Impaired Diabetic Wound Healing Research Articles

Mangiferin Represses Inflammation in Macrophages Under a Hyperglycemic Environment Through Nrf2 Signaling.

Inflammation in macrophages is exacerbated under hyperglycemic conditions, contributing to chronic inflammation and impaired wound healing in diabetes. This study investigates the potential of mangiferin, a natural polyphenol, to alleviate this inflammatory response by targeting a redox-sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2). Mangiferin, a known Nrf2 activator, was evaluated for its ability to counteract the hyperglycemia-induced inhibition of Nrf2 and enhance antioxidant defenses. The protective effects of mangiferin on macrophages in a hyperglycemic environment were assessed by examining the expression of Nrf2, NF-κB, NLRP3, HO-1, CAT, COX-2, IL-6, and IL-10 through gene and protein expression analyses using qPCR and immunoblotting, respectively. The mangiferin-mediated nuclear translocation of Nrf2 was evidenced, leading to a robust antioxidant response in macrophages exposed to a hyperglycemic microenvironment. This activation suppressed NF-κB signaling, reducing the expression of pro-inflammatory mediators such as COX-2 and IL-6. Additionally, mangiferin decreased NLRP3 inflammasome activation and reactive oxygen species accumulation in hyperglycemia exposed macrophages. Our findings revealed that mangiferin alleviated hyperglycemia-induced reductions in AKT phosphorylation, highlighting its potential role in modulating key signaling pathways. Furthermore, mangiferin significantly enhanced the invasiveness and migration of macrophages in a hyperglycemic environment, indicating its potential to improve wound healing. In conclusion, this study suggests that mangiferin may offer a promising therapeutic approach for managing inflammation and promoting wound healing in diabetic patients by regulating Nrf2 activity in hyperglycemia-induced macrophages.

Unlocking the potential of flavonoid-infused drug delivery systems for diabetic wound healing with a mechanistic exploration.

Diabetes is one of the common endocrine disorders generally characterized by elevated levels of blood sugar. It can originate either from the inability of the pancreas to synthesize insulin, which is considered as an autoimmune disorder, or the reduced production of insulin, considered as insulin resistivity. A wound can be defined as a condition of damage to living tissues including skin, mucous membrane and other organs as well. Wounds get complicated with respect to time based on specific processes like diabetes mellitus, obesity and immunocompromised conditions. Proper growth and functionality of the epidermis gets sustained due to impaired diabetic wound healing which shows a sign of dysregulated wound healing process. In comparison with synthetic medications, phytochemicals like flavonoids, tannins, alkaloids and glycosides have gained enormous importance relying on their distinct potential to heal diabetic wounds. Flavonoids are one of the most promising and important groups of natural compounds which can be used to treat acute as well as chronic wounds. Flavonoids show excellent properties due to the presence of hydroxyl groups in their chemical structure, which makes this class of compounds different from others. Based on the novel principles of nanotechnology via utilizing suitable drug delivery systems, the delivery of bioactive constituents from plant source amplifies the wound-healing mechanism, minimizes complexities and enhances bioavailability. Hence, the encapsulation and applicability of flavonoids with an emphasis on mechanistic route and wound-healing therapeutics have been highlighted in the subsequent study with focus on multiple drug delivery systems.

Effect of pomegranate peel with/without autologous bone marrow on healing of acute cutaneous wounds in alloxan-induced diabetic rabbits.

