Enhanced Fibroblast Proliferation Research Articles

Recombinant Human Collagen Type III Improves Hypertrophic Scarring by Regulating the Ratio of Type I/III Collagen.

Hypertrophic scar development is a complication associated with wound healing, impacting local appearance and function. The type I/III collagen ratio affects the extent of hypertrophic scarring; a reduced ratio can ameliorate this. In this study, recombinant human collagen type III was developed. Liquid chromatography-tandem mass spectrometry was used to determine its amino acid sequence and confirm its high level of homology with natural human type III collagen. Recombinant human collagen type III displayed no cytotoxicity and did not confer skin irritation and sensitization. Immunofluorescence and western blot analyses of histidine following incubation with fibroblasts suggested cell entry of recombinant human collagen type III. Furthermore, recombinant human collagen type III promoted the synthesis of the natural type III collagen in fibroblasts, resulting in a more obvious increase of type III collagen content in fibroblasts than that of type I collagen, and then decreased the ratio of type I/III collagen. The results of 5-ethynyl-2'-deoxyuridine staining assay suggested enhanced fibroblast proliferation. Following local injection of recombinant human collagen type III, rabbit ear scarring was significantly reduced after 60 days. Vancouver Scar Scale evaluation showed that all index scores were significantly reduced. Western blotting and Picro-Sirius red staining showed that the natural type III collagen increase in scar tissue was greater than that of type I collagen, decreasing the type I/III ratio. In summary, recombinant human collagen type III can be taken up by fibroblasts and promote natural collagen synthesis-especially that of type III-thereby reducing the type I/III ratio and improving hypertrophic scarring.

Electrically Stimulated Dental Implants Triggers Soft‐Tissue Integration and Bactericidal Functions

AbstractModulating cellular functions at the dental implant‐tissue interface to augment integration and prevent bacterial ingress is crucial for achieving early stability and long‐term implant success. Nano‐engineering strategies, such as anodized titanium implants with titania (TiO2) nanotubes/nanopores, are emerging as a promising dental implant surface modification approach to enhance integration and prevent infection. Achieving on‐demand therapy through electrical stimulation therapy (EST, supply of voltage/current to local tissue) may be advantageous but has not been explored for dental implants. Further, anodized implants with TiO2 nanotubes/nanopores represent a semi‐conducting modification that can impede EST effectiveness. In this pioneering study, TiO2 nanopores are converted into conducting Ti nanopores to perform EST to achieve superior soft‐tissue integration and antibacterial efficacy. In‐depth surface characterizations are followed by assays investigating the effect of EST on cultured human salivary biofilm and gingival fibroblasts. Significant bactericidal efficacy is demonstrated for EST (1.5 V for 5 min per day) using Ti nanopores. Further, EST enhanced fibroblast proliferation and collagen secretion. In summary, EST applied to Ti nanoporous implants promotes soft‐tissue healing and antibacterial functions and is proposed as a next‐generation approach in implant dentistry to achieve on‐demand therapy.

Accelerated wound healing after topical application of hyaluronic acid cotton to hemorrhoidectomy wounds in a rat model.

