhibiting inflammation and regulating autophagy

With the improvement of modern living standards, the challenge of diabetic wound healing has significantly impacted the public health system. In this study, our objective was to enhance the bioactivity of taxifolin (TAX) by encapsulating it in liposomes using a thin film dispersion method. Additionally, polyvinyl alcohol/carboxymethyl chitosan-based hydrogels were prepared through repeated freeze-thawing. In vitro and in vivo experiments were conducted to investigate the properties of the hydrogel and its effectiveness in promoting wound healing in diabetic mice. The results of the experiments revealed that the encapsulation efficiency of taxifolin liposomes (TL) was 89.80 ± 4.10 %, with a drug loading capacity of 17.58 ± 2.04 %. Scanning electron microscopy analysis demonstrated that the prepared hydrogels possessed a porous structure, facilitating gas exchange and the absorption of wound exudates. Furthermore, the wound repair experiments in diabetic mice showed that the TL-loaded hydrogels (TL-Gels) could expedite wound healing by suppressing the inflammatory response and promoting the expression of autophagy-related proteins. Overall, this study highlights that TL-Gels effectively reduce wound healing time by modulating the inflammatory response and autophagy-related protein expression, thus offering promising prospects for the treatment of hard-to-heal wounds induced by diabetes.

Photosynthetic live microorganism-incorporated hydrogels promote diabetic wound healing via self-powering and oxygen production

Electrical stimulation and oxygen are vital for promoting cell proliferation, migration, and differentiation to repair damaged tissues in chronic wound healing in patients with diabetes. The effective oxygen production by Chlorella has garnered attention in the medical field, but the potential of extracellular electron production in skin repair has not been explored. Inspired by this, we developed CHPS hydrogels, a composite of polyacrylamide and sodium alginate, with Chlorella loaded in a semi-interpenetrating network. This network is formed by crosslinking acrylamide initiated by free radicals, with alginate chains dispersed within the network. When applied to wounds, CHPS hydrogels effectively protect damaged tissue, provide mechanical support to Chlorella against external forces, and create an optimal artificial microenvironment to promote the proliferation of Chlorella. Our study demonstrated that CHPS hydrogels exhibit remarkable fracture elongation and adhesion properties and continuously produce oxygen and bioelectrical currents through photosynthesis. Furthermore, the sustained release of dissolved oxygen and bioelectricity by CHPS hydrogels significantly enhances cell proliferation, migration, and angiogenesis, leading to improved wound healing in diabetic mice. These findings provide compelling evidence for further exploration of CHPS hydrogels as a cost-effective, simple, and accessible strategy for enhancing the clinical treatment of chronic wounds in diabetic patients.

Effect of Mexican Propolis on Wound Healing in a Murine Model of Diabetes Mellitus.

Diabetes mellitus (DM) affects the wound healing process, resulting in impaired healing or aberrant scarring. DM increases reactive oxygen species (ROS) production, fibroblast senescence and angiogenesis abnormalities, causing exacerbated inflammation accompanied by low levels of TGF-β and an increase in Matrix metalloproteinases (MMPs). Propolis has been proposed as a healing alternative for diabetic patients because it has antimicrobial, anti-inflammatory, antioxidant and proliferative effects and important properties in the healing process. An ethanolic extract of Chihuahua propolis (ChEEP) was obtained and fractionated, and the fractions were subjected to High-Performance Liquid Chromatography with diode-array (HPLC-DAD), High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) and Gas Chromatography-Mass Spectrometry (GC-MS) analyses and 46 compounds were detected. Deep wounds were made in a murine DM model induced by streptozotocin, and the speed of closure and the wound tensile strength were evaluated by the tensiometric method, which showed that ChEEP had similar activity to Recoveron, improving the speed of healing and increasing the wound tensile strength needed to open the wound again. A histological analysis of the wounds was performed using H&E staining, and when Matrix metalloproteinase 9 (MMP9) and α-actin were quantified by immunohistochemistry, ChEEP was shown to be associated with improved histological healing, as indicated by the reduced MMP9 and α-actin expression. In conclusion, topical ChEEP application enhances wound healing in diabetic mice.