Healing of bum wounds is commonly associated with many complications. Every year various new repair materials are developed and experimentally used for treating burn wounds. Humans with diabetes mellitus usually suffer from chronic wound healing. Vascular, neuropathic, immune function, and biochemical abnormalities each contribute to the altered tissue repair. One underlying factor that accompanies all diabetic ulcerations is poor vascular flow, a circumstance that impedes proper wound healing. Numerous studies have highlighted the importance of adequate vascular sufficiency and vessel proliferation in tissue repair and the lack thereof in diabetic wound healing. Other studies have looked at whether disarrayed capillary remodeling and maturation of vessels might play a role in impaired diabetic wound healing. This investigation has been planned to report the influence of treatment with a mixture of both the powder of pomegranate peel (PP) accompanied with an autologous bone marrow (BM) on the cure of burn injuries in experimentally induced diabetic rabbits. Alloxan monohydrate has been applied to create diabetes in 50 rabbits. Then in each rabbit, two deep second-degree burn wounds were experimentally created. The animals were then divided randomly into 5 treatment sections: non-treatment controls (C1), treated with an available commercial powder for wound (C2), treatment with powder of PP, treatment with alone BM, and the final group treated with PP powder with bone marrow (PPBM). The speed of wound closure and the histopathological changes during healing were measured. The levels of the biomarkers of rabbit platelet-derived growth factor AA (PDGF-AA) and rabbit protease-activated receptor 1 (PAR-1) were measured on days 0, 4, 8, and 12. Wound healing was markedly more rapid in all the treatment groups versus the control non-treated group. Interestingly, a rapid wound cure was significantly observed in the PPBM group versus the other treatment ones. The histological assessment clarified a significant elevation in the fibroblast and collagen scores in the PPBM group versus the other sections. In addition, there were significant increases in the serum levels of the biomarkers PDGF-AA and PAR-1 among groups. Dependent on the results of current research, it can be concluded that both PP powder with BM PPBM significantly accelerate the healing process of burn wounds in experimentally induced diabetic rabbits.

Keratinocyte-derived small extracellular vesicles delay diabetic wound healing by triggering fibroblasts autophagy

Keratinocyte and fibroblast dysfunctions contribute to delayed healing of diabetic wounds. Small extracellular vesicles (sEV) are key mediators of intercellular communication and are involved in the pathogenesis of several diseases. Recent findings suggest that sEV derived from high-glucose-treated keratinocyte (HaCaT-HG-sEV) can transport LINC01435 to inhibit tube formation and migration of HUVECs, thereby delaying wound healing. This study aimed to elucidate sEV-related communication mechanisms between keratinocytes and fibroblasts during diabetic wound healing. HaCaT-HG-sEV treatment and LINC01435 overexpression significantly decreased fibroblast collagen level and migration ability but significantly increased fibroblast autophagy. However, treatment with an autophagy inhibitor suppressed LINC01435 overexpression-induced decrease in collagen levels in fibroblasts. In diabetic mice, HaCaT-HG-sEV treatment decreased collagen levels and increased the expression of the autophagy-related proteins Beclin-1 and LC3 at the wound site, thereby delaying wound healing. Conclusively, LINC01435 in keratinocyte-derived sEV activates fibroblast autophagy and reduces fibroblast collagen synthesis, leading to impaired diabetic wound healing.

KRT17 from skin cells with high glucose stimulation promotes keratinocytes proliferation and migration.

Impaired diabetic wound healing is an important issue in diabetic complications. Proliferation and migration of keratinocytes are major processes of skin wound repair after injury. However, hyperkeratosis can affect the speed of wound healing. Based on the results of preliminary experiments on increased KRT17 expression after high glucose stimulation of human skin tissue cells, a cell model of human immortalized keratinocyte (HaCaT) stimulation with different concentrations of KRT17 was established in vitro, and the promotion in cell proliferation and migration were discovered. KRT17 silencing promoted diabetic wound healing in the db/db diabetic wound model. Transcriptome sequencing (RNA-seq) was performed on HaCaT cells after KRT17 stimulation, and analysis showed significant enrichment in the PI3K-AKT signaling pathway, in which the regulation of cell c-MYB mRNA, a key molecule regulating cell proliferation and migration, was significantly upregulated. In vitro assays showed increased c-MYB expression and enhanced pAKT activity after HaCaT cell stimulation by KRT17. We speculate that KRT17 is upregulated under high glucose and promotes keratinocyte proliferation and migration caused hyperkeratosis, through the c-MYB/PI3K-AKT pathway, contributing to delayed wound healing.

Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles.