Anal wounds following hemorrhoidectomy can lead to severe pain and postoperative bleeding, impacting patient recovery and quality of life. Hyaluronic acid (HA) stimulates tissue regeneration and wound healing by accelerating cell migration and proliferation. This study aimed to investigate the differences in wound healing rate and completeness of recovery of perianal wounds topically treated with HA-soaked cotton in a murine model. Forty-eight 8-week-old Sprague-Dawley rats with perianal wounds created using a biopsy punch were divided into 2 groups: simple dressing with gauze (control) and topical HA-soaked cotton. A single application of HA-soaked cotton was administered after surgery. Wound healing rate and completeness of recovery were evaluated by measuring the healed area and conducting histological analyses. The HA-cotton group exhibited a shorter complete wound healing duration compared to the control group (13.9 days vs. 16.4 days, P = 0.031). Differences in wound healing area between the 2 groups were greatest on postoperative day 2 (51.6% vs. 28.8%, P < 0.001). The HA-cotton group exhibited fewer cases of granulation tissue (2 vs. 5) or redness (0 vs. 3) upon complete wound healing. Histologically, the HA-cotton group showed accelerated reepithelialization, rapid shift to lymphocyte-dominant inflammation, enhanced fibroblast proliferation, and increased collagen deposition compared to the control group. Herein, topical application of HA-soaked cotton on perianal wounds in rats resulted in accelerated wound healing, particularly in the initial stages, and improved completeness of recovery, underscoring the potential of the topical application of HA-soaked cotton on hemorrhoidectomy wounds in human patients to improve wound healing.

A bismuth-based double-network hydrogel-mediated synergistic photothermal-chemodynamic therapy for accelerated wound healing.

Multidrug-resistant bacterial infections present a significant challenge to wound healing. Non-antibiotic approaches such as photothermal therapy (PTT) and chemodynamic therapy (CDT) are promising but have suboptimal anti-bacterial efficacy. Herein, we developed a green bismuth-based double-network hydrogel (Bi@P-Cu) as a PTT/CDT synergistic platform for accelerated drug-resistant bacteria-infected wound healing. Bismuth (Bi) nanoparticles fabricated using a microwave method were used as a highly efficient and biocompatible PTT agent while the integration of a small amount of CDT agent Cu2+ endowed the hydrogel with excellent mechanical and self-healing properties, markedly increased photothermal efficiency, promoted cell migration ability, and negligible toxicity. Importantly, PTT enhanced the production of hydroxyl radicals in CDT and the destruction of bacterial cell membranes, which in turn enhanced the thermal sensitivity of bacteria. This synergistic anti-bacterial effect, together with the demonstrated capability to promote angiogenesis and anti-inflammation as well as enhanced fibroblast proliferation, led to accelerated wound healing in a full-thickness mouse model of resistant bacterial infection. This study provides an effective and safe strategy to eliminate drug-resistant bacteria and accelerate wound healing through green, non-antibiotic, double-network hydrogel-mediated synergistic PTT and CDT.

Effects of low-level Er:YAG laser irradiation on proliferation and gene expression in primary gingival fibroblasts isolated from mouse maxilla.

We investigated the effects of low-level Er:YAG laser irradiation on proliferation and alternations in early gene expression of gingival fibroblasts. Mice primary gingival fibroblasts were irradiated with an Er:YAG laser (1.8, 3.9, and 5.8 J/cm2 ). Irradiation at 3.9 J/cm2 promoted cell proliferation without significant changes in lactate dehydrogenase or Hspa1a expression. Three hours after irradiation at 3.9 J/cm2 , the Fn1 expression level was significantly increased. RNA-seq identified 15 differentially expressed genes between irradiated and non-irradiated cells, some of which belonged to immediate early genes (IEGs). Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated MAPK pathway enhancement, and gene set enrichment analysis showed enrichment in the TGF-β signaling gene set. Enhanced proliferation via laser irradiation disappeared upon inhibition of Dusp4, Dusp5, and Tgfr1 expression. Low-level Er:YAG laser irradiation, especially at 3.9 J/cm2 without a major temperature elevation, enhanced fibroblast proliferation, via TGF-β and the MAPK signaling pathway following IEG expression.

Unraveling FOXO3a and USP18 Functions in Idiopathic Pulmonary Fibrosis through Single-Cell RNA Sequencing of Mouse and Human Lungs.