Exosomes derived from BMSCs enhance diabetic wound healing through circ-Snhg11 delivery

BackgroundExosomes (Exos) generated from bone mesenchymal stem cells (BMSCs) are elucidated to enhance cutaneous wound healing in mice models of diabetes mellitus (DM). While underlying mechanisms remain unknown.MethodsNext-generation sequencing (NGS) was used to examine changes in circRNA expression levels following Exo treatment. Luciferase assays were used to determine the interactions between RNAs. Immunofluorescence staining was used to examine reactive oxygen species (ROS) in endothelial progenitor cells (EPCs) cultured in high glucose (HG) conditions. Therapeutic effects regarding Exos were also examined by immunofluorescence.ResultsWe found that Exo treatment enhanced cutaneous wound healing significantly. NGS indicated that circ-Snhg11 was involved in Exo-mediated tissue repairing. Downregulation of circ-Snhg11 decreased Exo-mediated therapy responses during wound healing in diabetic mouse. Our luciferase reporter data confirmed that SLC7A11 and miR-144-3p were circ-Snhg11 downstream targets. miR-144-3p overexpression or SLC7A11 knockdown altered the protective effects of circ-Snhg11 upon EPCs exposed to HG conditions. Upregulation of circ-Snhg11 incremented therapy effects of Exo treatment during wound healing in DM mice through enhanced angiogenesis along with a reduction in GPX4-mediated ferroptosis.Conclusionscirc-Snhg11 in BMSC-Exos enhanced SLC7A11/GPX4-mediated anti-ferroptosis signals via miR-144-3p sponging resulting in enhanced diabetic wound healing and improved angiopoiesis.

Fabrication, Characterization and Wound-Healing Properties of Core-Shell SF@chitosan/ZnO/Astragalus Arbusculinus Gum Nanofibers.

Silk fibroin/chitosan/ZnO/Astragalus arbusculinus (Ast) gum fibrous scaffolds along with adipose-derived mesenchymal stem cells (ADSCs) were investigated for accelerating diabetic wound healing. Scaffolds with a core-shell structure and different compositions were synthesized using the electrospinning method. Biological in vitro investigations included antibacterial testing, cell viability analysis and cell attachment evaluation. In vivo experiments, including the chicken chorioallantoic membrane (CAM) test, were conducted to assess wound-healing efficacy and histopathological changes. The incorporation of Ast to the silk fibroin@ chitosan/ZnO scaffold improved wound healing in diabetic mice. In addition, seeding of ADSCs on the scaffold accelerated wound healing. These findings suggest that the designed scaffold can be useful for skin regeneration applications.

Hybrid Self-Assembled Peptide Hydrogels Promote Skin Wound Healing in Diabetic Mice

Hybrid Self-Assembled Peptide Hydrogels Promote Skin Wound Healing in Diabetic Mice

Apigenin accelerates wound healing in diabetic mice by promoting macrophage M2-type polarization via increasing miR-21 expression.

The alteration of inflammatory phenotype by macrophage polarization plays an important role in diabetic wound repair. Apigenin has been reported to be anti-inflammatory and promote tissue repair; however, whether it regulates macrophage polarization to participate in diabetic wound repair remains to be investigated. We found that apigenin promoted miR-21 expression in LPS-stimulated RAW264.7 cells, inhibited cellular M1-type factor TNF-α and IL-1β secretion and increased M2-type factor IL-10 and TGF-β secretion, and accelerated macrophage conversion from M1 type to M2 type, whereas this protective effect of apigenin was counteracted by a miR-21 inhibitor. Moreover, we established a macrophage-HUVECs cell in vitro co-culture system and found that apigenin accelerated the migration, proliferation, and VEGF secretion of HUVECs by promoting macrophage miR-21 expression. Further, mechanistic studies revealed that this was mediated by the TLR4/Myd88/NF-κB axis. In in vivo study, diabetic mice had significantly delayed wound healing compared to non-diabetic mice, accelerated wound healing in apigenin-treated diabetic mice, and decreased M1-type macrophages and increased M2-type macrophages in wound tissues.

Genome-wide screening of m6A profiling of cutaneous wound healing in diabetic mice.

Impaired wound healing in diabetes mellitus (DM) is a major health burden on patients, their families, and society. The present study aimed to systematically profile the m6A modification landscape in cutaneous wounds in a diabetic mouse model. Diabetes was induced in mice through a single intraperitoneal injection of streptozotocin (STZ); a single intraperitoneal injection of PBS was made in control mice for comparisons. Both groups then received an 8-mm diameter, full-thickness dorsal body wound with a biopsy punch. Five days after wound surgery, western blot analysis of harvested wound tissues from both groups was used to assess the expression of m6A-related enzymes. Genome-wide profiling of m6A-tagged transcripts was performed through MeRIP-seq and RNA-seq. ALKBH5, an m6A eraser, was significantly upregulated, while METTL3, METTL14, and WTAP, m6A writers, were markedly downregulated in the diabetic wounds. Additionally, a total of 1335 m6A peaks were differentially expressed in MeRIP-seq and RNA-seq analyses, with 558 upregulated and 777 downregulated peaks. Finally, there was hypomethylated and hypermethylated differentiation at the gene and transcript levels. The present study was the first to reveal the m6A landscape in diabetic wounds in an animal model. This study, by deeply analyzing the role of m6A modifications in diabetic wound healing, provides new insights and understanding into the molecular mechanisms of diabetic wound healing. Future research could further explore how m6A modifications regulate the wound healing process, thereby offering new potential targets for the treatment of diabetic wounds.