Neutrophil extracellular traps (NETs) have been considered a significant unfavorable factor for wound healing in diabetes, but the mechanisms remain unclear. The therapeutic application of small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) has received considerable attention for their properties. Hypoxic preconditioning is reported to enhance the therapeutic potential of MSC-derived sEVs in regenerative medicine. Therefore, the aim of this study is to illustrate the detailed mechanism of NETs in impairment of diabetic wound healing and develop a promising NET-targeting treatment based on hypoxic pretreated MSC-derived sEVs (Hypo-sEVs). Excessive NETs were found in diabetic wounds and in high glucose (HG)-induced neutrophils. Further research showed that high concentration of NETs impaired the function of fibroblasts through activating endoplasmic reticulum (ER) stress. Hypo-sEVs efficiently promoted diabetic wound healing and reduced the excessive NET formation by transferring miR-17-5p. Bioinformatic analysis and RNA interference experiment revealed that miR-17-5p in Hypo-sEVs obstructed the NET formation by targeting TLR4/ROS/MAPK pathway. Additionally, miR-17-5p overexpression decreased NET formation and overcame NET-induced impairment in fibroblasts, similar to the effects of Hypo-sEVs. Overall, we identify a previously unrecognized NET-related mechanism in diabetic wounds and provide a promising NET-targeting strategy for wound treatment.

Expression of concern “Simvastatin enhances VEGF production and ameliorates impaired wound healing in experimental diabetes” [Pharmacol. Res. 57/2 (2008) 159–169

Expression of concern “Simvastatin enhances VEGF production and ameliorates impaired wound healing in experimental diabetes” [Pharmacol. Res. 57/2 (2008) 159–169

Exploring the contribution of pro-inflammatory cytokines to impaired wound healing in diabetes.

Impaired wound healing is the most common and significant complication of Diabetes. While most other complications of Diabetes have better treatment options, diabetic wounds remain a burden as they can cause pain and suffering in patients. Wound closure and repair are orchestrated by a sequence of events aided by the release of pro-inflammatory cytokines, which are dysregulated in cases of Diabetes, making the wound environment unfavorable for healing and delaying the wound healing processes. This concise review provides an overview of the dysregulation of pro-inflammatory cytokines and offers insights into better therapeutic outcomes. Although many therapeutic approaches have been lined up nowadays to treat Diabetes, there are no proper treatment modalities proposed yet in treating diabetic wounds due to the lack of understanding about the role of inflammatory mediators, especially Pro-inflammatory mediators- Cytokines, in the process of Wound healing which we mainly focus on this review. Although complications of Diabetes mellitus are most reported after years of diagnosis, the most severe critical complication is impaired Wound Healing among Diabetes patients. Even though Trauma, Peripheral Artery Disease, and Peripheral Neuropathy are the leading triggering factors for the development of ulcerations, the most significant issue contributing to the development of complicated cutaneous wounds is wound healing impairment. It may even end up with amputation. Newer therapeutic approaches such as incorporating the additives in the present dressing materials, which include antimicrobial molecules and immunomodulatory cytokines is of better therapeutic value. The adoption of these technologies and the establishment of novel therapeutic interventions is difficult since there is a gap in terms of a complete understanding of the pathophysiological mechanisms at the cellular and molecular level and the lack of data in terms of the assessment of safety and bioavailability differences in the individuals' patients. The target-specific pro-inflammatory cytokines-based therapies, either by upregulation or downregulation of them, will be helpful in the wound healing process and thereby enhances the Quality of life in patients, which is the goal of drug therapy.

Panthenol Citrate Biomaterials Accelerate Wound Healing and Restore Tissue Integrity.

Impaired wound healing is a common complication for diabetic patients and effective diabetic wound management remains a clinical challenge. Furthermore, a significant problem that contributes to patient morbidity is the suboptimal quality of healed skin, which often leads to reoccurring chronic skin wounds. Herein, a novel compound and biomaterial building block, panthenol citrate (PC), is developed. It has interesting fluorescence and absorbance properties, and it is shown that PC can be used in soluble form as a wash solution and as a hydrogel dressing to address impaired wound healing in diabetes. PC exhibits antioxidant, antibacterial, anti-inflammatory, and pro-angiogenic properties, and promotes keratinocyte and dermal fibroblast migration and proliferation. When applied in a splinted excisional wound diabetic rodent model, PC improves re-epithelialization, granulation tissue formation, and neovascularization. It also reduces inflammation and oxidative stress in the wound environment. Most importantly, it improves the regenerated tissue quality with enhanced mechanical strength and electrical properties. Therefore, PC could potentially improve wound care management for diabetic patients and play a beneficial role in other tissue regeneration applications.