Background Idiopathic pulmonary fibrosis (IPF) is identified as a chronic, progressive lung disease, predominantly marked by enhanced fibroblast proliferation and excessive deposition of extracellular matrix. The intricate interactions between diverse molecular pathways in fibroblasts play a crucial role in driving the pathogenesis of IPF. Methods This research is focused on elucidating the roles of FOXO3a, a transcription factor, and USP18, a ubiquitin-specific protease, in modulating fibroblast functionality in the context of IPF. FOXO3a is well-known for its regulatory effects on cellular responses, including apoptosis and oxidative stress, while USP18 is generally associated with protein deubiquitination. Results Our findings highlight that FOXO3a acts as a critical regulator in controlling fibroblast activation and differentiation, illustrating its vital role in the pathology of IPF. Conversely, USP18 seems to promote fibroblast proliferation and imparts resistance to apoptosis, thereby contributing to the exacerbation of fibrotic processes. The synergistic dysregulation of both FOXO3a and USP18 in fibroblasts was found to significantly contribute to the fibrotic alterations characteristic of IPF. Conclusion Deciphering the complex molecular interactions between FOXO3a and USP18 in fibroblasts provides a deeper understanding of IPF pathogenesis and unveils novel therapeutic avenues, offering a promising potential for not just halting but potentially reversing the progression of this debilitating disease.

ApoSEVs-Mediated Modulation of Versatile Target Cells Promotes Diabetic Wound Healing: Unveiling a Promising Strategy.

Diabetic chronic wounds present a formidable challenge in clinical management, lacking effective treatment options. Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for tissue repair and regeneration. However, transplanted MSCs often undergo rapid apoptosis, giving rise to heterogeneous extracellular vesicles (EVs), including apoptotic bodies (apoBDs) and apoptotic small extracellular vesicles (apoSEVs). The potential stimulatory role of these EVs in diabetic wound healing remains unknown. In this study, we investigated the effects of apoSEVs derived from adipose-derived mesenchymal/stromal cells (ADSCs) on the recovery of diabetic wounds by modulating the function of versatile target cells. First, we characterized the apoSEVs and apoBDs derived from apoptotic ADSCs. Subsequently, we evaluated the effects of apoSEVs and apoBDs on macrophages, endothelial cells, and fibroblasts, three essential cell types in wound healing, under high-glucose conditions. Furthermore, we developed a gelatin methacryloyl (GelMA) hydrogel for the sustained release of apoSEVs and investigated its therapeutic effects on wound healing in type 2 diabetic mice in vivo. apoSEVs facilitated the polarization of M1 phenotype macrophages to M2 phenotype, promoted proliferation, migration, and tube formation of endothelial cells, and enhanced fibroblast proliferation and migration. However, apoBDs failed to improve the function of endothelial cells and fibroblasts. In vivo, the apoSEVs-loaded GelMA effectively promoted wound healing by facilitating collagen fiber deposition, angiogenesis, and immune regulation. Our study elucidates the beneficial effects of apoSEVs on wound recovery in diabetes and introduces a novel strategy for diabetic wound treatment based on apoSEVs.

Carbon Dots' Potential in Wound Healing: Inducing M2 Macrophage Polarization and Demonstrating Antibacterial Properties for Accelerated Recovery.

Bacterial infections and persistent inflammation can impede the intrinsic healing process of wounds. To combat this issue, researchers have delved into the potential use of carbon dots (CDs) in the regulation of inflammation and counteract infections. These CDs were synthesized using a microwave-assisted hydrothermal process and have demonstrated outstanding antibacterial and antibiofilm properties against Gram-positive and Gram-negative bacteria. Additionally, CDs displayed biocompatibility at therapeutic concentrations and the ability to specifically target mitochondria. CD treatment effectively nullified lipopolysaccharide-triggered reactive oxygen species production by macrophages, while simultaneously promoting macrophage polarization toward an anti-inflammatory phenotype (M2), leading to a reduction in inflammation and an acceleration in wound healing. In vitro scratch assays also revealed that CDs facilitated the tissue-repairing process by stimulating epithelial cell migration during reepithelialization. In vivo studies using CDs topically applied to lipopolysaccharide (LPS)-stimulated wounds in C57/BL6 mice demonstrated significant improvements in wound healing due to enhanced fibroblast proliferation, angiogenesis, and collagen deposition. Crucially, histological investigations showed no indications of systemic toxicity in vital organs. Collectively, the application of CDs has shown immense potential in speeding up the wound-healing process by regulating inflammation, preventing bacterial infections, and promoting tissue repair. These results suggest that further clinical translation of CDs should be considered.