Cascade-driven nanomotors promote diabetic wound healing by eradicating MRSA biofilm infection

Bacterial infection, hypoxia, and inflammatory stress responses are the key obstacles that delay the healing of diabetic ulcers. Herein, DMSNs-Pt-LOX@Nisin (DPLN) nanomotors that exhibits cascade propulsion and can specifically target methicillin-resistant Staphylococcus aureus (MRSA) is developed. The DPLN can facilitate the conversion of the abundant lactic acid existed in diabetic wounds, resulting in the generation of hydrogen peroxide (H2O2). Meanwhile, the unilateral Pt nanodendrites (Pt DNs) catalyze H2O2 to produce O2, driving the nanomotors to rapidly penetrate into the biofilm. Moreover, by loading Nisin, which can bind to lipid II of Gram-positive bacteria, the nanomotors can target MRSA through a self-driven process. Both in vitro and in vivo experiments demonstrate that the nanomotors can eradicate MRSA biofilms. Furthermore, animal studies show that DPLN are able to expedite the process of wound healing in diabetic mice through the eradication of biofilms, facilitation of angiogenesis, and mitigation of inflammation. These novel nanomotors combining cascade propulsion and MRSA targeting represent an encouraging and potentially effective approach in diabetic ulcer treatment.

Polyvinylpyrrolidone/chitosan-loaded dihydromyricetin-based nanofiber membrane promotes diabetic wound healing by anti-inflammatory and regulating autophagy-associated protein expression

The healing of wounds in diabetics is commonly delayed by recurring infections and persistent inflammation at the wound site. For this reason, we conducted a study using the electrospinning technique to create nanofiber membranes consisting of polyvinylpyrrolidone/chitosan (PVP/CS) and incorporated dihydromyricetin (DHM) into them. Infrared Fourier transform spectroscopy and scanning electron microscopy were used to analyze the nanofiber membrane. Experimental results in vitro have shown that PVP/CS/DHM has exceptional properties such as hydrophilicity, porosity, water vapor transport rate, antioxidant capacity, and antibacterial activity. Moreover, our study has demonstrated that the application of PVP/CS/DHM can significantly improve wound healing in diabetic mice. After an 18-day treatment period, a remarkable wound closure rate of 88.63 ± 1.37 % was achieved. The in vivo experiments revealed that PVP/CS/DHM can promote diabetic wound healing by suppressing the activation of TLR4/MyD88/NF-κB signaling pathway and enhancing autophagy-related protein as well as CD31 and HIF-1α expression in skin tissues. This study showed that PVP/CS/DHM is a promising wound dressing.

P75NTR regulates autophagy through the YAP-mTOR pathway to increase the proliferation of interfollicular epidermal cells and promote wound healing in diabetic mice

Wound healing is delayed in diabetic patients. Increased autophagy and dysfunction of interfollicular epidermal (IFE) cells are closely associated with delayed healing of diabetic wounds. Autophagy plays an important role in all stages of wound healing, but its role in diabetic wound healing and the underlying molecular mechanisms are not clear. Here, we found that diabetic mice had delayed wound healing and increased autophagy in wounds compared with normal mice and that chloroquine, an inhibitor of autophagy, decreased the level of autophagy, improved the function of IFE cells, and accelerated wound healing in diabetic mice. Treatment of IFE cells with advanced glycosylation end products (AGEs) resulted in increased microtubule-associated protein chain (LC3) expression and decreased prostacyclin-62 (P62) expression, indicating increased autophagy in AGE-treated IFE cells. Moreover, P75NTR reduced autophagy in IFE cells in the presence of AGEs and significantly increased the proliferation of IFE cells. In addition, P75NTR participated in regulating autophagy in IFE cells and in wounds in diabetic mice through the YAP-mTOR signalling pathway, which increased the functional activity of the cells and the healing rate of wounds in diabetic mice. Thus, our study suggests that P75NTR protects IFE cells against AGEs by affecting autophagy and accelerating wound healing in diabetic mice, providing a basis for understanding the role of autophagy in diabetic wound healing.