Dysregulation of endoplasmic reticulum stress response in skin wounds in a streptozotocin-induced diabetes mouse model.

Dysfunction in key cellular organelles has been linked to diabetic complications. This study intended to investigate the alterations in the unfolded protein response (UPR), autophagy, and mitochondrial function, which are part of the endoplasmic reticulum (ER) stress response, in wound healing (WH) under diabetes conditions. WH mouse models were used to evaluate the UPR, autophagy, mitochondrial fusion, fission, and biogenesis as well as mitophagy in the skin of control and diabetic mice at baseline and 10 days after wounding. The autophagic flux in response to high-glucose conditions was also evaluated in keratinocyte and fibroblast cell cultures. WH was impaired in the diabetic mouse model, and we found that the UPR and autophagy pathways were activated in skin wounds of control mice and in the non-wounded skin of diabetic mice. Moreover, high-glucose conditions induced autophagy in the keratinocyte and fibroblast cell cultures. However, mitophagy did not change in the skin of diabetic mice or the wounded skin. In addition, mitochondrial fusion was activated in control but not in the skin wounds of diabetic mice, while mitochondrial biogenesis is downregulated in the skin of diabetic mice. In conclusion, the activation of the UPR, autophagy, and mitochondrial remodeling are crucial for a proper WH. These results suggest that the increase in ER stress and autophagy in the skin of diabetic mice at baseline significantly escalated to pathological levels after wounding, contributing to impaired WH in diabetes.

Infected Diabetic Wound Regeneration Using Peptide-Modified Chiral Dressing to Target Revascularization.

Revascularization plays a critical role in the healing of diabetic wounds. Accumulation of advanced glycation end products (AGEs) and refractory multidrug resistant bacterial infection are the two major barriers to revascularization, directly leading to impaired healing of diabetic wounds. Here, an artfully designed chiral gel dressing is fabricated (named as HA-LM2-RMR), which consists of l-phenylalanine and cationic hexapeptide coassembled helical nanofibers cross-linked with hyaluronic acid via hydrogen bonding. This chiral gel possesses abundant chiral and cationic sites, not only effectively reducing AGEs via stereoselective interaction but also specifically killing multidrug resistant bacteria rather than host cells since cationic hexapeptides selectively interact with negatively charged microbial membrane. Surprisingly, the HA-LM2-RMR fibers present an attractive ability to activate sprouted angiogenesis of Human Umbilical Vein Endothelial Cells by upregulating VEGF and OPA1 expression. In comparison with clinical Prontosan Wound Gel, the HA-LM2-RMR gel presents superior healing efficiency in the infected diabetic wound with respect to angiogenesis and re-epithelialization, shortening the healing period from 21 days to 14 days. These findings for chiral wound dressing provide insights for the design and construction of diabetic wound dressings that target revascularization, which holds great potential to be utilized in tissue regenerative medicine.

Response Surface Methodology Assisted Surfactant Optimization on the Novel Resveratrol Self-assembly Nanoemulsions

Resveratrol, a strong antioxidant and anti-inflammatory phytoalexin is potential to relieve impaired diabetic wound healing. Self-assembly nanoemulsions were developed to formulate good quality of resveratrol topical preparation. The surfactant system consisted of Kolliphor® RH 40 and Transcutol® were further optimized in terms of viscosity, pH and the percentage of transmittance. A central composite design combined with the response surface methodology successfully resulted in surface responses with the desirability value for viscosity, pH, and transmittance percentage were 0.99742, 0.60598, and 0.37137, respectively. These results contributed to the composite desirability of 0.6077. The optimal condition was obtained at a composition 5.70 g and 2.30 g of Kolliphor® RH 40 and Transcutol®, correspondingly.