WTAP boosts lipid oxidation and induces diabetic cardiac fibrosis by enhancing AR methylation

Dysregulated lipid metabolism occurs in pathological processes characterized by cell proliferation and migration. Nonetheless, the mechanism of increased mitochondrial lipid oxidation is poorly appreciated in diabetic cardiac fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. Herein, increased WTAP expression promotes cardiac fibroblast proliferation and migration, contributing to diabetic cardiac fibrosis. Knockdown of WTAP suppresses mitochondrial lipid oxidation, fibroblast proliferation and migration to ameliorate diabetic cardiac fibrosis. Mechanistically, WTAP-mediated m6A methylation of AR induced its degradation, dependent on YTHDF2. Additionally, AR directly interacts with mitochondrial lipid oxidation enzyme Decr1; overexpression of AR-suppressed Decr1-mediates mitochondrial lipid oxidation, inhibiting cardiac fibroblast proliferation and migration. Knockdown of AR produced the opposite effect. Clinically, increased WTAP and YTHDF2 levels correlate with decreased AR expression in human DCM heart tissue. We describe a mechanism wherein WTAP boosts higher mitochondrial lipid oxidation, cardiac fibroblast proliferation, and migration by enhancing AR methylation in a YTHDF2-dependent manner.

METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation

Dysregulated mitochondrial metabolism occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the role of mitochondrial fission is not well appreciated in cardiac fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. We investigated the causes and consequences of mitochondrial fission in cardiac fibrosis using cultured cells, animal models, and clinical samples. Increased METTL3 expression caused excessive mitochondrial fission, resulting in the proliferation and migration of cardiac fibroblasts that lead to cardiac fibrosis. Knockdown of METTL3 suppressed mitochondrial fission, inhibiting fibroblast proliferation and migration for ameliorating cardiac fibrosis. Elevated METTL3 and N6-methyladenosine (m6A) levels were associated with low expression of long non-coding RNA GAS5. Mechanistically, METTL3-mediated m6A methylation of GAS5 induced its degradation, dependent of YTHDF2. GAS5 could interact with mitochondrial fission marker Drp1 directly; overexpression of GAS5 suppressed Drp1-mediated mitochondrial fission, inhibiting cardiac fibroblast proliferation and migration. Knockdown of GAS5 produced the opposite effect. Clinically, increased METTL3 and YTHDF2 levels corresponded with decreased GAS5 expression, increased m6A mRNA content and mitochondrial fission, and increased cardiac fibrosis in human heart tissue with atrial fibrillation. We describe a novel mechanism wherein METTL3 boosts mitochondrial fission, cardiac fibroblast proliferation, and fibroblast migration: METTL3 catalyzes m6A methylation of GAS5 methylation in a YTHDF2-dependent manner. Our findings provide insight into the development of preventative measures for cardiac fibrosis.

Intrafracture Recombinant Platelet-Derived Growth Factor Improves Fracture Healing Process on Wistar Rat