Identification of a tsRNA Contributor to Impaired Diabetic Wound Healing via High Glucose-Induced Endothelial Dysfunction

Delayed skin healing in diabetic wounds is a major clinical problem. The tRNA-derived small RNAs (tsRNAs) were reported to be associated with diabetes. However, the role of tsRNAs in diabetic wound healing is unclear. Our study was designed to explore the tsRNA expression profile and mine key potential tsRNAs and their mechanism in diabetic wounds. Skin tissues of patients with diabetic foot ulcers and healthy controls were subjected to small RNA sequencing. The role of candidate tsRNA was explored by loss- and gain-of-function experiments in HUVECs. A total of 55 differentially expressed tsRNAs were identified, including 12 upregulated and 43 downregulated in the diabetes group compared with the control group. These tsRNAs were mainly concentrated in intercellular interactions and neural function regulation in GO terms and enriched in MAPK, insulin, FoxO, calcium, Ras, ErbB, Wnt, T cell receptor, and cGMP-PKG signaling pathways. tRF-Gly-CCC-039 expression was upregulated in vivo and in vitro in the diabetic model. High glucose disturbed endothelial function in HUVECs, and tRF-Gly-CCC-039 mimics further harmed HUVECs function, characterized by the suppression of proliferation, migration, tube formation, and the expression of Coll1a1, Coll4a2, and MMP9. Conversely, the tRF-Gly-CCC-039 inhibitor could attenuate high-glucose-induced endothelial injury to HUVECs. We investigated the tsRNAs expression profile in diabetic foot ulcers and defined the impairment role of tRF-Gly-CCC-039 in endothelial function in HUVECs. This study may provide novel insights into accelerating diabetic skin wound healing.

Negative-Pressure Wound Therapy Induces Lymphangiogenesis in Murine Diabetic Wound Healing.

Decreased lymphangiogenesis contributes to impaired diabetic wound healing. Although negative-pressure wound therapy (NPWT) has been shown to be effective in the treatment of recalcitrant wounds, its impact on lymphangiogenesis remains to be elucidated. In this study, the authors investigate the mechanisms of lymphangiogenesis following NPWT treatment of diabetic murine wound healing. Full-thickness dorsal skin wounds (1 × 1 cm 2 ) were excised on 30 db/db mice. The mice were either treated with occlusive covering (control group, n = 15), or received a 7-day treatment of continuous NPWT at -125 mmHg (NPWT group, n = 15). The wounds were photographed on days 0, 7, 10, 14, 21, and 28. Wound tissue was harvested on days 10, 14, 21, and 28 for quantitative analysis. Functional analysis of lymphatic drainage was performed on days 14 and 28 with Evans blue dye tracing. Lymphatic density and diameter, as visualized through podoplanin probing, was significantly higher in the NPWT group compared to the control group ( P < 0.001). NPWT up-regulated the expression of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) at the protein level ( P = 0.04), and significant differences were noted in lymphatic density as assessed by LYVE-1 staining ( P = 0.001). Leukocyte infiltration was significantly higher in the NPWT group ( P = 0.01). A higher speed of wound closure ( P < 0.0001) and greater wound bed thickness ( P < 0.0001) were noted in the NPWT group compared to the control group. NPWT increased the lymphatic vessel density and diameter with LYVE-1 up-regulation. NPWT therefore plays a positive role in lymphangiogenesis in diabetic wound healing. The authors' study investigates the association of NPWT and lymphatics and underlines the importance of a more in-depth investigation of the role of lymphatic vessels in wound healing.

The Signaling Pathways Induced by Exosomes in Promoting Diabetic Wound Healing: A Mini-Review

Impaired healing of diabetic wounds harms patients’ quality of life and even leads to disability and death, which is an urgent issue to be solved clinically. Despite the great progress that has been achieved, it remains a worldwide challenge to develop effective therapeutic treatments for diabetic wounds. Recently, exosomes have attracted special attention because they can be involved in immune response, antigen presentation, cell migration, cell differentiation, tumor invasion and other processes. Meanwhile, exosomes have been proven to hold great potential in the treatment of diabetic wounds. Mechanistic studies of exosomes based on signaling pathways could not only help to uncover the mechanisms by which exosomes promote diabetic wound healing but could also provide a theoretical basis for the clinical application of exosomes. Herein, our mini-review aims to summarize the progress of research on the use of various exosomes derived from different cell types to promote diabetic wound healing, with a focus on the classical signaling pathways, including PI3K/Akt, Wnt, NF-κB, MAPK, Notch, Nrf2, HIF-1α/VEGF and TGF-β/Smad. The results show that exosomes could regulate these signaling pathways to down-regulate inflammation, reduce oxidative stress, increase angiogenesis, promote fibroblast proliferation, induce re-epithelization and inhibit scar formation, making exosomes attractive candidates for the treatment of diabetic wounds.

EVALUATION OF WOUND HEALING POTENTIAL OF YASHADAMRITA MALHARA IN DIABETIC WOUND MODELS

Due to unclear aetiology, the healing impairment of diabetic patients is still a severe clinical problem for physicians worldwide. Hence impaired wound healing in diabetes has caught the attention of the world to help promote the healing process and prevent rising complications. The present study was designed to investigate the comparative wound healing efficacy of Yashadamrita Malhara with standard formulation, i.e., Framycetin Sulphate, using excision wound models in Diabetic rats. Streptozotocin (50 mg/kg, IP) induced diabetic rat model was used to evaluate the wound healing effect of Yashadamrita Malhara in comparison to Framycetin sulphate. Yashadamrita Malhara was applied for 12 days. Wound contraction % and estimation of hydroxyproline, collagen and hexosamine were studied. Obtained data were analyzed statistically. On the 12th day, there were no positive changes in the wound area contraction of the Yashadamrita Malhara treated group compared to the Framycetin sulphate treated group. The histopathology reports also showed no healing in the test drug group. Yashadamrita Malhara did not show any statistically significant Vrana Ropana (wound healing) activity in Diabetic Rats.

Biodegradable and Antioxidant DNA Hydrogel as a Cytokine Delivery System for Diabetic Wound Healing.

Impaired diabetic wound healing is associated with the persistence of chronic inflammation and excessive oxidative stress, which has become one of the most serious clinical challenges. Wound dressings with anti-inflammatory and reactive oxygen species (ROS)-scavenging properties are desirable for diabetic wound treatment. In this study, a shape-adaptable, biodegradable, biocompatible, antioxidant, and immunomodulatory interleukin-33 (IL-33)-cytogel is developed by encapsulating IL-33into physically cross-linked DNA hydrogels and used as wound dressings to promote diabetic wound healing. The porous microstructures and biodegradable properties of the IL-33-cytogel ensure the local sustained-release of IL-33 in the wound area, where the sustained-release of IL-33 is maintained for at least 7 days. IL-33-cytogel can induce local accumulation of group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs), as well as M1-to-M2 transition at the wound sites. Additionally, the antioxidant and biocompatible characteristics of DNA hydrogels promote thescavengingofintracellular ROSwithout affecting cell viability. As a result, local inflammation in the diabetic wound area is resolved upon IL-33-cytogel treatment, which is accompanied by improved granulation tissue regeneration and accelerated wound closure. This study demonstrates a promising strategy in tissue engineering and regenerative medicine by incorporating DNA hydrogels and cytokine immunotherapy for promoting diabetic wound healing.

Egg yolk oil accelerates wound healing in streptozotocin induced diabetic rats

ABSTRACT Impaired diabetic wound healing causes foot ulcers. We investigated egg yolk oil for skin wound healing in streptozotocin (STZ) induced diabetic rats. Rats were allocated into three groups of six. Group 1, nondiabetic control group, was treated topically with 2% fusidic acid ointment. Group 2, STZ diabetic control, was treated topically with 2% fusidic acid ointment. Group 3, STZ diabetic group, was treated topically with egg yolk oil. Three days after STZ injection, two full thickness excisional skin wounds were created on the back of each animal. Wound diameter was measured for 14 days and wound contraction was calculated. Re-epithelization time also was determined. Three rats from each group were sacrificed on experimental day 7 and the remaining rats on day 14. Wound samples were examined using hematoxylin and eosin, periodic acid-Schiff, Masson’s trichrome, Taenzer-Unna orcein and toluidine blue staining. Expression of endoglin (CD105), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) were investigated using immunohistochemistry. Egg yolk oil increased the proliferation of epithelial cells and angiogenesis, and stimulated collagen deposition in the lesion area. Egg yolk oil increased CD105, EGF and VEGF expression in blood vessels, and EGF and VEGF expression in epidermis of the lesions. The predominant fatty acids in egg yolk oil are oleic, palmitic and linoleic, which likely were responsible for the beneficial effects of egg yolk oil on diabetic wound healing. Egg yolk oil appears to be a promising therapeutic agent for healing of diabetic wounds.