Background: Femoral fracture is associated with high morbidity and mortality, especially in young adults with high-energy injuries. Abnormal fracture healing presents as a significant matter in management of femoral fracture. Platelet Derived Growth Factor (PDGFBB) is proposed as potential agent in fracture healing. Up to this point, PDGF has been scientifically studied improve wound healing by enhancing fibroblast proliferation, extracellular matrix synthesis, and revascularization. This study aims to evaluate role of PDGF on fractured bone healing.Subjects and Method: This was a randomized controlled trial conducted at Animal and Biomedical Laboratory of Udayana University, from March to September 2022. 36 male and healthy Wistar Rats at 34 months old and weighs 140160 grams were selected for this study. The dependent variables were Allen score, type I and type III collagen levels. The independent variable was administration of 10 mcg PDGFBB following femoral osteotomy and intramedullary wire fixation. Type I and III collagen levels are assessed using ELISA methods. Statistical analysis is performed using independent T-test in SPSS ver 25.0 software.Results: Allen score in the PDGFBB group (Mean= 3.89; SD= 1.40) was higher than control group (Mean= 2.28; SD= 1.48), with p=0.002. Type I collagen in the PDGFBB group (Mean= 4.97; SD= 0.54) was higher than control group (Mean= 4.41; SD= 0.74), with p=0.014. Type III collagen in the PDGFBB group (Mean= 12.1; SD= 2.49) was higher than control group (Mean= 10.01; SD= 1.61), with p=0.005.Conclusion: In comparison to the nonPDGFBB group, Wistar rats that had their femurs osteotomized and joined with intramedullary wire in the PDGFBB group has higher mean of Allen score, type I and type III collagen levels.Keywords: femoral fracture, allen score, type I collagen, type III collagen, PDGFBBCorrespondence: IGN Wien Aryana, Consultant of Sports Medicine, Dept. Orthopaedic and Traumatology, Prof IGNG Ngoerah General Hospital, Faculty of Medicine, Udayana University. Jl. Diponegoro, Dauh Puri Klod. Denpasar City, Bali 80113. Email: wienaryanaortho@gmail.com. Mobile: +62811385263.Indonesian Journal of Medicine (2023), 08(02): 136141https://doi.org/10.26911/theijmed.2023.08.02.02

A therapeutic role of exosomal lncRNA H19 from adipose mesenchymal stem cells in cutaneous wound healing by triggering macrophage M2 polarization

BackgroundEmerging evidence has figured out that adipose mesenchymal stem cells (ADSCs) promote wound healing. Exosomes, which act as main paracrine factors and contains various protein, lncRNA, and miRNAs, play a critical role in wound healing. Nevertheless, the mechanism remains to be elucidated. This study aims to identify the underlying mechanism of ADSCs-derived exosome (ADSCs-exos)-mediated wound healing. MethodsADSCs-exos were characterized using the transmission electron microscope, dynamic light scattering, and western blot. ELISA, RT-qPCR, flow cytometry, western blot, CCK-8 assay, transwell assay and tube formation were employed to validate the actions of ADSCs-exos harboring H19 in cell polarization, proliferation, migration and angiogenesis. The regulatory axis among H19, miR-130b-3p and PPARγ or STAT3 was confirmed by RNA pull-down, RIP assay and dual-luciferase reporter assays. ResultsADSCs-exos harboring H19 promoted macrophage M2 polarization, thereby enhancing fibroblast proliferation, migration and endothelial cell angiogenesis. However, their promotive effects were disrupted within H19 depletion in ADSCs-exos. Additionally, miR-130b-3p, directly targeting PPARγ or STAT3, was identified to be a downstream effector to participate in H19-mediated biological effects. Moreover, ADSCs-exos carrying H19 modulated cutaneous wound healing via H19/miR-130b-3p -mediated macrophage M2 polarization in vivo. ConclusionCollectively, ADSCs-derived exosomal H19 accelerates cutaneous wound healing via the miR-130b-3p/PPARγ/STAT3 axis, indicating potential therapeutic strategies for the treatment of wound healing.

Antimicrobial Peptide Pt5‐1c Promotes Keratinocyte Migration and Proliferation via EGFR‐mediated Akt/MAPK/STAT3 pathways

AbstractKeratinocytes, as the most dominant cell type in the epidermis, play multiple roles in skin wound healing. Recently, we have shown that a short antimicrobial peptide Pt5‐1c can promote skin wound healing via enhancing fibroblast proliferation and migration in vitro, and accelerating re‐epithelialization of murine dermal wounds in vivo.[1] However, its effects on keratinocytes is unknown. Here we clearly showed that Pt5‐1c markedly enhanced keratinocyte migration and proliferation. Moreover, Pt5‐1c stimulated keratinocyte activation by inducing the phosphorylation of epidermal growth factor receptor (EGFR), Akt, extracellular signal‐regulated kinase (ERK), p38, and signal transducer and activator of transcription 3 (STAT3) in keratinocytes. Importantly, Pt5‐1c also increased collagen production, stimulated cell proliferation, and enhanced the phosphorylation of Akt, p38 and STAT3 in the wound skin tissues. These together indicate that Pt5‐1c can promote keratinocyte migration and proliferation via activation of EGFR‐mediated Akt, MAPK, and STAT3 pathways, thereby contributing to skin wound healing.

Plasma-Functionalised Dressings for Enhanced Wound Healing.

Fundamental knowledge about cell-surface interactions can be applied in the development of wound dressings and scaffolds to encourage wounds to heal. As surfaces produced with acid-functionalised monomers encourage keratinocyte adhesion, proliferation and migration, whilst amine functionalisation enhances fibroblast proliferation and migration in vitro, standard care wound dressings were plasma-coated with either acrylic acid or allylamine and applied to 6 mm excisional wounds on the backs of mice to test their effectiveness in vivo. At day 3, the rate of wound healing was increased in mice treated with dressings that were plasma-coated with allylamine compared to uncoated dressings, with a significantly reduced wound area. However, healing may be impaired following prolonged treatment with allylamine-functionalised dressings, with delayed re-epithelialisation and increased cellularisation of the wound site at later timepoints. Acrylic acid functionalisation, however, offered no early improvement in wound healing, but wounds treated with these dressings displayed increased collagen deposition at day 7 post wounding. These results suggest that plasma polymerisation may allow for the development of new dressings which can enhance wound closure by directing cell behaviour, but that the application of these dressings may require a timed approach to enhance specific phases of the wound healing response.

Docosahexaenoic Acid Attenuates Radiation-Induced Myocardial Fibrosis by Inhibiting the p38/ET-1 Pathway in Cardiomyocytes

Radiation-induced myocardial fibrosis (RIMF) is a severe delayed complication of thoracic irradiation (IR). Endothelin-1 (ET-1) is critical in cardiac fibroblast activation, and docosahexaenoic acid (DHA) is protective against various cardiac diseases. This study aimed to explore the roles of ET-1 in RIMF and the potential of DHA in preventing RIMF. Hematoxylin and eosin, sirius red, and Masson trichrome staining were carried out to evaluate the histopathologic conditions in mouse models. Enzyme-linked immunosorbent assays were used to detect the concentration of ET-1 in serum and cell supernatants. Western blotting, immunofluorescence, and immunohistochemistry were used to assess the protein levels. The phenotypic alterations of cardiac fibroblasts were evaluated by cell proliferation/migration assays and α-smooth muscle actin (α-SMA) detection. Radiation increased ET-1 expression and secretion by increasing p38 phosphorylation in cardiomyocytes, and ET-1 markedly promoted the activation of cardiac fibroblasts, which were characterized by enhanced fibroblast proliferation, migration, and α-SMA expression. Cardiomyocyte-derived ET-1 mediated radiation-induced fibroblast activation by targeting the PI3K-AKT and MEK-ERK pathways in fibroblasts. DHA suppressed ET-1 levels by blocking p38 signaling in cardiomyocytes and significantly attenuated the activation of cardiac fibroblasts induced by the IR/ET-1 axis. Importantly, DHA decreased collagen deposition and α-SMA expression, alleviating cardiac fibrosis caused by radiation in mouse models. Our findings demonstrate that radiation facilitates cardiac fibroblast activation by enhancing p38/ET-1 signaling in cardiomyocytes, revealing the IR/p38/ET-1 regulatory axis in RIMF for the first time. DHA effectively inhibits fibroblast activation by targeting p38/ET-1 and can be recognized as a promising protective agent against RIMF.