Regulatory role of miR-146a in corneal epithelial wound healing via its inflammatory targets in human diabetic cornea

PurposeMiR-146a upregulated in limbus vs. central cornea and in diabetic vs. non-diabetic limbus has emerged as an important immune and inflammatory signaling mediator in corneal epithelial wound healing. Our aim was to investigate the potential inflammation-related miR-146a target genes and their roles in normal and impaired diabetic corneal epithelial wound healing. MethodsOur previous data from RNA-seq combined with quantitative proteomics of limbal epithelial cells (LECs) transfected with miR-146a mimic vs. mimic control were analyzed. Western blot and immunostaining were used to confirm the expression of miR-146a inflammatory target proteins in LECs and organ-cultured corneas. Luminex assay was performed on conditioned media at 6- and 20-h post-wounding in miR-146a mimic/inhibitor transfected normal and diabetic cultured LECs. ResultsOverexpression of miR-146a decreased the expression of pro-inflammatory TRAF6 and IRAK1 and downstream target NF-κB after challenge with lipopolysaccharide (LPS) or wounding. Additionally, miR-146a overexpression suppressed the production of downstream inflammatory mediators including secreted cytokines IL-1α, IL-1β, IL-6 and IL-8, and chemokines CXCL1, CXCL2 and CXCL5. These cytokines and chemokines were upregulated in normal but not in diabetic LEC during wounding. Furthermore, we achieved normalized levels of altered secreted cytokines and chemokines in diabetic wounded LEC via specific inhibition of miR-146a. ConclusionOur study documented significant impact of miR-146a on the expression of inflammatory mediators at the mRNA and protein levels during acute inflammatory responses and wound healing, providing insights into the regulatory role of miR-146a in corneal epithelial homeostasis in normal and diabetic conditions.

Fluoxetine Ecofriendly Nanoemulsion Enhances Wound Healing in Diabetic Rats: In Vivo Efficacy Assessment.

Impaired diabetic wound healing is a major concern for health care professionals worldwide, imposing an intense financial burden and reducing the quality of life of patients. A dysregulation of this process can be responsible for the development of intractable ulcers and the formation of excessive scars. Therefore, the identification of novel pharmacological strategies able to promote wound healing and restore the mechanical integrity of injured tissue becomes essential. In the present study, fluoxetine ecofriendly nanoemulsion (FLX-EFNE) was prepared and its potential efficacy in enhancing wound healing was tested in diabetic rats. The Box–Behnken response surface design was used to select the optimized formulation that was prepared by the high-shear homogenization-based technique. A Zetasizer was used for the characterization of the optimized formulation, providing a FLX-EFNE with a globule size of 199 nm. For the in vivo study, a wound was induced by surgical methods, and diabetic rats (streptozotocin-induced) were divided into five groups: untreated control, vehicle-treated, FLX, FLX-EFNE, and positive control receiving a commercially available formula. The treatment continued from the day of wound induction to day 21. Then, the animals were sacrificed and skin tissues were collected at the site of wounding and used for biochemical, histopathological, immunohistochemical, and mRNA expression assessments. In the FLX-EFNE treated group, the rate of wound contraction and signs of healing were significantly higher compared to all other groups. In addition, angiogenesis, proliferation, and collagen deposition were enhanced, while oxidative stress and inflammation decreased. The present data highlight the enhanced wound healing activity of the optimized FLX-EFNE formulation.