Tumor-derived exosomes elicit cancer-associated fibroblasts shaping inflammatory tumor microenvironment in head and neck squamous cell carcinoma

ObjectivesExosome-mediated reciprocal crosstalk between tumor and stromal cells plays a crucial role in tumor development and progression. This study investigated whether exosomes released from head and neck squamous cell carcinoma (HNSCC) tumor cells can convert normal fibroblasts into cancer-associated fibroblasts (CAF)-like cells and further analyzed the functional characterization of fibroblasts educated by tumor-derived exosomes. Materials and methodsExosomes secreted from HNSCC cell lines were isolated and normal fibroblasts were established from normal oropharyngeal mucosa. The effects of the exosomes on fibroblasts were examined by proliferation and migration assays, and exosome-educated fibroblasts were analyzed for the expression of eight genes (IL1B, IL6, CXCL8, TGFB1, ACTA2, FAP, CD274, and PDCD1LG2) by RT-qPCR. Moreover, T cells or CD14-positive cells were co-cultured with culture supernatants from exosome-educated fibroblasts. T-cell proliferation and macrophage polarization were examined using flow cytometry. Then, RNA sequencing (RNA-seq) of exosome-educated fibroblasts and the corresponding control fibroblasts was performed. ResultsTumor-derived exosomes enhanced fibroblast proliferation and migration. Moreover, gene expression analysis revealed upregulation of the gene expression of proinflammatory cytokines and immunoregulatory genes, and activated fibroblast marker genes. The culture supernatants of tumor-derived exosome-educated fibroblasts suppressed T cell proliferation and the induction of protumoral macrophages compared with those of control fibroblasts. Next, comprehensive RNA-seq analysis data revealed the activation of 11 signaling pathways, including IL-6- and IL-17-related signaling. ConclusionThese results indicate that HNSCC tumor cells induce and/or differentiate into CAFs through exosome-based cell-to-cell communication to create an inflammatory tumor microenvironment.

Successful Treatment of Radiation-Induced Colitis and Enteritis with Hyperbaric Oxygen Therapy

Introduction Previously irradiated tissue is characterized by changes including decreased vascularity, impaired cellular proliferation, and local hypoxia consistent with fibroblastic atrophy which can persist long after radiation therapy. Hyperbaric oxygen therapy has been shown to be beneficial in the treatment of complications arising from these late effects of radiation on normal tissue through enhancing fibroblast proliferation, collagen maturation, stem cell recruitment, and angiogenesis. Methods We report on three patients with debilitating radiation enterocolitis causing issues including recurrent bowel obstruction, anorexia requiring total parenteral nutrition, pain, diarrhea, fecal incontinence, dehydration, and malnutrition. Results In all three cases marked improvement was the outcome with hyperbaric treatment. Conclusion Hyperbaric oxygen therapy should be routinely considered in the treatment of radiation-induced enteritis or colitis.

Dissolving microneedles for long-term storage and transdermal delivery of extracellular vesicles

Extracellular vesicles (EVs) have shown great potential in disease diagnosis and treatment; however, their clinical applications remain challenging due to their unsatisfactory long-term stability and the lack of effective delivery strategies. In this study, we prepared human adipose stem cell-derived EV (hASC-EV)-loaded hyaluronic acid dissolving microneedles (EV@MN) to investigate the feasibility of EVs for their clinical applications. The biological activities of the EVs in this formulation were maintained for more than six months under mild storage conditions, especially at temperatures lower than 4 °C. Moreover, the EV@MN enabled precise and convenient intradermal delivery for sustained release of EVs in the dermis layer. Therefore, EV@MN significantly improved the biological functions of hASC-EVs on dermal fibroblasts by promoting syntheses of proteins for the extracellular matrix such as collagen and elastin, enhancing fibroblast proliferation, and regulating the phenotype of fibroblast, compared with other administration methods. This research revealed a possible and feasible formulation for the clinical application of EVs.

Topical bilirubin-deferoxamine hastens excisional wound healing by modulating inflammation, oxidative stress, angiogenesis, and collagen deposition in diabetic rats

Aim of the studyThe study was performed to understand the detailed mechanism of diabetic wound healing by bilirubin-deferoxamine (DFO) combination on topical application. Materials and methodsThere were two study groups, control, and treatment. The granulation tissues collected on different days (3, 7, 14, and 19) were studied in detail for inflammatory mediators, angiogenesis markers, epithelialization, and oxidative stress parameters. ResultsA significant increase in wound contraction percentage was observed from day 7 in the bilirubin-DFO treatment group. The combinatorial treatment significantly reduced tumour necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), and enhanced IL-10 levels. Upregulated mRNAs of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1 α) along with CD31 immunohistochemistry showed the pro-angiogenesis potential of the combination. Hematoxylin and Eosin (H and E) staining and Masson's trichrome staining showed reduced inflammatory cell infiltration, enhanced fibroblast proliferation, well-organized collagen fibers, and the development of new blood vessels. Collagen deposition is further supported by immunohistochemistry studies and Masson's trichrome staining. Bilirubin-DFO combination also reduced lipid peroxidation and elevated antioxidative enzymes. ConclusionTopical application of bilirubin-DFO showed immense potential in augmenting skin wound regeneration in diabetes by upregulating the antioxidant status as well as increasing angiogenesis, collagen deposition, and modulating cytokines.

Nigeria bee honey-enhanced adherence, neovascularisation and epithelisation of full-thickness skin autografts on distal extremities of dogs

BackgroundFull thickness skin grafts (FTSGs), although ideal for resurfacing large defects of the distal extremities in veterinary patients, have a high failure rate due to issues of adherence, infection and inadequate revascularisation because of its thickness and high nutritional demand. This study investigated the effect of Nigeria bee honey on FTSG take at the distal extremities of dogs. The study was conducted on 6 adult male Nigerian indigenous dogs using 3 of the 4 limbs of each dog randomly divided into 3 treatment groups: Nigerian bee honey (HON group), platelet-rich plasma (PRP group) and normal saline (CON group). Full‐thickness skin wounds (3 cm × 1.5 cm) were created on the lateral aspect of the radioulnar or metatarsal areas and dressed till adequate granulation tissues formed. Donor skins harvested from the lateral thorax of each dog were sutured to the recipient bed following application of the assigned treatment, and evaluated grossly and histologically on days 0, 4, 7, 10, 14, 17, and 21.ResultsA higher percentage (4/6 representing 66.7%) of complete graft take was observed in the HON and PRP groups as compared to 3/6 (50%) in the CON group. The HON group had a greater percentage (5/6 representing 83.3%) of adhered grafts as compared to the PRP (4/6 representing 66.7%) and CON (3/6 representing 50%) groups at day 4. There was a significant decrease (p = 0.022) in percentage necrosis between the CON and HON/PRP groups on day 10, 14 and 17. The percentage open mesh area for the HON group was significantly lesser at day 4, 7 and 10 when compared with CON (p < 0.001) and at day 4 when compared with PRP (p = 0.001). At histology, graft neovascularisation score was highest in the HON group on days 4, 14 and 21.ConclusionNigeria bee honey enhanced take of meshed full-thickness skin autografts by promoting adherence to the recipient bed, enhancing fibroblast proliferation and collagen laydown, and accelerating the rate of neovascularisation suggesting promising application as an alternative modality to enhance FTSG take.